1. |
- Khan, David, et al.
(författare)
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Predicting mutant selection in competition experiments with ciprofloxacin-exposed Escherichia coli
- 2018
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 0924-8579 .- 1872-7913. ; 51:3, s. 399-406
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Tidskriftsartikel (refereegranskat)abstract
- Predicting competition between antibiotic-susceptible wild-type (WT) and less susceptible mutant (MT) bacteria is valuable for understanding how drug concentrations influence the emergence of resistance. Pharmacokinetic/pharmacodynamic (PK/PD) models predicting the rate and extent of takeover of resistant bacteria during different antibiotic pressures can thus be a valuable tool in improving treatment regimens. The aim of this study was to evaluate a previously developed mechanism-based PK/PD model for its ability to predict in vitro mixed-population experiments with competition between Escherichia coli (E. coli) WT and three well-defined E. coli resistant MTs when exposed to ciprofloxacin. Model predictions for each bacterial strain and ciprofloxacin concentration were made for in vitro static and dynamic time–kill experiments measuring CFU (colony forming units)/mL up to 24 h with concentrations close to or below the minimum inhibitory concentration (MIC), as well as for serial passage experiments with concentrations well below the MIC measuring ratios between the two strains with flow cytometry. The model was found to reasonably well predict the initial bacterial growth and killing of most static and dynamic time–kill competition experiments without need for parameter re-estimation. With parameter re-estimation of growth rates, an adequate fit was also obtained for the 6-day serial passage competition experiments. No bacterial interaction in growth was observed. This study demonstrates the predictive capacity of a PK/PD model and further supports the application of PK/PD modelling for prediction of bacterial kill in different settings, including resistance selection.
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2. |
- Nielsen, Elisabet I., 1973-, et al.
(författare)
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Can a pharmacokinetic/pharmacodynamic (PKPD) model be predictive across bacterial densities and strains? : External evaluation of a PKPD model describing longitudinal in vitro data
- 2017
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Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 72:11, s. 3108-3116
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pharmacokinetic/pharmacodynamic (PKPD) models developed based on data from in vitro time-kill experiments have been suggested to contribute to more efficient drug development programmes and better dosing strategies for antibiotics. However, for satisfactory predictions such models would have to show good extrapolation properties. Objectives: To evaluate if a previously described mechanism-based PKPD model was able also to predict drug efficacy for higher bacterial densities and across bacterial strains. Methods: A PKPD model describing the efficacy of ciprofloxacin on Escherichia coli was evaluated. The predictive performance of the model was evaluated across several experimental conditions with respect to: (i) bacterial start inoculum ranging from the standard of similar to 10(6) cfu/mL up to late stationary-phase cultures; and (ii) efficacy for seven additional strains (three laboratory and four clinical strains), not included during the model development process, based only on information regarding their MIC. Model predictions were performed according to the intended experimental protocol and later compared with observed bacterial counts. Results: The mechanism-based PKPD model structure developed based on data from standard start inoculum experiments was able to accurately describe the inoculum effect. The model successfully predicted the time course of drug efficacy for additional laboratory and clinical strains based on only the MIC values. The model structure was further developed to better describe the stationary phase data. Conclusions: This study supports the use of mechanism-based PKPD models based on preclinical data for predictions of untested scenarios.
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3. |
- Zhao, Chenyan, et al.
(författare)
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Quantifying combined effects of colistin and ciprofloxacin against Escherichia coli in an in silico pharmacokinetic-pharmacodynamic model
- 2024
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Co-administering a low dose of colistin (CST) with ciprofloxacin (CIP) may improve the antibacterial effect against resistant Escherichia coli, offering an acceptable benefit-risk balance. This study aimed to quantify the interaction between ciprofloxacin and colistin in an in silico pharmacokinetic-pharmacodynamic model from in vitro static time-kill experiments (using strains with minimum inhibitory concentrations, MICCIP 0.023–1 mg/L and MICCST 0.5–0.75 mg/L). It was also sought to demonstrate an approach of simulating concentrations at the site of infection with population pharmacokinetic and whole-body physiologically based pharmacokinetic models to explore the clinical value of the combination when facing more resistant strains (using extrapolated strains with lower susceptibility). The combined effect in the final model was described as the sum of individual drug effects with a change in drug potency: for ciprofloxacin, concentration at half maximum killing rate (EC50) in combination was 160% of the EC50 in monodrug experiments, while for colistin, the change in EC50 was strain-dependent from 54.1% to 119%. The benefit of co-administrating a lower-than-commonly-administrated colistin dose with ciprofloxacin in terms of drug effect in comparison to either monotherapy was predicted in simulated bloodstream infections and pyelonephritis. The study illustrates the value of pharmacokinetic-pharmacodynamic modelling and simulation in streamlining rational development of antibiotic combinations.
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4. |
- Abrantes, João A., et al.
(författare)
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Bayesian Forecasting Utilizing Bleeding Information to Support Dose Individualization of Factor VIII
- 2019
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Ingår i: CPT. - : Wiley. - 2163-8306. ; 8:12, s. 894-903
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Tidskriftsartikel (refereegranskat)abstract
- Bayesian forecasting for dose individualization of prophylactic factor VIII replacement therapy using pharmacokinetic samples is challenged by large interindividual variability in the bleeding risk. A pharmacokinetic‐repeated time‐to‐event model‐based forecasting approach was developed to contrast the ability to predict the future occurrence of bleeds based on individual (i) pharmacokinetic, (ii) bleeding, and (iii) pharmacokinetic, bleeding and covariate information using observed data from the Long‐Term Efficacy Open‐Label Program in Severe Hemophilia A Disease (LEOPOLD) clinical trials (172 severe hemophilia A patients taking prophylactic treatment). The predictive performance assessed by the area under receiver operating characteristic (ROC) curves was 0.67 (95% confidence interval (CI), 0.65–0.69), 0.78 (95% CI, 0.76–0.80), and 0.79 (95% CI, 0.77–0.81) for patients ≥ 12 years when using pharmacokinetics, bleeds, and all data, respectively, suggesting that individual bleed information adds value to the optimization of prophylactic dosing regimens in severe hemophilia A. Further steps to optimize the proposed tool for factor VIII dose adaptation in the clinic are required.
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5. |
- Abrantes, João A., et al.
(författare)
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Elucidation of Factor VIII Activity Pharmacokinetics : A Pooled Population Analysis in Patients With Hemophilia A Treated With Moroctocog Alfa
- 2017
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Ingår i: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 102:6, s. 977-988
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Tidskriftsartikel (refereegranskat)abstract
- This study investigated the disposition of coagulation factor VIII activity in 754 patients with moderate to severe hemophilia A following the administration of moroctocog alfa, a B-domain deleted recombinant factor VIII. Data analyzed included patients aged 1 day to 73 years enrolled in 13 studies conducted over a period of 20 years in 25 countries. A two-compartment population pharmacokinetic model with a baseline model described the pooled data well. Body size, age, inhibitors, race, and analytical assay were identified as significant predictors of factor VIII disposition. In addition, simulations of prophylactic dosing schedules in several pediatric cohorts showed large variability and suggest that younger patients would require higher weight-adjusted doses than adolescents to achieve target factor VIII trough activity when receiving every other day or twice weekly dosing.
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6. |
- Abrantes, João A., et al.
(författare)
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Handling interoccasion variability in model-based dose individualization using therapeutic drug monitoring data
- 2019
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Ingår i: British Journal of Clinical Pharmacology. - : John Wiley & Sons. - 0306-5251 .- 1365-2125. ; 85:6, s. 1326-1336
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: This study aims to assess approaches to handle interoccasion variability (IOV) in a model-based therapeutic drug monitoring (TDM) context, using a population pharmacokinetic model of coagulation factor VIII as example.METHODS: We assessed five model-based TDM approaches: empirical Bayes estimates (EBEs) from a model including IOV, with individualized doses calculated based on individual parameters either (i) including or (ii) excluding variability related to IOV; and EBEs from a model excluding IOV by (iii) setting IOV to zero, (iv) summing variances of interindividual variability (IIV) and IOV into a single IIV term, or (v) re-estimating the model without IOV. The impact of varying IOV magnitudes (0-50%) and number of occasions/observations was explored. The approaches were compared with conventional weight-based dosing. Predictive performance was assessed with the prediction error (PE) percentiles.RESULTS: When IOV was lower than IIV, the accuracy was good for all approaches (50th percentile of the PE [P50] <7.4%), but the precision varied substantially between IOV magnitudes (P97.5 61-528%). Approach (ii) was the most precise forecasting method across a wide range of scenarios, particularly in case of sparse sampling or high magnitudes of IOV. Weight-based dosing led to less precise predictions than the model-based TDM approaches in most scenarios.CONCLUSIONS: Based on the studied scenarios and theoretical expectations, the best approach to handle IOV in model-based dose individualisation is to include IOV in the generation of the EBEs, but exclude the portion of unexplained variability related to IOV in the individual parameters used to calculate the future dose.
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7. |
- Abrantes, João A.
(författare)
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Pharmacometric Approaches to Improve Dose Individualization Methods in Hemophilia A
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hemophilia A is a bleeding disorder caused by the lack of functional coagulation factor VIII (FVIII). The overall aim of this thesis was to improve dose individualization of FVIII replacement therapy in hemophilia A using pharmacometric approaches.A population pharmacokinetic (PK) model of FVIII activity following the administration of moroctocog alfa was developed based on data from a large heterogeneous cohort of moderate to severe hemophilia A patients. Body weight, age, neutralizing anti-FVIII inhibitors, race, and analytical assay were found to be significant predictors of FVIII activity PK. In addition, large inter-individual variability (IIV) and inter-occasion variability (IOV) was identified highlighting the need for dose individualization.High magnitudes of IOV are known to impair model-based therapeutic drug monitoring. Using a population PK model of FVIII activity, several approaches to handle IOV in Bayesian forecasting of individual PK parameters were assessed across a wide range of features. Considering IOV in Bayesian forecasting, but ignoring IOV in dose calculation, led to the most precise individualized doses, in particular, when sparse data was used.The dose-exposure-response relationship of FVIII replacement therapy remains unclear. A parametric repeated time-to-categorical event (RTTCE) model was developed to characterize the relationship between the dose of octocog alfa, plasma FVIII activity, bleeding frequency and severity, and covariates, using data from clinical trials. The bleeding hazard was found to decrease throughout time and to be affected by plasma FVIII activity and number of previous bleeds. Unexplained IIV in the bleeding hazard was found to be large.Bayesian forecasting based on the RTTCE model was used to predict the future occurrence of bleeds, and to contrast the predicted outcome using individual i) PK, ii) bleeding, and iii) PK, bleeding and covariate information, from data collected in clinical trials. The results support that individual bleed information can inform the optimization of prophylactic dosing regimens in severe hemophilia A patients.In summary, the pharmacometric approaches presented provide a valuable quantitative framework to improve dose individualization in hemophilia A. Furthermore, enhanced dosing has the potential to reduce bleeding frequency and to lower the high costs associated to treatment.
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8. |
- Abrantes, João A., et al.
(författare)
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Relationship between factor VIII activity, bleeds and individual characteristics in severe hemophilia A patients
- 2020
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Ingår i: Haematologica. - : Ferrata Storti Foundation. - 0390-6078 .- 1592-8721. ; 105:5, s. 1443-1453
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Tidskriftsartikel (refereegranskat)abstract
- Pharmacokinetic-based prophylaxis of replacement factor VIII products has been encouraged in the past years, but the exposure (factor VIII activity)-response (bleeding frequency) relationship remains unclear. The aim of this study was to characterize the relationship between factor VIII dose, plasma factor VIII activity, bleeding patterns and individual characteristics in severe hemophilia A patients. Pooled pharmacokinetic and bleeding data during prophylactic treatment with BAY 81-8973 (octocog alfa) were obtained from the three LEOPOLD trials. The population pharmacokinetics of factor VIII activity and longitudinal bleeding frequency, as well as bleeding severity, were described using nonlinear mixed effects modelling in NONMEM. In total, 183 patients (median age 22 years [range, 1-61]; weight 60 kg [11-124]) contributed with 1535 plasma factor VIII activity observations, 633 bleeds and 11 patient/study characteristics (median observation period 12 months [3.1-13.1]). A parametric repeated time-to-categorical bleed model, guided by plasma factor VIII activity from a 2-compartment population pharmacokinetic model, described the time to the occurrence of bleeds and their severity. Bleeding probability decreased with time of study, and a bleed was not found to affect the time of the next bleed. Several covariate effects were identified, including the bleeding history in the 12-month pre-study period increasing the bleeding hazard. However, unexplained inter-patient variability for the phenotypic bleeding pattern remained large (111%CV). Further studies to translate the model into a tool for dose individualization that considers the individual bleeding risk are required. Research based on a post-hoc analysis of the LEOPOLD studies (ClinicalTrials.gov identifiers NCT01029340, NCT01233258 and NCT01311648).
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9. |
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10. |
- Bahnasawy, Salma M., et al.
(författare)
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Predicting cytokine kinetics during sepsis; a modelling framework from a porcine sepsis model with live Escherichia coli
- 2023
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Ingår i: Cytokine. - : Elsevier BV. - 1043-4666 .- 1096-0023. ; 169
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Tidskriftsartikel (refereegranskat)abstract
- Background: Describing the kinetics of cytokines involved as biomarkers of sepsis progression could help to optimise interventions in septic patients. This work aimed to quantitively characterise the cytokine kinetics upon exposure to live E. coli by developing an in silico model, and to explore predicted cytokine kinetics at different bacterial exposure scenarios.Methods: Data from published in vivo studies using a porcine sepsis model were analysed. A model describing the time courses of bacterial dynamics, endotoxin (ETX) release, and the kinetics of TNF and IL-6 was developed. The model structure was extended from a published model that quantifies the ETX-cytokines relationship. An external model evaluation was conducted by applying the model to literature data. Model simulations were performed to explore the sensitivity of the host response towards differences in the input rate of bacteria, while keeping the total bacterial burden constant.Results: The analysis included 645 observations from 30 animals. The blood bacterial count was well described by a one-compartment model with linear elimination. A scaling factor was estimated to quantify the ETX release by bacteria. The model successfully described the profiles of TNF, and IL-6 without a need to modify the ETXcytokines model structure. The kinetics of TNF, and IL-6 in the external datasets were well predicted. According to the simulations, the ETX tolerance development results in that low initial input rates of bacteria trigger the lowest cytokine release.Conclusion: The model quantitively described and predicted the cytokine kinetics triggered by E. coli exposure. The host response was found to be sensitive to the bacterial exposure rate given the same total bacterial burden.
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11. |
- Brem, Jürgen, et al.
(författare)
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Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors
- 2022
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Ingår i: Nature Chemistry. - : Springer Nature. - 1755-4330 .- 1755-4349. ; 14:1, s. 15-24
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Tidskriftsartikel (refereegranskat)abstract
- Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-β-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential β-lactamase stable β-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.
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12. |
- Brill, Margreke J. E., et al.
(författare)
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Semi-mechanistic pharmacokinetic-pharmacodynamic modelling of antibiotic drug combinations
- 2018
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Ingår i: Clinical Microbiology and Infection. - : Elsevier BV. - 1198-743X .- 1469-0691. ; 24:7, s. 697-706
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Forskningsöversikt (refereegranskat)abstract
- Background: Deriving suitable dosing regimens for antibiotic combination therapy poses several challenges as the drug interaction can be highly complex, the traditional pharmacokinetic-pharmacodynamic (PKPD) index methodology cannot be applied straightforwardly, and exploring all possible dose combinations is unfeasible. Therefore, semi-mechanistic PKPD models developed based on in vitro single and combination experiments can be valuable to suggest suitable combination dosing regimens. Aims: To outline how the interaction between two antibiotics has been characterized in semi-mechanistic PKPD models. We also explain how such models can be applied to support dosing regimens and design future studies. Sources: PubMed search for published semi-mechanistic PKPD models of antibiotic drug combinations. Content: Thirteen publications were identified where ten had applied subpopulation synergy to characterize the combined effect, i.e. independent killing rates for each drug and bacterial subpopulation. We report the various types of interaction functions that have been used to describe the combined drug effects and that characterized potential deviations from additivity under the PKPD model. Simulations from the models had commonly been performed to compare single versus combined dosing regimens and/or to propose improved dosing regimens.
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13. |
- Bulman, Zackery P., et al.
(författare)
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Research priorities towards precision antibiotic therapy to improve patient care
- 2022
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Ingår i: LANCET MICROBE. - : Elsevier. - 2666-5247. ; 3:10, s. e795-e802
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Tidskriftsartikel (refereegranskat)abstract
- Antibiotic resistance presents an incessant threat to our drug armamentarium that necessitates novel approaches to therapy. Over the past several decades, investigation of pharmacokinetic and pharmacodynamic (PKPD) principles has substantially improved our understanding of the relationships between the antibiotic, pathogen, and infected patient. However, crucial gaps in our understanding of the pharmacology of antibacterials and their optimal use in the care of patients continue to exist; simply attaining antibiotic exposures that are considered adequate based on traditional targets can still result in treatment being unsuccessful and resistance proliferation for some infections. It is this salient paradox that points to key future directions for research in antibiotic therapeutics. This Personal View discusses six priority areas for antibiotic pharmacology research: (1) antibiotic-pathogen interactions, (2) antibiotic targets for combination therapy, (3) mechanistic models that describe the time-course of treatment response, (4) understanding and modelling of host response to infection, (5) personalised medicine through therapeutic drug management, and (6) application of these principles to support development of novel therapies. Innovative approaches that enhance our understanding of antibiotic pharmacology and facilitate more accurate predictions of treatment success, coupled with traditional pharmacology research, can be applied at the population level and to individual patients to improve outcomes.
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14. |
- Cam, Henrik, et al.
(författare)
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Failure to Involve Older Hospitalised Patients in Medication Decisions : A Change of Approach is Called For
- 2024
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Ingår i: Research in Social and Administrative Pharmacy. - : Elsevier. - 1551-7411 .- 1934-8150. ; 20:2, s. 216-217
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patient involvement in medical-decision making is linked to improved patient outcomes and increased patient satisfaction.Objectives: The aim was to explore how hospitalised older patients are and wish to be involved in medication decisions affecting their medication therapy after hospital discharge.Methods: Naturalistic observations of consultations between healthcare professionals and hospitalised older patients who were about to be discharged were performed at in total three medical wards at two hospitals in Sweden. Subsequent semi-structured interviews with the patients were conducted within one week after discharge. The data were thematically analysed, guided by systematic text condensation.Results: Twenty patients were included (mean age: 81 (SD 8) years, 45 % female). Three themes were identified: 1) Predetermined authoritarian structures; describes that neither patients nor healthcare professionals expected patients to be involved in medication decisions. The medication decisions were frequently already taken by the healthcare professionals prior to the consultations, 2) Difficulties in finding the right time and setting; displays inhibitory factors in patient involvement in medication decisions when the consultations occur in hospital, and 3) Communication focusing on benefits over side-effects; demonstrates that newly prescribed medications were rarely accompanied with information about side-effects. Patients felt they lacked sufficient knowledge to take informed decisions about medications.Conclusions: There are structures limiting involvement of older patients in medication decisions prior to hospital discharge. A change in approach to consultations from both the patients and healthcare professionals is needed to provide patients with the knowledge they feel is needed to be sufficiently involved.
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15. |
- Cam, Henrik, et al.
(författare)
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The complexities of communication at hospital discharge of older patients : a qualitative study of healthcare professionals' views
- 2023
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Ingår i: BMC Health Services Research. - : BioMed Central (BMC). - 1472-6963. ; 23
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Tidskriftsartikel (refereegranskat)abstract
- Background: Hospital discharge of older patients is a high-risk situation in terms of patient safety. Due to the fragmentation of the healthcare system, communication and coordination between stakeholders are required at discharge. The aim of this study was to explore communication in general and medication information transfer in particular at hospital discharge of older patients from the perspective of healthcare professionals (HCPs) across different organisations within the healthcare system.Methods: We conducted a qualitative study using focus group and individual or group interviews with HCPs (physicians, nurses and pharmacists) across different healthcare organisations in Sweden. Data were collected from September to October 2021. A semi-structured interview guide including questions on current medication communication practices, possible improvements and feedback on suggestions for alternative processes was used. The data were analysed thematically, guided by the systematic text condensation method.Results: In total, four focus group and three semi-structured interviews were conducted with 23 HCPs. Three main themes were identified: 1) Support systems that help and hinder describes the use of support systems in the discharge process to compensate for the fragmentation of the healthcare system and the impact of these systems on HCPs' communication; 2) Communication between two separate worlds depicts the difficulties in communication experienced by HCPs in different healthcare organisations and how they cope with them; and 3) The large number of medically complex patients disrupts the communication reveals how the highly pressurised healthcare system impacts on HCPs' communication at hospital discharge.Conclusions: Communication at hospital discharge is hindered by the fragmented, highly pressurised healthcare system. HCPs are at risk of moral distress when coping with communication difficulties. Improved communication methods at hospital discharge are needed for the benefit of both patients and HCPs.
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16. |
- Damgaard, Tobias, et al.
(författare)
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Estimated glomerular filtration rate as a tool for early identification of patients with insufficient exposure to beta-lactam antibiotics in intensive care units
- 2024
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Ingår i: Infectious Diseases. - : Taylor & Francis Group. - 2374-4235 .- 2374-4243. ; 56:6, s. 451-459
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Tidskriftsartikel (refereegranskat)abstract
- Background: Only about 50% of intensive care unit (ICU) patients reach a free trough concentration above MIC (100% fT > MIC) of beta-lactam antibiotics. Although dose adjustments based on therapeutic drug monitoring (TDM) could be beneficial, TDM is not widely available. We investigated serum creatinine-based estimated GFR (eGFR) as a rapid screening tool to identify ICU patients at risk of insufficient exposure. Method: Ninety-three adult patients admitted to four ICUs in southeast Sweden treated with piperacillin/tazobactam, meropenem, or cefotaxime were included. Beta-lactam trough concentrations were measured. The concentration target was set to 100% fT > MICECOFF (2, 4, and 16 mg/L based on calculated free levels for meropenem, cefotaxime, and piperacillin, respectively). eGFR was primarily determined via Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) and compared to three other eGFR equations. Data was analysed using logistic regression and receiver operative characteristic (ROC) curves. Results: With intermittent standard dosing, insufficient exposure was common in patients with a relative eGFR >= 48mL/min/1.73m(2) [85%, (45/53)], particularly when treated with cefotaxime [96%, (24/25)]. This eGFR cut-off had a sensitivity of 92% and specificity of 82% (AUC 0.871, p < 0.001) in identifying insufficient exposure. In contrast, patients with eGFR <48mL/min/1.73m(2) had high target attainment [90%, (36/40)] with a wide variability in drug exposure. There was no difference between the four eGFR equations (AUC 0.866-0.872, cut-offs 44-51 ml/min/1.73m(2)). Conclusion: Serum creatinine-based eGFR is a simple and widely available surrogate marker with potential for early identification of ICU patients at risk of insufficient exposure to piperacillin, meropenem, and cefotaxime.
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17. |
- Johansson, Anna, et al.
(författare)
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A non-fatal intoxication and seven deaths involving the dissociative drug 3-MeO-PCP
- 2017
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Ingår i: Forensic Science International. - : ELSEVIER IRELAND LTD. - 0379-0738 .- 1872-6283. ; 275, s. 76-82
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: 3-methoxyphencyclidine (3-MeO-PCP) appeared on the illicit drug market in 2011 and is an analogue of phencyclidine, which exhibits anesthetic, analgesic and hallucinogenic properties. In this paper, we report data from a non-fatal intoxication and seven deaths involving 3-MeO-PCP in Sweden during the period March 2014 until June 2016. Case descriptions: The non-fatal intoxication case, a 19-year-old male with drug problems and a medical history of depression, was found awake but tachycardic, hypertensive, tachypnoeic and catatonic at home. After being hospitalized, his condition worsened as he developed a fever and lactic acidosis concomitant with psychomotor agitation and hallucinations. After 22 h of intensive care, the patient had made a complete recovery. During his hospitalization, a total of four blood samples were collected at different time points. The seven autopsy cases, six males and one female, were all in their twenties to thirties with psychiatric problems and/or an ongoing drug abuse. Methods: 3-MeO-PCP was identified with liquid chromatography (LC)/time-of-flight technology and quantified using LC-tandem mass spectrometry. Results: In the clinical case, the concentration of 3-MeO-PCP was 0.14 mu g/g at admission, 0.08 mu g/g 2.5 h after admission, 0.06 mu g/g 5 h after admission and 0.04 mu g/g 17 h after admission. The half-life of 3-MeO-PCP was estimated to 11 h. In the autopsy cases, femoral blood concentrations ranged from 0.05 mu g/g to 0.38 mu g/g. 3-MeO-PCP was the sole finding in the case with the highest concentration and the cause of death was established as intoxication with 3-MeO-PCP. In the remaining six autopsy cases, other medications and drugs of abuse were present as well. Conclusion: Despite being scheduled in January 2015, 3-MeO-PCP continues to be abused in Sweden. Exposure to 3-MeO-PCP may cause severe adverse events and even death, especially if the user does not receive life-supporting treatment.
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18. |
- Johansson, Anna, et al.
(författare)
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Quantitation of seven sedative and analgesic drugs in whole blood from intensive care patients using liquid chromatography mass spectrometry
- 2021
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Ingår i: TOXICOLOGIE ANALYTIQUE ET CLINIQUE. - : Elsevier. - 2352-0078 .- 2352-0086. ; 33:4, s. 327-337
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Tidskriftsartikel (refereegranskat)abstract
- We present the development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantification of clonidine, dexmedetomidine, fentanyl, ketamine, ketobemidone, midazolam and morphine in whole blood. These are drugs predominately used in intensive care units (ICUs) but they are also encountered in forensic investigations. The analytes were recovered from 0.25 g of blood by protein precipitation with a mixture of acetonitrile and ethanol. Separation was performed on a BEH phenyl column. Mobile phases consisted of 0.05% formic acid in 10 mM ammonium formate and 0.05% formic acid in methanol, respectively, and the flow rate was 600 mu L/min. The mass spectrometer was operated in positive electrospray ionization mode with multiple reaction monitoring. Validation included selectivity, qualitative matrix effects, calibration model, limit of detection, lower limit of quantification, within- and between-day accuracy and precision, process efficiency, dilution integrity, carry over and stability. Selectivity was high and no ion suppression or enhancementwas observed in the areas were the analytes eluted. Calibration curves were linear over arange of 0.25-50 ng/g for dexmedetomidine, 0.05-50 ng/g for fentanyl and 5.0-500 ng/g formorphine and quadratic over a range of 0.5-50 ng/g for clonidine, 50-5000 ng/g for ketamine, 5.0-500 ng/g for ketobemidone and midazolam. The method showed acceptable within- and betweenday accuracies and precisions. All analytes were stable in whole blood for three weeksat 4. C. Concentrations in patient samples ranged between 42-760 ng/g for midazolam (n = 15), 0.3-1.5 ng/g for dexmedetomidine (n = 13), 0.6-6.4 ng/g for clonidine (n = 13), 8-62 ng/g for morphine (n = 16), 5-19 ng/g for ketobemidone (n = 5), 0.07-3.1 ng/g for fentanyl (n = 43), and 562000 ng/g for ketamine (n = 10). We conclude that the method was successfully validatedand applied to ante-mortem and post-mortem blood samples from critically ill adult patientsin a general ICU.
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19. |
- Kempen, Thomas, et al.
(författare)
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Effects of Hospital-Based Comprehensive Medication Reviews Including Postdischarge Follow-up on Older Patients' Use of Health Care : A Cluster Randomized Clinical Trial
- 2021
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Ingår i: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 4:4
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Suboptimal use of medications is a leading cause of health care–related harm. Medication reviews improve medication use, but evidence of the possible benefit of inpatient medication review for hard clinical outcomes after discharge is scarce.Objective: To study the effects of hospital-based comprehensive medication reviews (CMRs), including postdischarge follow-up of older patients’ use of health care resources, compared with only hospital-based reviews and usual care.Design, Setting, and Participants: The Medication Reviews Bridging Healthcare trial is a cluster randomized crossover trial that was conducted in 8 wards with multiprofessional teams at 4 hospitals in Sweden from February 6, 2017, to October 19, 2018, with 12 months of follow-up completed December 6, 2019. The study was prespecified in the trial protocol. Outcome assessors were blinded to treatment allocation. In total, 2644 patients aged 65 years or older who had been admitted to 1 of the study wards for at least 1 day were included. Data from the modified intention-to-treat population were analyzed from December 10, 2019, to September 9, 2020.Interventions: Each ward participated in the trial for 6 consecutive 8-week periods. The wards were randomized to provide 1 of 3 treatments during each period: CMR, CMR plus postdischarge follow-up, and usual care without a clinical pharmacist.Main Outcomes and Measures: The primary outcome measure was the incidence of unplanned hospital visits (admissions plus emergency department visits) within 12 months. Secondary outcomes included medication-related admissions, visits with primary care clinicians, time to first unplanned hospital visit, mortality, and costs of hospital-based care.Results: Of the 2644 participants, 7 withdrew after inclusion, leaving 2637 for analysis (1357 female [51.5%]; median age, 81 [interquartile range, 74-87] years; median number of medications, 9 [interquartile range, 5-13]). In the modified intention-to-treat analysis, 922 patients received CMR, 823 received CMR plus postdischarge follow-up, and 892 received usual care. The crude incidence rate of unplanned hospital visits was 1.77 per patient-year in the total study population. The primary outcome did not differ between the intervention groups and usual care (adjusted rate ratio, 1.04 [95% CI, 0.89-1.22] for CMR and 1.15 [95% CI, 0.98-1.34] for CMR plus postdischarge follow-up). However, CMR plus postdischarge follow-up was associated with an increased incidence of emergency department visits within 12 months (adjusted rate ratio, 1.29; 95% CI, 1.05-1.59) compared with usual care. There were no differences between treatment groups regarding other secondary outcomes.Conclusions and Relevance: In this study of older hospitalized patients, CMR plus postdischarge follow-up did not decrease the incidence of unplanned hospital visits. The findings do not support the performance of hospital-based CMRs as conducted in this trial. Alternative forms of medication reviews that aim to improve older patients’ health outcomes should be considered and subjected to randomized clinical trials.
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20. |
- Kempen, Thomas G. H., 1988-
(författare)
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Medication reviews by clinical pharmacists in older hospitalised patients : Implementation, performance and effects
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Inappropriate use of medications is a leading cause of avoidable harm in health care. Medication reviews by clinical pharmacists improve medication use, but evidence on hard clinical outcomes in older hospitalised patients is scarce and implementation in practice is challenging. The aim of this thesis was to study the implementation, performance and effects of medication reviews by clinical pharmacists in older hospitalised patients.Methods A case study explored the factors involved in the implementation and sustainability of medication reviews by clinical pharmacists in Region Uppsala, Sweden. A pragmatic multicentre cluster-randomised crossover trial (MedBridge) was conducted to study the effects of hospital-based comprehensive medication reviews (CMRs) including post-discharge follow-ups on older patients’ healthcare utilisation, compared with only hospital-based reviews and usual care. The primary outcome measure was the incidence of unplanned hospital visits within 12 months. A process evaluation was conducted alongside the trial, for which different methods were applied: semi-structured interviews with patients and healthcare professionals, intervention fidelity assessment and process outcomes assessment. A practical tool to identify medication-related hospital admissions, one of the trial’s secondary outcomes, was developed and validated.Results Multiple factors involved in the implementation and sustainability of medication reviews by clinical pharmacists were identified. Examples of facilitating factors were a national focus on quality of care for the elderly and clinical pharmacy education. In total, 2637 participants (median age 81 years) were included in the MedBridge trial. The primary outcome measure did not differ between the treatment groups. Analysis of the interviews with patients and healthcare professionals resulted in seven and six themes, respectively, that were related to the performance of the trial’s interventions. A recurrent theme was the unclear role and responsibilities of the ward-based pharmacist. The intervention fidelity was high during hospital admission and lower surrounding discharge. In 77% of the intervention patients, at least one medication discrepancy or drug-related problem was solved. The developed tool, AT-HARM10, was deemed valid for use by pharmacy students to identify medication-related admissions in older patients.Conclusions This thesis suggests that, despite a high percentage of patients with medication discrepancies or drug-related problems being solved, hospital-based CMRs with and without post-discharge follow-ups, as conducted in the MedBridge trial, do not decrease the incidence of unplanned hospital visits in older patients. Future research and clinical initiatives may benefit from addressing the factors related to the implementation and performance of medication reviews that were identified in this thesis.
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21. |
- Kempen, Thomas, et al.
(författare)
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Intervention fidelity and process outcomes of medication reviews including post-discharge follow-up in older hospitalized patients : Process evaluation of the MedBridge trial.
- 2020
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Ingår i: Journal of Clinical Pharmacy and Therapeutics. - : Hindawi Limited. - 0269-4727 .- 1365-2710. ; 45:5, s. 1021-1029
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Tidskriftsartikel (refereegranskat)abstract
- WHAT IS KNOWN AND OBJECTIVE: Drug-related problems (DRPs) are a growing healthcare burden worldwide. In an ongoing cluster-randomized controlled trial in Sweden (MedBridge), comprehensive medication reviews (CMRs) including post-discharge follow-up have been conducted in older hospitalized patients to prevent and solve DRPs. As part of a process evaluation of the MedBridge trial, this study aimed to assess the intervention fidelity and process outcomes of the trial's interventions.METHODS: For intervention delivery, the percentage of patients that received intervention components was calculated per study group. Process outcomes, measured in about one-third of all intervention patients, included the following: the number of identified medication discrepancies, DRPs and recommendations to solve DRPs, correction rate of discrepancies, and implementation rate of recommendations.RESULTS AND DISCUSSION: The MedBridge trial included 2637 patients (mean age: 81 years). The percentage of intervention patients (n = 1745) that received the intended intervention components was 94%-98% during admission, and 40%-81% upon and after discharge. The percentage of control patients (n = 892) that received at least one unintended intervention component was 15%. On average, 1.1 discrepancies and 2.0 DRPs were identified in 652 intervention patients. The correction and implementation rates were 79% and 73%, respectively. Stop medication was the most frequently implemented recommendation (n = 293) and 77% of the patients had at least one corrected discrepancy or implemented recommendation.WHAT IS NEW AND CONCLUSION: The intervention fidelity within the MedBridge trial was high for CMRs during hospital stay and lower for intervention components upon and after discharge. The high prevalence of corrected discrepancies and implemented recommendations may explain potential effects of CMRs in the MedBridge trial.
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22. |
- Kempen, Thomas, et al.
(författare)
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Medication Reviews Bridging Healthcare (MedBridge) : Study protocol for a pragmatic cluster-randomised crossover trial
- 2017
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Ingår i: Contemporary Clinical Trials. - : Elsevier BV. - 1551-7144 .- 1559-2030. ; 61, s. 126-132
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Mismanaged prescribing and use of medication among elderly puts major pressure on current healthcare systems. Performing a medication review, a structured critical examination of a patient's medications, during hospital stay with active follow-up into primary care could optimise treatment benefit and minimise harm. However, a lack of high quality evidence inhibits widespread implementation. This manuscript describes the rationale and design of a pragmatic cluster-randomised, crossover trial to fulfil this need for evidence.AIM: To study the effects of hospital-initiated comprehensive medication reviews, including active follow-up, on elderly patients' healthcare utilisation compared to 1) usual care and 2) solely hospital based reviews.DESIGN: Multicentre, three-treatment, replicated, cluster-randomised, crossover trial.SETTING: 8 wards with a multidisciplinary team within 4 hospitals in 3 Swedish counties.PARTICIPANTS: Patients aged 65years or older, admitted to one of the study wards.EXCLUSION CRITERIA: Palliative stage; residing in other than the hospital's county; medication review within the last 30days; one-day admission.INTERVENTIONS: 1, comprehensive medication review during hospital stay; 2, same as 1 with the addition of active follow-up into primary care; 3, usual care.PRIMARY OUTCOME MEASURE: Incidence of unplanned hospital visits during a 12-month follow-up period.DATA COLLECTION AND ANALYSES: Extraction and collection from the counties' medical record system into a GCP compliant electronic data capture system. Intention-to-treat-analyses using hierarchical models.RELEVANCE: This study has a high potential to show a reduction in elderly patients' morbidity, contributing to more sustainable healthcare in the long run.
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23. |
- Kempen, Thomas, et al.
(författare)
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Risk factors for and preventability of drug-related hospital revisits in older patients: A post-hoc analysis of a randomized clinical trial
- 2023
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Ingår i: British Journal of Clinical Pharmacology. - : WILEY. - 0306-5251 .- 1365-2125. ; 89:5, s. 1575-1587
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Tidskriftsartikel (refereegranskat)abstract
- AimThe aims of this study were (1) to identify older patients risk factors for drug-related readmissions and (2) to assess the preventability of older patients drug-related revisits. MethodsPost hoc analysis of a randomized clinical trial with patients aged >= 65 years at eight wards within four hospitals in Sweden. (1) The primary outcome was risk factors for drug-related readmission within 12 months post-discharge. A Cox proportional hazards model was made with sociodemographic and clinical baseline characteristics. (2) Four hundred trial participants were randomly selected and their revisits (admissions and emergency department visits) were assessed to identify potentially preventable drug-related revisits, related diseases and causes. Results(1) Among 2637 patients (median age 81 years), 582 (22%) experienced a drug-related readmission within 12 months. Sixteen risk factors (hazard ratio >1, P < 0.05) related to age, previous hospital visits, medication use, multimorbidity and cardiovascular, liver, lung and peptic ulcer disease were identified. (2) The 400 patients experienced a total of 522 hospital revisits, of which 85 (16%) were potentially preventable drug-related revisits. The two most prevalent related diseases were heart failure (n = 24, 28%) and chronic obstructive pulmonary disease (n = 13, 15%). The two most prevalent causes were inadequate treatment (n = 23, 27%) and insufficient or no follow-up (n = 22, 26%). Conclusion(1) Risk factors for drug-related readmissions in older hospitalized patients were age, previous hospital visits, medication use and multiple diseases. (2) Potentially preventable drug-related hospital revisits are common and might be prevented through adequate pharmacotherapy and continuity of care in older patients with cardiovascular or lung disease.
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24. |
- Kristoffersson, Anders N., 1985-, et al.
(författare)
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A novel mechanism-based pharmacokinetic-pharmacodynamic (PKPD) model describing ceftazidime/avibactam efficacy against β-lactamase-producing Gram-negative bacteria
- 2020
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 75:2, s. 400-408
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Diazabicyclooctanes (DBOs) are an increasingly important group of non β-lactam β-lactamase inhibitors, employed clinically in combinations such as ceftazidime/avibactam. The dose finding of such combinations is complicated using the traditional pharmacokinetic/pharmacodynamic (PK/PD) index approach, especially if the β-lactamase inhibitor has an antibiotic effect of its own.OBJECTIVES: To develop a novel mechanism-based pharmacokinetic-pharmacodynamic (PKPD) model for ceftazidime/avibactam against Gram-negative pathogens, with the potential for combination dosage simulation.METHODS: Four β-lactamase-producing Enterobacteriaceae, covering Ambler classes A, B and D, were exposed to ceftazidime and avibactam, alone and in combination, in static time-kill experiments. A PKPD model was developed and evaluated using internal and external evaluation, and combined with a population PK model and applied in dosage simulations.RESULTS: The developed PKPD model included the effects of ceftazidime alone, avibactam alone and an 'enhancer' effect of avibactam on ceftazidime in addition to the β-lactamase inhibitory effect of avibactam. The model could describe an extensive external Pseudomonas aeruginosa data set with minor modifications to the enhancer effect, and the utility of the model for clinical dosage simulation was demonstrated by investigating the influence of the addition of avibactam.CONCLUSIONS: A novel mechanism-based PKPD model for the DBO/β-lactam combination ceftazidime/avibactam was developed that enables future comparison of the effect of avibactam with other DBO/β-lactam inhibitors in simulations, and may be an aid in translating PKPD results from in vitro to animals and humans.
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25. |
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26. |
- Kurland, Siri, et al.
(författare)
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Pharmacokinetics of Caspofungin in Critically Ill Patients in Relation to Liver Dysfunction : Differential Impact of Plasma Albumin and Bilirubin Levels
- 2019
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Ingår i: Antimicrobial Agents and Chemotherapy. - : AMER SOC MICROBIOLOGY. - 0066-4804 .- 1098-6596. ; 63:6
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Tidskriftsartikel (refereegranskat)abstract
- Caspofungin has a liver-dependent metabolism. Reduction of the dose is recommended based on Child-Pugh (C-P) score. In critically ill patients, drug pharmacokinetics (PK) may be altered. The aim of this study was to investigate the prevalence of abnormal liver function tests, increased C-P scores, their effects on caspofungin PK, and whether pharmacokinetic-pharmacodynamic (PK/PD) targets were attained in patients with suspected candidiasis. Intensive care unit patients receiving caspofungin were prospectively included. PK parameters were determined on days 2, 5, and 10, and their correlations to the individual liver function tests and the C-P score were analyzed. Forty-six patients were included with C-P class A (n = 5), B (n = 40), and C (n = 1). On day 5 (steady state), the median and interquartile range for area under the curve from 0 to 24 h (AUC(0-24)), clearance (CL), and central volume of distribution (V-1) were 57.8 (51.6 to 69.8) mg.h/liter, 0.88 (0.78 to 1.04) liters/h, and 11.9 (9.6 to 13.1) liters, respectively. The C-P score did not correlate with AUC(0-24) (r = 0.03; P = 0.84), CL (r = -0.07; P = 0.68), or V-1 (r = 0.19; P = 0.26), but there was a bilirubin-driven negative correlation with the elimination rate constant (r = -0.46; P = 0.004). Hypoalbuminemia correlated with low AUC(0-24) (r = 0.45; P = 0.005) and was associated with higher clearance (r = -0.31; P = 0.062) and somewhat higher V-1 (r = -0.15; P = 0.37), resulting in a negative correlation with the elimination rate constant (r = -0.34; P = 0.042). For Candida strains with minimal inhibitory concentrations of >= 0.064 mu g/ml, PK/PD targets were not attained in all patients. The caspofungin dose should not be reduced in critically ill patients in the absence of cirrhosis, and we advise against the use of the C-P score in patients with trauma- or sepsis-induced liver injury.
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27. |
- Lennborn, Ulrica, et al.
(författare)
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Recommended dosages of analgesic and sedative drugs in intensive care result in a low incidence of potentially toxic blood concentrations
- 2024
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Ingår i: Upsala Journal of Medical Sciences. - : Upsala Medical Society. - 0300-9734 .- 2000-1967. ; 129
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Tidskriftsartikel (refereegranskat)abstract
- Background: Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated.Methods: A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS).Results: Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations.Conclusion: Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs.
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28. |
- Maarbjerg, Sabine F., et al.
(författare)
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Continuous infusion of piperacillin‐tazobactam significantly improves target attainment in children with cancer and fever
- 2021
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Ingår i: Cancer Reports. - : John Wiley & Sons. - 2573-8348. ; 5:10
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundChildren with febrile neutropenia commonly exhibit alterations of pharmacokinetic (PK) parameters, leading to decreased β-lactam concentrations.AimsThis study evaluated piperacillin PK and probability of target attainment (PTA) with continuous infusion of piperacillin-tazobactam, in order to optimize the dosing regimen.MethodsThis prospective PK study included children with cancer, aged 1–17 years, who were treated with piperacillin-tazobactam for suspected or verified infection. A piperacillin-tazobactam loading dose (100 mg/kg) was administered followed by continuous infusion (300 mg/kg/day). The unbound fraction of piperacillin was quantified by high-performance liquid chromatography and PK were described using population PK modeling. PK data was used to update and extend a previous PK model built on data following intermittent administration. Monte Carlo simulations were performed to assess PTA for targets of 100% time above the minimum inhibitory concentration (100% fT > MIC) and 50% fT > 4xMIC.ResultsWe included 68 fever episodes among 38 children with a median (IQR) age of 6.5 years and body weight of 27.4 kg (15.1–54.0). A three-compartment model adequately described the concentration-time data. Median (95% confidence interval) estimates for clearance and piperacillin concentration at steady state were 14.2 L/h/70 kg (13.0; 15.3) and 47.6 mg/L (17.2; 129.5), respectively. Body weight or lean body weight was significantly associated with the PK parameters, and body weight was integrated in the final PK model. Based on piperacillin exposure, continuous infusion was the only dosing regimen to achieve optimal PTA for the P. aeruginosa breakpoint (16 mg/L) with the target of 100% fT > MIC, and a daily dose of 300 mg/kg reached optimal PTA. The strict target of 50% fT > 4xMIC (64 mg/L) was not feasibly attained by any dosing regimen at recommended doses.ConclusionUnlike conventional piperacillin intermittent administration and extended infusion regimens, continuous infusion allows the target of 100% fT > MIC to be reached for children with febrile neutropenia.
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29. |
- Maarbjerg, Sabine F., et al.
(författare)
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Piperacillin pharmacokinetics and target attainment in children with cancer and fever : Can we optimize our dosing strategy?
- 2019
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Ingår i: Pediatric Blood & Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 66:6
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Tidskriftsartikel (refereegranskat)abstract
- Background Data on piperacillin-tazobactam pharmacokinetics and optimal dosing in children with cancer and fever are limited. Our objective was to investigate piperacillin pharmacokinetics and the probability of target attainment (PTA) with standard intermittent administration (IA), and to simulate PTA in other dosing regimens.Procedure This prospective pharmacokinetic study was conducted from April 2016 to January 2018. Children with cancer receiving empiric piperacillin-tazobactam to treat infections were included. Piperacillin-tazobactam 100 mg/kg was infused over 5 min every 8 hours (IA). An optimized sample schedule provided six blood samples per subject for piperacillin concentration determination. The evaluated targets included: (1) 100% time of free piperacillin concentration above the minimum inhibitory concentration (fT > MIC) and (2) 50% fT > 4x MIC. MIC50 and MIC90 were defined based on an intrainstitutional MIC range.Results A total of 482 piperacillin concentrations were obtained from 43 children (aged 1-18 years) during 89 fever episodes. Standard IA resulted in insufficient target attainment, with significant differences in piperacillin pharmacokinetics for different body weights. Median fT > MIC was 61.2%, 53.5%, and 36.3% for MIC50 (2.0 mg/L), MIC90 (4.0 mg/L), and breakpoint for Pseudomonas aeruginosa (16.0 mg/L), respectively. Correspondingly, the median fT > 4x MIC was 43%, 36.3%, and 20.1%. Simulations showed that only continuous infusion reached a PTA of 95% for MIC = 16.0 mg/L, while extended infusion lasting half of the dosing interval reached a PTA of 95% for MIC <= 8 mg/L.Conclusions Our data revealed insufficient PTA with standard IA of piperacillin-tazobactam in children with cancer and fever. Alternative dosing strategies, preferably continuous infusion, are required to ensure adequate PTA.
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30. |
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31. |
- Netterberg, Ida, et al.
(författare)
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Model-based prediction of myelosuppression and recovery based on frequent neutrophil monitoring
- 2017
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 80:2, s. 343-353
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To investigate whether a more frequent monitoring of the absolute neutrophil counts (ANC) during myelo-suppressive chemotherapy, together with model-based predictions, can improve therapy management, compared to the limited clinical monitoring typically applied today. Methods Daily ANC in chemotherapy-treated cancer patients were simulated from a previously published population model describing docetaxel-induced myelosuppression. The simulated values were used to generate predictions of the individual ANC time-courses, given the myelosuppression model. The accuracy of the predicted ANC was evaluated under a range of conditions with reduced amount of ANC measurements. Results The predictions were most accurate when more data were available for generating the predictions and when making short forecasts. The inaccuracy of ANC predictions was highest around nadir, although a high sensitivity (>= 90%) was demonstrated to forecast Grade 4 neutropenia before it occurred. The time for a patient to recover to baseline could be well forecasted 6 days (+/- 1 day) before the typical value occurred on day 17. Conclusions Daily monitoring of the ANC, together with model-based predictions, could improve anticancer drug treatment by identifying patients at risk for severe neutropenia and predicting when the next cycle could be initiated.
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32. |
- Netterberg, Ida, 1988-
(författare)
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Pharmacometric Evaluation of Biomarkers to Improve Treatment in Oncology
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer is a family of many different diseases with substantial heterogeneity also within the same cancer type. In the era of personalized medicine, it is desirable to identify an early response to treatment (i.e., a biomarker) that can predict the long-term outcome with respect to both safety and efficacy. It is however not uncommon to categorize continuous data, e.g., using tumor size data to classify patients as responders or non-responders, resulting in loss of valuable information. Pharmacometric modeling offers a way of analyzing longitudinal time-courses of different variables (e.g., biomarker and tumor size), and therefore minimizing information loss.Neutropenia is the most common dose-limiting toxicity for chemotherapeutic drugs and manifests by a low absolute neutrophil count (ANC). This thesis explored the potential of using model-based predictions together with frequent monitoring of the ANC to identify patients at risk of severe neutropenia and potential dose delay. Neutropenia may develop into febrile neutropenia (FN), a potentially life-threatening condition. Interleukin 6, an immune-related biomarker, was identified as an on-treatment predictor of FN in breast cancer patients treated with adjuvant chemotherapy. C-reactive protein, another immune-related biomarker, rather demonstrated confirmatory value to support FN diagnosis.Cancer immunotherapy is the most recent advance in anticancer treatment, with immune checkpoint inhibitors, e.g., atezolizumab, leading the breakthrough. In a pharmacometric modeling framework, the area under the curve of atezolizumab was related to tumor size changes in non-small cell lung cancer patients treated with atezolizumab. The relative change from baseline of Interleukin 18 at 21 days after start of treatment added predictive value on top of the drug effect. The tumor size time-course predicted overall survival (OS) in the same population.Circulating tumor cells (CTCs) are tumor cells that have shed from a tumor and circulate in the blood. CTCs may cause distant metastases, which is related to a poor prognosis. A novel modeling framework was developed in which the relationship between tumor size and CTC count was quantified in patients with metastatic colorectal cancer treated with chemotherapy and targeted therapy. It was also demonstrated that the CTC count was a superior predictor of OS in comparison to tumor size changes.In summary, IL-6 predicted FN, IL-18 predicted tumor size changes and tumor size changes and CTC counts predicted OS. The results in this thesis were obtained by using pharmacometrics to evaluate biomarkers to improve treatment in oncology.
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33. |
- Netterberg, Ida, et al.
(författare)
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The risk of febrile neutropenia in breast cancer patients following adjuvant chemotherapy is predicted by the time course of interleukin-6 and C-reactive protein by modelling.
- 2018
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 84:3, s. 490-500
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Early identification of patients with febrile neutropenia (FN) is desirable for initiation of preventive treatment, such as with antibiotics. In this study, the time courses of two inflammation biomarkers, interleukin (IL)-6 and C-reactive protein (CRP), following adjuvant chemotherapy of breast cancer, were characterized. The potential to predict development of FN by IL-6 and CRP, and other model-derived and clinical variables, was explored.METHODS: The IL-6 and CRP time courses in cycles 1 and 4 of breast cancer treatment were described by turnover models where the probability for an elevated production following initiation of chemotherapy was estimated. Parametric time-to-event models were developed to describe FN occurrence to assess: (i) predictors available before chemotherapy is initiated; (ii) predictors available before FN occurs; and (iii) predictors available when FN occurs.RESULTS: The IL-6 and CRP time courses were successfully characterized with peak IL-6 typically occurring 2 days prior to CRP peak. Of all evaluated variables the CRP time course was most closely associated with the occurrence of FN. Since the CRP peak typically occurred at the time of FN diagnosis it will, however, have limited value for identifying the need for preventive treatment. The time course of IL-6 was the predictor that could best forecast FN events. Of the variables available at baseline, age was the best, although in comparison a relatively weak, predictor.CONCLUSIONS: The developed models add quantitative knowledge about IL-6 and CRP and their relationship to the development of FN. The study suggests that IL-6 may have potential as a clinical predictor of FN if monitored during myelosuppressive chemotherapy.
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34. |
- Nielsen, Elisabet I, 1973-
(författare)
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Pharmacometric Models for Antibacterial Agents to Improve Dosing Strategies
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Antibiotics are among the most commonly prescribed drugs. Although the majority of these drugs were developed several decades ago, optimal dosage (dose, dosing interval and treatment duration) have still not been well defined. This thesis focuses on the development and evaluation of pharmacometric models that can be used as tools in the establishment of improved dosing strategies for novel and already clinically available antibacterial drugs. Infectious diseases are common causes of death in preterm and term newborn infants. A population pharmacokinetic (PK) model for gentamicin was developed based on data from a prospective study. Body-weight and age (gestational and post-natal age) were found to be major factors contributing to variability in gentamicin clearance and therefore important patient characteristics to consider for improved dosing regimens. A semi-mechanistic pharmacokinetic-pharmacodynamic (PKPD) model was also developed, to characterize in vitro bacterial growth and killing kinetics following exposure to six antibacterial drugs, representing a broad selection of mechanisms of action and PK as well as PD characteristics. The model performed well in describing a wide range of static and dynamic drug exposures and was easily applied to other bacterial strains and antibiotics. It is, therefore, likely to find application in early drug development programs. Dosing of antibiotics is usually based on summary endpoints such as the PK/PD indices. Predictions based on the PKPD model showed that the commonly used PK/PD indices were well identified for all investigated drugs, supporting that models based on in vitro data can be predictive of antibacterial effects observed in vivo. However, the PK/PD indices were sensitive to the study conditions and were not always consistent between patient populations. The PK/PD indices may therefore extrapolate poorly across sub-populations. A semi-mechanistic modeling approach, utilizing the type of models described here, may thus have higher predictive value in a dose optimization tailored to specific patient populations.
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35. |
- Nielsen, Elisabet I., 1973-, et al.
(författare)
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Population Pharmacokinetic Analysis of Vaginally and Intravenously Administered Oxytocin in Postmenopausal Women
- 2017
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Ingår i: Journal of clinical pharmacology. - : Wiley. - 0091-2700 .- 1552-4604. ; 57:12, s. 1573-1581
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Tidskriftsartikel (refereegranskat)abstract
- Oxytocin is a neuropeptide hormone used clinically for more than 50 years due to its ability to induce uterine contractions and milk ejection. Vagitocin is a vaginal oxytocin gel developed as a potential treatment of vaginal atrophy in postmenopausal women. The aim of this study was to characterize the oxytocin pharmacokinetics following vaginal and intravenous administration in postmenopausal women. Data from 33 participants enrolled in 2 clinical studies were used in the analysis, with a total of 651 observed oxytocin plasma concentrations, of which 78 were baseline observations, 178 observations following intravenous administration (10 IU), and 395 observations following vaginal administration (100 or 400 IU). The population pharmacokinetics of oxytocin was described using a 2-compartment disposition model with a flexible parallel absorption model accounting for double-peak profiles following vaginal administration. The clearance, volume of distribution at steady state, distribution half-life, and terminal half-life were estimated to be 27 L/h, 15 L, 5.5 minutes, and 1.2 hours, respectively. The bioavailability following vaginal administration was estimated to be 2.5% for the typical patient, but with considerable variability both between individuals (interindividual variability of 374%) and between occasions (interoccasion variability of 79%). The data and the developed model add new and important information as to the clinical pharmacokinetics of oxytocin.
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36. |
- Olsson, Anna, et al.
(författare)
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Efficacy of Antibiotic Combinations against Multidrug-Resistant Pseudomonas aeruginosa in Automated Time-Lapse Microscopy and Static Time-Kill Experiments
- 2020
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Ingår i: Antimicrobial Agents and Chemotherapy. - : AMER SOC MICROBIOLOGY. - 0066-4804 .- 1098-6596. ; 64:6
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Tidskriftsartikel (refereegranskat)abstract
- Antibiotic combination therapy is used for severe infections caused by multidrug-resistant (MDR) Gram-negative bacteria, yet data regarding which combinations are most effective are lacking. This study aimed to evaluate the in vitro efficacy of polymyxin B in combination with 13 other antibiotics against four clinical strains of MDR Pseudomonas aeruginosa. We evaluated the interactions of polymyxin B in combination with amikacin, aztreonam, cefepime, chloramphenicol, ciprofloxacin, fosfomycin, linezolid, meropenem, minocycline, rifampin, temocillin, thiamphenicol, or trimethoprim by automated time-lapse microscopy using predefined cutoff values indicating inhibition of growth (<= 10(6) CFU/ml) at 24 h. Promising combinations were subsequently evaluated in static time-kill experiments. All strains were intermediate or resistant to polymyxin B, antipseudomonal beta-lactams, ciprofloxacin, and amikacin. Genes encoding beta-lactamases (e.g., bla(PAO) and bla(OXA-50)) and mutations associated with permeability and efflux were detected in all strains. In the time-lapse microscopy experiments, positive interactions were found with 39 of 52 antibiotic combination/bacterial strain setups. Enhanced activity was found against all four strains with polymyxin B used in combination with aztreonam, cefepime, fosfomycin, minocycline, thiamphenicol, and trimethoprim. Time-kill experiments showed additive or synergistic activity with 27 of the 39 tested polymyxin B combinations, most frequently with aztreonam, cefepime, and meropenem. Positive interactions were frequently found with the tested combinations, against strains that harbored several resistance mechanisms to the single drugs, and with antibiotics that are normally not active against P. aeruginosa. Further study is needed to explore the clinical utility of these combinations.
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37. |
- Olsson, Anna, et al.
(författare)
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Synergy of polymyxin B and minocycline against KPC-3- and OXA-48-producing Klebsiella pneumoniae in dynamic time-kill experiments : agreement with in silico predictions.
- 2023
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Ingår i: Journal of Antimicrobial Chemotherapy. - 0305-7453 .- 1460-2091.
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Combination therapy is often used for carbapenem-resistant Gram-negative bacteria. We previously demonstrated synergy of polymyxin B and minocycline against carbapenem-resistant Klebsiella pneumoniae in static time-kill experiments and developed an in silico pharmacokinetic/pharmacodynamic (PK/PD) model. The present study assessed the synergistic potential of this antibiotic combination in dynamic experiments.METHODS: Two clinical K. pneumoniae isolates producing KPC-3 and OXA-48 (polymyxin B MICs 0.5 and 8 mg/L, and minocycline MICs 1 and 8 mg/L, respectively) were included. Activities of the single drugs and the combination were assessed in 72 h dynamic time-kill experiments mimicking patient pharmacokinetics. Population analysis was performed every 12 h using plates containing antibiotics at 4× and 8× MIC. WGS was applied to reveal resistance genes and mutations.RESULTS: The combination showed synergistic and bactericidal effects against the KPC-3-producing strain from 12 h onwards. Subpopulations with decreased susceptibility to polymyxin B were frequently detected after single-drug exposures but not with the combination. Against the OXA-48-producing strain, synergy was observed between 4 and 8 h and was followed by regrowth. Subpopulations with decreased susceptibility to polymyxin B and minocycline were detected throughout experiments. For both strains, the observed antibacterial activities showed overall agreement with the in silico predictions.CONCLUSIONS: Polymyxin B and minocycline in combination showed synergistic effects, mainly against the KPC-3-producing K. pneumoniae. The agreement between the experimental results and in silico predictions supports the use of PK/PD models based on static time-kill data to predict the activity of antibiotic combinations at dynamic drug concentrations.
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38. |
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39. |
- Sadiq, Muhammad W, et al.
(författare)
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A whole-body physiologically based pharmacokinetic (WB-PBPK) model of ciprofloxacin : a step towards predicting bacterial killing at sites of infection.
- 2017
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 44:2, s. 69-79
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model for ciprofloxacin for ICU patients, based on only plasma concentration data. In a next step, tissue and organ concentration time profiles in patients were predicted using the developed model. The WB-PBPK model was built using a non-linear mixed effects approach based on data from 102 adult intensive care unit patients. Tissue to plasma distribution coefficients (Kp) were available from the literature and used as informative priors. The developed WB-PBPK model successfully characterized both the typical trends and variability of the available ciprofloxacin plasma concentration data. The WB-PBPK model was thereafter combined with a pharmacokinetic-pharmacodynamic (PKPD) model, developed based on in vitro time-kill data of ciprofloxacin and Escherichia coli to illustrate the potential of this type of approach to predict the time-course of bacterial killing at different sites of infection. The predicted unbound concentration-time profile in extracellular tissue was driving the bacterial killing in the PKPD model and the rate and extent of take-over of mutant bacteria in different tissues were explored. The bacterial killing was predicted to be most efficient in lung and kidney, which correspond well to ciprofloxacin's indications pneumonia and urinary tract infections. Furthermore, a function based on available information on bacterial killing by the immune system in vivo was incorporated. This work demonstrates the development and application of a WB-PBPK-PD model to compare killing of bacteria with different antibiotic susceptibility, of value for drug development and the optimal use of antibiotics.
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40. |
- Senek, Marina, et al.
(författare)
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Levodopa-entacapone-carbidopa intestinal gel in Parkinson's disease : A randomized crossover study
- 2017
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 32:2, s. 283-286
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe addition of oral entacapone to levodopa-carbidopa intestinal gel treatment leads to less conversion of levodopa to 3-O-methyldopa, thereby increasing levodopa plasma concentration. The objective of this study was to compare systemic levodopa exposure of the newly developed levodopa-entacapone-carbidopa intestinal gel after a 20% dose reduction with levodopa exposure after the usual levodopa-carbidopa intestinal gel dose in a randomized crossover trial in advanced Parkinson's disease patients. MethodsIn this 48-hour study, 11 patients treated with levodopa-carbidopa intestinal gel were randomized to a treatment sequence. Blood samples were drawn at prespecified times, and patient motor function was assessed according to the treatment response scale. ResultsSystemic exposure of levodopa did not differ significantly between treatments (ratio, 1.10 [95% confidence interval, 0.951-1.17]). Treatment response scale scores did not significantly differ between treatments (P=0.84). ConclusionsLevodopa-entacapone-carbidopa intestinal gel allowed a lower amount of levodopa administration and was well tolerated. Long-term studies are needed to confirm the results.
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41. |
- Senek, Marina, et al.
(författare)
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Population pharmacokinetics of levodopa/carbidopa microtablets in healthy subjects and Parkinson’s disease patients
- 2018
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 74:10, s. 1299-1307
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Low dose, dispersible, levodopa/carbidopa microtablets with an automatic dose dispenser have been developed to facilitate individualized levodopa treatment. The aim of this study was to characterize the pharmacokinetics (PK) of levodopa and carbidopa after microtablet administration, and evaluate the impact of potential covariates.Methods: The population PK analysis involved data from 18 healthy subjects and 18 Parkinson's disease patients included in two single-dose, open-label levodopa/carbidopa microtablet studies. The analysis was carried out using non-linear mixed effects modeling. Bodyweight was included on all disposition parameters according to allometric scaling. Potential influence of additional covariates was investigated using graphical evaluation and adjusted adaptive least absolute shrinkage and selection operator.Results: Dispositions of levodopa and carbidopa were best described by a two- and one-compartment model respectively. Double-peak profiles were described using two parallel absorption compartments. Levodopa apparent clearance was found to decrease with increasing carbidopa dose (15% lower with 75 compared to 50mg of carbidopa) and disease stage (by 18% for Hoehn and Yahr 1 to 4). Carbidopa apparent clearance was found to decrease with age (28% between the age of 60 and 80years). An external evaluation showed the model to be able to reasonably well predict levodopa concentrations following multiple-dose microtablet administration in healthy subjects.Conclusions: The presented models adequately described the PK of levodopa and carbidopa, following microtablet administration. The developed model may in the future be combined with a pharmacokinetic-pharmacodynamic target and used for individualized dose selection, utilizing the flexibility offered by the microtablets.
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42. |
- Senek, Marina, et al.
(författare)
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Population pharmacokinetics of levodopa gel infusion in Parkinson's disease : effects of entacapone infusion and genetic polymorphism
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Levodopa-entacapone-carbidopa intestinal gel (LECIG) provides continuous drug delivery through intrajejunal infusion. The aim of this study was to characterize the population pharmacokinetics of levodopa following LECIG and levodopa-carbidopa intestinal gel (LCIG) infusion to investigate suitable translation of dose from LCIG to LECIG treatment, and the impact of common variations in the dopa-decarboxylase (DDC) and catechol-O-methyltransferase (COMT) genes on levodopa pharmacokinetics. A non-linear mixed-effects model of levodopa pharmacokinetics was developed using plasma concentration data from a double-blind, cross-over study of LCIG compared with LECIG in patients with advanced Parkinson's disease (n = 11). All patients were genotyped for rs4680 (polymorphism of the COMT gene), rs921451 and rs3837091 (polymorphisms of the DDC gene). The final model was a one compartment model with a high fixed absorption rate constant, and a first order elimination, with estimated apparent clearances (CL/F), of 27.9 L/h/70 kg for LCIG versus 17.5 L/h/70 kg for LECIG, and apparent volume of distribution of 74.4 L/70 kg. Our results thus suggest that the continuous maintenance dose of LECIG, on a population level, should be decreased by approximately 35%, to achieve similar drug exposure as with LCIG. An effect from entacapone was identified on all individuals, regardless of COMT rs4680 genotype. The individuals with higher DDC and COMT enzyme activity showed tendencies towards higher levodopa CL/F. The simultaneous administration of entacapone to LCIG administration results in a 36.5% lower apparent levodopa clearance, and there is a need for lower continuous maintenance doses, regardless of patients' COMT genotype.
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43. |
- Sulku, Johanna, et al.
(författare)
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A Cross-Sectional Study Assessing Appropriateness Of Inhaled Corticosteroid Treatment In Primary And Secondary Care Patients With COPD In Sweden
- 2019
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Ingår i: The International Journal of Chronic Obstructive Pulmonary Disease. - : DOVE MEDICAL PRESS LTD. - 1176-9106 .- 1178-2005. ; 14, s. 2451-2460
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Inhaled corticosteroids (ICS) are often more widely prescribed in the treatment of chronic obstructive pulmonary disease (COPD) than what is recommended in the guidelines. The aim of this study was to evaluate the appropriateness of ICS treatment in COPD patients using the algorithm proposed by the International Primary Care Respiratory Group (IPCRG) and to identify factors associated with ICS treatment.Patients and methods: Appropriateness of ICS therapy was studied with respect to concomitant asthma, history of exacerbations and blood eosinophils (B-Eos) in a Swedish cohort of primary and secondary care patients with COPD. Factors associated with ICS were investigated using multivariable logistic regression.Results: Triple treatment was found to be the most common treatment combination, used by 46% of the 561 included patients, and in total 63% were using ICS. When applying the IPCRG algorithm, there was a possible indication for discontinuation of ICS in 55% of the patients with ICS treatment. Of the patients not using ICS, 18% had an indication for starting such treatment. The strongest factors associated with ICS therapy were frequent exacerbations (aOR 8.61, 95% CI 4.06, 20.67), secondary care contacts (aOR 6.99, 95% CI 2.48, 25.28) and very severe airflow limitation (aOR 5.91, 95% CI 1.53, 26.58).Conclusion: More than half of the COPD patients on ICS met the criteria where withdrawal of the treatment could be tried. There was, however, also a subgroup of patients not using ICS for whom there was an indication for starting ICS treatment. Patients using ICS were characterized by more frequent exacerbations and lower lung function.
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44. |
- Sulku, Johanna, et al.
(författare)
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Changes in critical inhaler technique errors in inhaled COPD treatment : A one-year follow-up study in Sweden
- 2022
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Ingår i: Respiratory Medicine. - : Elsevier. - 0954-6111 .- 1532-3064. ; 197
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Tidskriftsartikel (refereegranskat)abstract
- Background: Critical inhaler technique errors have been associated with lower treatment efficacy in chronic obstructive pulmonary disease (COPD). We aimed to assess and follow-up critical inhaler technique errors, and to investigate their association with COPD symptoms and exacerbations.Methods: COPD-diagnosed primary and secondary care outpatients (n = 310) demonstrated inhaler technique with inhaler devices they were currently using. Critical errors in opening, positioning and loading the inhaler device, and exhalation through dry-powder inhalers were assessed and corrected, and the assessment was repeated one year later. COPD Assessment Test, the modified Medical Research Council dyspnoea scale and history of exacerbations were collected at both visits.Results: The proportion of patients making >1 critical inhaler technique error was lower at follow-up in the total population (46% vs 37%, p = 0.01) and among patients with unchanged device models (46% vs 35%, p = 0.02), but not among patients with a new inhaler device model (46% vs 41%, p = 0.56). Not positioning the device correctly was the most common critical error at both visits (30% and 22%). Seventy-four percent of the patients had unchanged COPD treatment from baseline to follow-up. Treatment escalation, de-escalation, and switch was observed in 14%, 11%, and 1% of the patients, respectively. No association was found between critical errors and COPD symptoms or exacerbations.Conclusions: Assessment and correction of inhaler technique was associated with a decrease in critical inhaler technique errors. This effect was most pronounced in patients using the same device models throughout the follow-up period.
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45. |
- Sulku, Johanna, et al.
(författare)
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Critical inhaler technique errors in Swedish patients with COPD : a cross-sectional study analysing video-recorded demonstrations
- 2021
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Ingår i: npj Primary Care Respiratory Medicine. - : Springer Nature. - 2055-1010. ; 31:1
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Tidskriftsartikel (refereegranskat)abstract
- A correct use of inhaler devices is essential in chronic obstructive pulmonary disease (COPD) treatment. Critical errors were studied by analysing 659 video-recorded demonstrations of inhaler technique from 364 COPD patients using six different inhaler device models. The majority of the included patients used two (55%) or more (20%) device models. Overall, 66% of the patients made ≥1 critical error with at least one device model. The corresponding numbers for patients using 1, 2 and ≥3 device models were 43%, 70% and 86%, respectively. The only factor associated with making ≥1 critical error was simultaneous use of two (adjusted odds ratios (aOR) 3.17, 95% confidence interval (95% CI) 1.81, 5.64) or three or more (aOR 8.97, 95% CI 3.93, 22.1) device models. In conclusion, the proportion of patients making critical errors in inhaler technique was substantial, particularly in those using several different device models. To obtain optimal COPD treatment, it is important to assess a patient's inhaler technique and to minimise the number of inhaler device models.
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46. |
- Sulku, Johanna
(författare)
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Inhaled pharmacological treatment and critical inhaler technique errors in patients with chronic obstructive pulmonary disease
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease characterised by persistent respiratory symptoms and a high risk of exacerbations. Preventive and maintenance pharmacological treatment is primarily administered through handheld inhalers, which are available in several different device-drug combinations. This thesis is about increasing the quality of drug treatment in COPD, where problems related to inhaled drugs are common. The overall aim was to assess and evaluate inhaled pharmacological treatment and critical inhaler technique errors in patients with COPD. The four studies included in this thesis derived from the Tools for Identifying Exacerbations study, which is an observational multicentre study in primary and secondary care in Sweden including 571 patients with COPD.The consequences of a change in the Global Initiative for Obstructive Lung Disease guidelines were investigated (Paper I). The refined COPD assessment of symptoms/risk of exacerbations lead to a high proportion of patients being reclassified to a lower risk group, which in turn had consequences for patients’ pharmacological treatment.The patients’ inhaled pharmacological treatments were assessed (Paper II). A high prevalence of inhaled corticosteroids (ICS) was identified, especially as a triple treatment, i.e., in combination with dual long-acting bronchodilators. Based on a previously developed tool, discontinuation of ICS could be tried in more than half of the patients.Proper inhaler technique is a prerequisite for adequate COPD treatment. Video-recorded demonstrations of inhaler technique were analysed (Paper III). Two-thirds of the patients made at least one critical inhaler technique error. The majority of the patients used a combination of different inhaler device models, which was the only factor associated with critical inhaler technique errors.The changes in inhaled pharmacological COPD treatment and inhaler technique were investigated one year after an initial evaluation and training (Paper IV). A reduction in the proportion of patients making critical inhaler technique errors was found but not in the subgroup of patients who had switched device models during the year. However, no association with COPD symptoms or exacerbations could be detected.The overall results contribute to increased knowledge and understanding of drug treatment in COPD. In order to optimise pharmacological treatment, it is essential to assess disease severity and inhaler technique, particularly in patients who switch device models. Further research is warranted to determine the most optimal educational intervention regarding inhaler technique, which has not yet been settled.
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47. |
- Swartling, Maria, et al.
(författare)
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Population pharmacokinetics of cefotaxime in intensive care patients
- 2022
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 78:2, s. 251-258
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To characterise the pharmacokinetics and associated variability of cefotaxime in adult intensive care unit (ICU) patients and to assess the impact of patient covariates.METHODS: This work was based on data from cefotaxime-treated patients included in the ACCIS (Antibiotic Concentrations in Critical Ill ICU Patients in Sweden) study. Clinical data from 51 patients at seven different ICUs in Sweden, given cefotaxime (1000-3000 mg given 2-6 times daily), were collected from the first day of treatment for up to three consecutive days. In total, 263 cefotaxime samples were included in the population pharmacokinetic analysis.RESULTS: A two-compartment model with linear elimination, proportional residual error and inter-individual variability (IIV) on clearance and central volume of distribution best described the data. The typical individual was 64 years, with body weight at ICU admission of 92 kg and estimated creatinine clearance of 94 mL/min. The resulting typical value of clearance was 11.1 L/h, central volume of distribution 5.1 L, peripheral volume of distribution 18.2 L and inter-compartmental clearance 14.5 L/h. The estimated creatinine clearance proved to be a significant covariate on clearance (p < 0.001), reducing IIV from 68 to 49%.CONCLUSION: A population pharmacokinetic model was developed to describe cefotaxime pharmacokinetics and associated variability in adult ICU patients. The estimated creatinine clearance partly explained the IIV in cefotaxime clearance. However, the remaining unexplained IIV is high and suggests a need for dose individualisation using therapeutic drug monitoring where the developed model, after evaluation of predictive performance, may provide support.
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48. |
- Swartling, Maria, et al.
(författare)
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Therapeutic drug monitoring of vancomycin and meropenem : Illustration of the impact of inaccurate information in dose administration time
- 2023
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier. - 0924-8579 .- 1872-7913. ; 63:1
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To illustrate the impact of errors in documented dose administration time on therapeutic drug monitoring (TDM)-based target attainment evaluation for vancomycin and meropenem, and to explore the influence of drug and patient characteristics, and TDM sampling strategies.Methods: Bedside observations of errors in documented dose administration times were collected. Population pharmacokinetic simulations were performed for vancomycin and meropenem, evaluating different one- and two-sampling strategies for populations with estimated creatinine clearance (CLcr) of 30, 80 or 130 mL/min. The impact of errors was evaluated as the proportion of individuals incorrectly considered to have reached the target.Results: Of 143 observed dose administrations, 97% of doses were given within ±30 min of the documented time. For vancomycin, a +30 min error was predicted to result in a 0.1-3.9 percentage point increase of cases incorrectly evaluated as reaching area under the concentration-time curve during a 24-hour period (AUC24)/minimum inhibitory concentration (MIC) >400, with the largest increase for patients with augmented renal clearance and peak and trough sampling. For meropenem, a +30 min error resulted in a 1.3-6.4 and 0-20 percentage point increase of cases incorrectly evaluated as reaching 100% T>MIC, and 50% T>MIC, respectively. Overall, mid-dose and trough sampling was most favourable for both antibiotics.Conclusions: For vancomycin, simulations indicate that TDM-based target attainment evaluation is robust with respect to the observed errors in dose administration time of ±30 min; however, the errors had a potentially clinically important impact in patients with augmented renal clearance. For meropenem, extra measures to promote correct documentation are warranted when using TDM, as the impact of errors was evident even in patients with normal renal function.
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49. |
- Thorsted, Anders, et al.
(författare)
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A non-linear mixed effect model for innate immune response : In vivo kinetics of endotoxin and its induction of the cytokines tumor necrosis factor alpha and interleukin-6
- 2019
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:2
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Tidskriftsartikel (refereegranskat)abstract
- Endotoxin, a component of the outer membrane of Gram-negative bacteria, has been extensively studied as a stimulator of the innate immune response. However, the temporal aspects and exposure-response relationship of endotoxin and resulting cytokine induction and tolerance development is less well defined. The aim of this work was to establish an in silico model that simultaneously captures and connects the in vivo time-courses of endotoxin, tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and associated tolerance development. Data from six studies of porcine endotoxemia in anesthetized piglets (n = 116) were combined and used in the analysis, with purified endotoxin (Escherichia coli O111: B4) being infused intravenously for 1-30 h in rates of 0.063-16.0 mu g/kg/h across studies. All data were modelled simultaneously by means of importance sampling in the non-linear mixed effects modelling software NONMEM. The infused endotoxin followed one-compartment disposition and non-linear elimination, and stimulated the production of TNF-alpha to describe the rapid increase in plasma concentration. Tolerance development, observed as declining TNF-alpha concentration with continued infusion of endotoxin, was also driven by endotoxin as a concentration-dependent increase in the potency parameter related to TNF-alpha production (EC50). Production of IL-6 was stimulated by both endotoxin and TNF-a, and four consecutive transit compartments described delayed increase in plasma IL-6. A model which simultaneously account for the time-courses of endotoxin and two immune response markers, the cytokines TNF-alpha and IL-6, as well as the development of endotoxin tolerance, was successfully established. This model-based approach is unique in its description of the time-courses and their interrelation and may be applied within research on immune response to bacterial endotoxin, or in pre-clinical pharmaceutical research when dealing with study design or translational aspects.
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50. |
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