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1.	Ayoun Alsoud, Rami, et al. (författare) Combined quantitative tuberculosis biomarker model for time-to-positivity and colony forming unit to support tuberculosis drug development 2023 Ingår i: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 14 Tidskriftsartikel (refereegranskat)abstract Biomarkers are quantifiable characteristics of biological processes. In Mycobacterium tuberculosis, common biomarkers used in clinical drug development are colony forming unit (CFU) and time-to-positivity (TTP) from sputum samples. This analysis aimed to develop a combined quantitative tuberculosis biomarker model for CFU and TTP biomarkers for assessing drug efficacy in early bactericidal activity studies. Daily CFU and TTP observations in 83 previously patients with uncomplicated pulmonary tuberculosis after 7 days of different rifampicin monotherapy treatments (10-40 mg/kg) from the HIGHRIF1 study were included in this analysis. The combined quantitative tuberculosis biomarker model employed the Multistate Tuberculosis Pharmacometric model linked to a rifampicin pharmacokinetic model in order to determine drug exposure-response relationships on three bacterial sub-states using both the CFU and TTP data simultaneously. CFU was predicted from the MTP model and TTP was predicted through a time-to-event approach from the TTP model, which was linked to the MTP model through the transfer of all bacterial sub-states in the MTP model to a one bacterial TTP model. The non-linear CFU-TTP relationship over time was well predicted by the final model. The combined quantitative tuberculosis biomarker model provides an efficient approach for assessing drug efficacy informed by both CFU and TTP data in early bactericidal activity studies and to describe the relationship between CFU and TTP over time.
2.	Susanto, Budi Octasari, et al. (författare) Rifampicin can be given as flat-dosing instead of weight-band dosing 2020 Ingår i: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1058-4838 .- 1537-6591. ; 71:12, s. 3055-3060 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: The weight-band dosing in tuberculosis treatment regimen has been implemented in clinical practice for decades. Patients will receive different number of fixed dose combination (FDC) tablets according to their weight-band. However, some analysis have shown that weight was not the best covariate to explain variability of rifampicin exposure. Furthermore, the rationale for using weight-band dosing instead of flat-dosing becomes questionable. Therefore, this study aimed to compare the average and the variability of rifampicin exposure after weight-band dosing and flat-dosing.METHODS: Rifampicin exposure were simulated using previously published population pharmacokinetics model at dose 10-40 mg/kg for weight-band dosing and dose 600-2400 mg for flat-dosing. The median AUC0-24h after day 7 and 14 were compared as well as the variability of each dose group between weight-band and flat-dosing.RESULTS: The difference of median AUC0-24h of all dose groups between flat-dosing and weight-band dosing were considered low (< 20%) except for the lowest dose. At the dose of 10 mg/kg (600 mg for flat-dosing), flat-dosing resulted in higher median AUC0-24h compared to the weight-band dosing. A marginal decrease in between-patient variability was predicted for weight-band dosing compared to flat-dosing.CONCLUSIONS: Weight-band dosing yields a small and non-clinically relevant decrease in variability of AUC0-24h.
3.	Svensson, Elin M., 1985-, et al. (författare) The Potential for Treatment Shortening With Higher Rifampicin Doses : Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis 2018 Ingår i: Clinical Infectious Diseases. - : OXFORD UNIV PRESS INC. - 1058-4838 .- 1537-6591. ; 67:1, s. 34-41 Tidskriftsartikel (refereegranskat)abstract Background. Tuberculosis remains a huge public health problem and the prolonged treatment duration obstructs effective tuberculosis control. Higher rifampicin doses have been associated with better bactericidal activity, but optimal dosing is uncertain. This analysis aimed to characterize the relationship between rifampicin plasma exposure and treatment response over 6 months in a recent study investigating the potential for treatment shortening with high-dose rifampicin. Methods. Data were analyzed from 336 patients with pulmonary tuberculosis (97 with pharmacokinetic data) treated with rifampicin doses of 10, 20, or 35 mg/kg. The response measure was time to stable sputum culture conversion (TSCC). We derived individual exposure metrics with a previously developed population pharmacokinetic model of rifampicin. TSCC was modeled using a parametric time-to-event approach, and a sequential exposure-response analysis was performed. Results. Higher rifampicin exposures increased the probability of early culture conversion. No maximal limit of the effect was detected within the observed range. The expected proportion of patients with stable culture conversion on liquid medium at week 8 was predicted to increase from 39% (95% confidence interval, 37%-41%) to 55% (49%-61%), with the rifampicin area under the curve increasing from 20 to 175 mg/L.h (representative for 10 and 35 mg/kg, respectively). Other predictors of TSCC were baseline bacterial load, proportion of culture results unavailable, and substitution of ethambutol for either moxifloxacin or SQ109. Conclusions. Increasing rifampicin exposure shortened TSCC, and the effect did not plateau, indicating that doses >35 mg/kg could be yet more effective. Optimizing rifampicin dosage while preventing toxicity is a clinical priority.
4.	Svensson, Robin J., et al. (författare) Greater Early Bactericidal Activity at Higher Rifampicin Doses Revealed by Modeling and Clinical Trial Simulations 2018 Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 218:6, s. 991-999 Tidskriftsartikel (refereegranskat)abstract Background. The currently recommended rifampicin dose (10 mg/kg) for treating tuberculosis is suboptimal. The PanACEA HIGHRIF1 trial evaluated the pharmacokinetics and early bactericidal activity of rifampicin doses of up to 40 mg/kg. Conventional statistical analyses revealed no significant exposure-response relationship. Our objectives were to explore the exposure-response relationship for high-dose rifampicin by using pharmacokinetic-pharmacodynamic modeling and to predict the early bactericidal activity of 50 mg/kg rifampicin.Methods. Data included time to Mycobacterium tuberculosis positivity of liquid cultures of sputum specimens from 83 patients with tuberculosis who were treated with 10 mg/kg rifampicin (n = 8; reference arm) or 20, 25, 30, 35, or 40 mg/kg rifampicin (n = 15/arm) for 7 days. We used a semimechanistic time-to-event approach to model the time-to-positivity data. Rifampicin exposure and baseline time to culture positivity were explored as covariates.Results. The baseline time to culture positivity was a significant covariate on the predicted initial bacterial load, and rifampicin exposure was a significant covariate on the bacterial kill rate in sputum resulting in increased early bactericidal activity. The 90% prediction interval for the predicted median day 7 increase in time to positivity for 50 mg/kg rifampicin was 7.25-10.3 days.Conclusions. A significant exposure-response relationship was found between rifampicin exposure and early bactericidal activity. Clinical trial simulations showed greater early bactericidal activity for 50 mg/kg rifampicin.
5.	Abdelwahab, Mahmoud Tareq, et al. (författare) Clofazimine pharmacokinetics in patients with TB : dosing implications 2020 Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 75:11, s. 3269-3277 Tidskriftsartikel (refereegranskat)abstract Background: Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization. Objectives: To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients. Patients and methods: Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-Linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L. Results: We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a Loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant. Conclusions: Clofazimine was widely distributed with a Long elimination half-Life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.
6.	Abdelwahab, Mahmoud Tareq, et al. (författare) Effect of Clofazimine Concentration on QT Prolongation in Patients Treated for Tuberculosis 2021 Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 65:7 Tidskriftsartikel (refereegranskat)abstract Clofazimine is classified as a WHO group B drug for the treatment of rifampin-resistant tuberculosis. QT prolongation, which is associated with fatal cardiac arrhythmias, is caused by several antitubercular drugs, including clofazimine, but there are no data quantifying the effect of clofazimine concentration on QT prolongation. Our objective was to describe the effect of clofazimine exposure on QT prolongation. Fifteen adults drug-susceptible tuberculosis patients received clofazimine monotherapy as 300mg daily for 3 days, followed by 100mg daily in one arm of a 2-week, multiarm early bactericidal activity trial in South Africa. Pretreatment Fridericia-corrected QT (QTcF) (105 patients, 524 electrocardiograms [ECGs]) and QTcFs from the clofazimine monotherapy arm matched with clofazimine plasma concentrations (199 ECGs) were interpreted with a nonlinear mixed-effects model. Clofazimine was associated with significant QT prolongation described by a maximum effect (Emax) function. We predicted clofazimine exposures using 100-mg daily doses and 2 weeks of loading with 200 and 300mg daily, respectively. The expected proportions of patients with QTcF change from baseline above 30 ms (DQTcF. 30) were 2.52%, 11.6%, and 23.0% for 100-, 200-, and 300-mg daily doses, respectively. At steady state, the expected proportion with Delta QTcF of >30 ms was 23.7% and with absolute QTcF of >450 ms was 3.42% for all simulated regimens. The use of loading doses of 200 and 300mg is not predicted to expose patients to an increased risk of QT prolongation, compared with the current standard treatment, and is, therefore, an alternative option for more quickly achieving therapeutic concentrations.
7.	Abulfathi, Ahmed Aliyu, et al. (författare) Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis 2019 Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 58:9, s. 1103-1129 Forskningsöversikt (refereegranskat)abstract The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6months when combined with pyrazinamide in the first 2months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600mg (8-12mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of >= 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600mg. Rifampicin maximum (peak) concentration (C-max) > 8.2 mu g/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of >= 8 mu g/mL. A higher rifampicin C-max is required for severe forms TB such as TB meningitis, with C-max >= 22 mu g/mL and area under the concentration-time curve (AUC) from time zero to 6h (AUC(6)) >= 70 mu g.h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35mg/kg were found to be safe and well-tolerated over a period of 12weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as C-max/MIC (minimum inhibitory concentration) and AUC/MIC.
8.	Abulfathi, Ahmed A., et al. (författare) Pharmacometrics - tools to assure optimal medicine use in low- and middle-income countries : Editorial 2022 Ingår i: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 13 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
9.	Abulfathi, Ahmed A., et al. (författare) Probability of mycobactericidal activity of para-aminosalicylic acid with novel dosing regimens 2020 Ingår i: European Journal of Clinical Pharmacology. - : Springer Nature. - 0031-6970 .- 1432-1041. ; 76:11, s. 1557-1565 Tidskriftsartikel (refereegranskat)abstract Purpose Para-aminosalicylic acid (PAS) is currently one of the add-on group C medicines recommended by the World Health Organization for multidrug-resistant tuberculosis treatment. At the recommended doses (8-12 g per day in two to three divided doses) of the widely available slow-release PAS formulation, studies suggest PAS exposures are lower than those reached with older PAS salt formulations and do not generate bactericidal activity. Understanding the PASER dose-exposure-response relationship is crucial for dose optimization. The objective of our study was to establish a representative population pharmacokinetics model for PASER and evaluate the probability of bactericidal and bacteriostatic target attainment with different dosing regimens.Methods To this end, we validated and optimized a previously published population pharmacokinetic model on an extended dataset. The probability of target attainment was evaluated for once-daily doses of 12 g, 14 g, 16 g and 20 g PASER. Results The final optimized model included the addition of variability in bioavailability and allometric scaling with body weight on disposition parameters. Peak PAS concentrations over minimum inhibitory concentration of 100, which is required for bactericidal activity are achieved in 53%, 65%, 72% and 84% of patients administered 12, 14, 16 and 20 g once-daily PASER, respectively, when MIC is 1 mg/L. For the typical individual, the exposure remained above 1 mg/L for >= 98% of the dosing interval in all the evaluated PASER regimens.Conclusion The pharmacokinetic/pharmacodynamic parameters linked to bactericidal activity should be determined for 14 g, 16 g and 20 g once-daily doses of PASER.
10.	Abulfathi, Ahmed A., et al. (författare) The pharmacokinetics of para-aminosalicylic acid and its relationship to efficacy and intolerance 2020 Ingår i: British Journal of Clinical Pharmacology. - : WILEY. - 0306-5251 .- 1365-2125. ; 86:11, s. 2123-2132 Forskningsöversikt (refereegranskat)abstract Following its introduction as an antituberculosis agent close to 75 years ago, the use of para-aminosalicylic acid (PAS) has been limited by gastrointestinal intolerance and multiple formulations were produced in attempts to reduce its occurrence. More recently, an enteric-coated, granular, slow-release PAS formulation (PASER) was introduced and is now in wide-spread use for the treatment of drug-resistant tuberculosis. The current PASER dosing regimen is based on recommendations derived from older studies using a variety of different PAS formulations and relegate PAS to a role as an exclusively bacteriostatic agent. However, there is ample evidence that if sufficiently high serum concentrations are reached, PAS can be bactericidal and that intolerance following once daily dosing, that aids the achievement of such concentrations, is no worse than that following intermittent daily dosing. In particular, prevention of resistance to companion drugs appears to be dependent on the size of the single dose, and hence the peak concentrations, and not on maintaining serum levels consistently above minimum inhibitory concentration. We present a narrative review of the development of PAS formulations, dosing practices, and published data regarding pharmacokinetics and pharmacodynamics and the relationship of PAS dosage to intolerance and efficacy. Our conclusions suggests that we are at present not using PAS to its maximum ability to contribute to regimen efficacy and protect companion drugs.
11.	Abulfathi, Ahmed A., et al. (författare) The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis 2021 Ingår i: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 12 Tidskriftsartikel (refereegranskat)abstract Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability.Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5-1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise.Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified.Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.
12.	Alffenaar, J. W. C., et al. (författare) Clinical standards for the dosing and management of TB drugs 2022 Ingår i: The International Journal of Tuberculosis and Lung Disease. - Paris, France : International Union Against Tuberculosis and Lung Disease. - 1027-3719 .- 1815-7920. ; 26:6, s. 483- Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract Background: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice' for dosing and management of TB drugs.Methods: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.Results: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.Conclusion: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.
13.	Badr, Sara, 1985, et al. (författare) Combined basic and fine chemical biorefinery concepts with integration of processes at different technology readiness levels 2018 Ingår i: Computer Aided Chemical Engineering. - 1570-7946. ; 43, s. 1577-1582 Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract Biorefineries offer promising alternatives to the use of fossil fuels to produce energy and chemicals. This work describes the development of a biorefinery concept to produce adipic acid from Swedish forest residues and lutein from micro-algae. A description is provided for each process line available, its technology readiness level (TRL) and the tools available to model it. Scenarios of the integrated concept are built with associated material flow analysis. Key results of the material inventory of the base case scenario are presented as well as insights into the development of further scenarios. Material flow inventories can then be further used for economic and environmental assessment. Major challenges of integration are discussed in terms of uncertainties and data gaps for processes with low TRL such as scaling up lab experiments, understanding the restrictions of material recycling and its impact on process performance. The feedback given through these scenarios can help guide further experimental efforts.
14.	Badr, Sara, 1985, et al. (författare) Prospective analysis of an intergrated biorefinery concept for the production of balk and fine chemicals 2018 Ingår i: 23rd International Congress of Chemical and Process Engineering, CHISA 2018 and 21st Conference on Process Integration, Modelling and Optimisation for Energy Saving and Pollution Reduction, PRES 2018. ; 2, s. 737- Konferensbidrag (refereegranskat)
15.	Bukkems, Vera E., et al. (författare) A population pharmacokinetics analysis assessing the exposure of raltegravir once-daily 1200 mg in pregnant women living with HIV 2021 Ingår i: CPT. - : John Wiley & Sons. - 2163-8306. ; 10:2, s. 161-172 Tidskriftsartikel (refereegranskat)abstract Once-daily two 600 mg tablets (1200 mg q.d.) raltegravir offers an easier treatment option compared to the twice-daily regimen of one 400 mg tablet. No pharmacokinetic, efficacy, or safety data of the 1200 mg q.d. regimen have been reported in pregnant women to date as it is challenging to collect these clinical data. This study aimed to develop a population pharmacokinetic (PopPK) model to predict the pharmacokinetic profile of raltegravir 1200 mg q.d. in pregnant women and to discuss the expected pharmacodynamic properties of raltegravir 1200 mg q.d. during pregnancy based on previously reported concentration-effect relationships. Data from 11 pharmacokinetic studies were pooled (n = 221). A two-compartment model with first-order elimination and absorption through three sequential transit compartments best described the data. We assessed that the bio-availability of the 600 mg tablets was 21% higher as the 400 mg tablets, and the bio-availability in pregnant women was 49% lower. Monte-Carlo simulations were performed to predict the pharmacokinetic profile of 1200 mg q.d. in pregnant and nonpregnant women. The primary criteria for efficacy were that the lower bound of the 90% confidence interval (CI) of the concentration before next dose administration (C-trough) geometric mean ratio (GMR) of simulated pregnant/nonpregnant women had to be greater than 0.75. The simulated raltegravir C-trough GMR (90% CI) was 0.51 (0.41-0.63), hence not meeting the primary target for efficacy. Clinical data from two pregnant women using 1200 mg q.d. raltegravir showed a similar C-trough ratio pregnant/nonpregnant. Our pharmacokinetic results support the current recommendation of not using the raltegravir 1200 mg q.d. regimen during pregnancy until more data on the exposure-response relationship becomes available.
16.	Bukkems, V. E., et al. (författare) Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments 2022 Ingår i: Clinical Pharmacokinetics. - : Springer Nature. - 0312-5963 .- 1179-1926. ; 61:8, s. 1129-1141 Tidskriftsartikel (refereegranskat)abstract Background and Objective Doravirine is currently not recommended for pregnant women living with human immunodeficiency virus because efficacy and safety data are lacking. This study aimed to predict maternal and fetal doravirine exposure by integrating human placenta perfusion experiments with pregnancy physiologically based pharmacokinetic (PBPK) modeling.Methods Ex vivo placenta perfusions were performed in a closed-closed configuration, in both maternal-to-fetal and fetal-to-maternal directions (n = 8). To derive intrinsic placental transfer parameters from perfusion data, we developed a mechanistic placenta model. Next, we developed a maternal and fetal full-body pregnancy PBPK model for doravirine in Simcyp, which was parameterized with the derived intrinsic placental transfer parameters to predict in vivo maternal and fetal doravirine exposure at 26, 32, and 40 weeks of pregnancy. The predicted total geometric mean (GM) trough plasma concentration (C-trough) values were compared with the target (0.23 mg/L) derived from in vivo exposure-response analysis.Results A decrease of 55% in maternal doravirine area under the plasma concentration-time curve (AUC)(0-24h) was predicted in pregnant women at 40 weeks of pregnancy compared with nonpregnant women. At 26, 32, and 40 weeks of pregnancy, predicted maternal total doravirine GM C-trough values were below the predefined efficacy target of 0.23 mg/L. Perfusion experiments showed that doravirine extensively crossed the placenta, and PBPK modeling predicted considerable fetal doravirine exposure.Conclusion Substantially reduced maternal doravirine exposure was predicted during pregnancy, possibly resulting in impaired efficacy. Therapeutic drug and viral load monitoring are advised for pregnant women treated with doravirine. Considerable fetal doravirine exposure was predicted, highlighting the need for clinical fetal safety data.
17.	Cresswell, Fiona, V, et al. (författare) High-Dose Oral and Intravenous Rifampicin for the Treatment of Tuberculous Meningitis in Predominantly Human Immunodeficiency Virus (HIV)-Positive Ugandan Adults : A Phase II Open-Label Randomized Controlled Trial 2021 Ingår i: Clinical Infectious Diseases. - : Oxford University Press. - 1058-4838 .- 1537-6591. ; 73:5, s. 876-884 Tidskriftsartikel (refereegranskat)abstract Background: High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in human immunodeficiency virus (HIV) coinfection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. Methods: In this phase II open-label trial, Ugandan adults with suspected TBM were randomized to standard-of-care control (PO-10, rifampicin 10 mg/kg/day), intravenous rifampicin (IV-20, 20 mg/kg/day), or high-dose oral rifampicin (PO-35, 35 mg/kg/day). We performed PK sampling on days 2 and 14. The primary outcomes were total exposure (AUC(0-24)), maximum concentration (C-max), CSF concentration, and grade 3-5 adverse events. Results: We enrolled 61 adults, 92% were living with HIV, median CD4 count was 50 cells/mu L (interquartile range [IQR] 46-56). On day 2, geometric mean plasma AUC(0-24hr) was 42.9.h mg/L with standard-of-care 10 mg/kg dosing, 249.h mg/L for IV-20 and 327.h mg/L for PO-35 (P<.001). In CSF, standard of care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC(0-24hr) 0.27 mg/L, compared with 1.74 mg/L (95% confidence interval [CI] 1.2-2.5) for IV-20 and 2.17 mg/L (1.6-2.9) for PO-35 regimens (P<.001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (P=.34). Conclusions: Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe and respectively resulted in exposures similar to 6- and similar to 8-fold higher than standard of care, and CSF levels above the MIC.
18.	Danho, Rabi, et al. (författare) Mycobacterium Growth Indicator Tube Time-To-Positivity Can Serve As an Early Biomarker of Treatment Response in Mycobacterium avium Complex Pulmonary Disease 2022 Ingår i: Chest. - : Elsevier. - 0012-3692 .- 1931-3543. ; 161:2, s. 370-372 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
19.	De Jager, Veronique, et al. (författare) Early Bactericidal Activity of Meropenem plus Clavulanate (with or without Rifampin) for Tuberculosis : The COMRADE Randomized, Phase 2A Clinical Trial 2022 Ingår i: American Journal of Respiratory and Critical Care Medicine. - : American Thoracic Society. - 1073-449X .- 1535-4970. ; 205:10, s. 1228-1235 Tidskriftsartikel (refereegranskat)abstract Rationale: Carbapenems are recommended for treatment of drug-resistant tuberculosis. Optimal dosing remains uncertain.Objectives: To evaluate the 14-day bactericidal activity of meropenem, at different doses, with or without rifampin.Methods: Individuals with drug-sensitive pulmonary tuberculosis were randomized to one of four intravenous meropenem-based arms: 2 g every 8 hours (TID) (arm C), 2 g TID plus rifampin at 20 mg/kg once daily (arm D), 1 g TID (arm E), or 3 g once daily (arm F). All participants received amoxicillin/clavulanate with each meropenem dose. Serial overnight sputum samples were collected from baseline and throughout treatment. Median daily fall in colony-forming unit (CFU) counts per milliliter of sputum (solid culture) (EBA(CFU0-14)) and increase in time to positive culture (TTP) in liquid media were estimated with mixed-effects modeling. Serial blood samples were collected for pharmacokinetic analysis on Day 13.Measurements and Main Results: Sixty participants enrolled. Median EBA(CFU0-14) counts (2.5th-97.5th percentiles) were 0.22 (0.12-0.33), 0.12 (0.057-0.21), 0.059 (0.033-0.097), and 0.053 (0.035-0.081); TTP increased by 0.34 (0.21-0.75), 0.11 (0.052-037), 0.094 (0.034-0.23), and 0.12 (0.04-0.41) (log(10) h), for arms C-F, respectively. Meropenem pharmacokinetics were not affected by rifampin coadministration. Twelve participants withdrew early, many of whom cited gastrointestinal adverse events.Conclusions: Bactericidal activity was greater with the World Health Organization-recommended total daily dose of 6 g daily than with a lower dose of 3 g daily. This difference was only detectable with solid culture. Tolerability of intravenous meropenem, with amoxicillin/clavulanate, though, was poor at all doses, calling into question the utility of this drug in second-line regimens.
20.	de Rouw, Nikki, et al. (författare) Rethinking the Application of Pemetrexed for Patients with Renal Impairment : A Pharmacokinetic Analysis 2021 Ingår i: Clinical Pharmacokinetics. - : ADIS INT LTD. - 0312-5963 .- 1179-1926. ; 60:5, s. 649-654 Tidskriftsartikel (refereegranskat)abstract Background Pemetrexed is used for the treatment for non-small cell lung cancer and mesothelioma. Patients with renal impairment are withheld treatment with this drug as it is unknown what dose is well tolerated in this population. Objective The purpose of our study was to investigate the pharmacokinetics (PK) of pemetrexed in patients with renal impairment. Methods A population PK analysis of pemetrexed was performed using non-linear mixed-effects modelling with phase I data obtained from the manufacturer. Additionally, the impact of renal function on pemetrexed PK was assessed with a simulation study using the developed PK model and a previously developed PK model lacking the phase I data. Results The dataset included 548 paired observations of 47 patients, with a wide range of estimated glomerular filtration rates (eGFR; 14.4-145.6 mL/min). Pemetrexed PK were best described by a three-compartment model with eGFR (calculated using the Chronic Kidney Disease-Epidemiology Collaboration [CKD-EPI] formula) as a linear covariate on renal pemetrexed clearance. Using the developed model, we found that renal clearance accounts for up to 84% (95% confidence interval 69-98%) of total pemetrexed clearance, whereas the manufacturer previously reported a 50% contribution of renal clearance. Conclusion Renal function is more important for the clearance of pemetrexed than previously thought and this should be taken into account in patients with renal impairment. Furthermore, a third compartment may contribute to prolonged exposure to pemetrexed during drug washout.
21.	Denti, Paolo, et al. (författare) Optimizing Dosing and Fixed-Dose Combinations of Rifampicin, Isoniazid, and Pyrazinamide in Pediatric Patients With Tuberculosis : A Prospective Population Pharmacokinetic Study 2022 Ingår i: Clinical Infectious Diseases. - : OXFORD UNIV PRESS INC. - 1058-4838 .- 1537-6591. ; 75:1, s. 141-151 Tidskriftsartikel (refereegranskat)abstract Background In 2010, the World Health Organization (WHO) revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis drug exposures under these guidelines, explore dose optimization using the current dispersible fixed-dose combination (FDC) tablet of rifampicin/isoniazid/pyrazinamide; 75/50/150 mg, and suggest a new FDC with revised weight bands. Methods Children with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modeling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC(0-24h) for rifampicin (38.7-72.9), isoniazid (11.6-26.3), and pyrazinamide (233-429 mg center dot h/L). Results In total, 180 children (42% female; 13.9% living with human immunodeficiency virus [HIV]; median [range] age 1.9 [0.22-12] years; weight 10.7 [3.20-28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) daily for 4-8, 8-12, 12-16, and 16-25 kg weight bands, respectively. Rifampicin exposure (for weight and age) was up to 50% lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130 mg) to children < 6, 6-13, 13-20. and 20-25 kg, and 0.5 tablet in < 3-month-olds with immature metabolism, improved exposures to all 3 drugs. Conclusions Current pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. We propose a new FDC formulation and revised weight bands. Current pediatric dosing guidelines lead to infant rifampicin exposures much lower than in adults, whereas isoniazid and pyrazinamide exposures are similar. A new fixed-dose combination (FDC) with rifampicin/isoniazid/pyrazinamide 120/35/130 mg and weight bands of < 6, 6-13, 13-20, and 20-25 kg could improve treatment.
22.	Diaz, Jessica M. Aguilar, et al. (författare) New and Repurposed Drugs for the Treatment of Active Tuberculosis : An Update for Clinicians 2023 Ingår i: Respiration. - : S. Karger. - 0025-7931 .- 1423-0356. ; 102:2, s. 83-100 Forskningsöversikt (refereegranskat)abstract Although tuberculosis (TB) is preventable and curable, the lengthy treatment (generally 6 months), poor patient adherence, high inter-individual variability in pharmacokinetics (PK), emergence of drug resistance, presence of comorbidities, and adverse drug reactions complicate TB therapy and drive the need for new drugs and/or regimens. Hence, new compounds are being developed, available drugs are repurposed, and the dosing of existing drugs is optimized, resulting in the largest drug development portfolio in TB history. This review highlights a selection of clinically available drug candidates that could be part of future TB regimens, including bedaquiline, delamanid, pretomanid, linezolid, clofazimine, optimized (high dose) rifampicin, rifapentine, and para-aminosalicylic acid. The review covers drug development history, preclinical data, PK, and current clinical development.
23.	Dierig, A., et al. (författare) A phase IIb, open-label, randomized controlled dose ranging multi-centre trial to evaluate the safety, tolerability, pharmacokinetics and exposure-response relationship of different doses of delpazolid in combination with bedaquiline delamanid moxifloxacin in adult subjects with newly diagnosed, uncomplicated, smear-positive, drug-sensitive pulmonary tuberculosis 2023 Ingår i: Trials. - : BMC. - 1745-6215. ; 24:1 Tidskriftsartikel (refereegranskat)abstract Background: Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure-response and exposure-toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin.Methods: Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course.Discussion: DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages.
24.	Gafar, Fajri, et al. (författare) Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents : a systematic review and individual patient data meta-analysis 2023 Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 61:3 Forskningsöversikt (refereegranskat)abstract Background Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level.Methods We systematically searched MEDLINE, Embase and Web of Science (1990–2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration–time curve from 0 to 24 h post-dose (AUC0–24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0–24 and Cmax were assessed with linear mixed-effects models.Results Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0–24 were summarised for isoniazid (18.7 (95% CI 15.5–22.6) h·mg·L−1), rifampicin (34.4 (95% CI 29.4–40.3) h·mg·L−1), pyrazinamide (375.0 (95% CI 339.9–413.7) h·mg·L−1) and ethambutol (8.0 (95% CI 6.4–10.0) h·mg·L−1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0–24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0–24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0–24 and slow acetylators had higher isoniazid AUC0–24 than intermediate acetylators. Determinants of Cmax were generally similar to those for AUC0–24.Conclusions This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.
25.	Garcia-Prats, Anthony J., et al. (författare) Children deserve simple, short, safe, and effective treatment for rifampicin-resistant tuberculosis 2023 Ingår i: The Lancet - Infectious diseases. - : Elsevier. - 1473-3099 .- 1474-4457. ; 23:7, s. 778-780 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
26.	Garcia-Prats, Anthony J., et al. (författare) Pharmacokinetics and safety of high-dose rifampicin in children with TB : the Opti-Rif trial 2021 Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 76:12, s. 3237-3246 Tidskriftsartikel (refereegranskat)abstract Background: Rifampicin doses of 40 mg/kg in adults are safe and well tolerated, may shorten anti-TB treatment and improve outcomes, but have not been evaluated in children. Objectives: To characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB. Patients and methods: The Opti-Rif trial enrolled dosing cohorts of 20 children aged 0-12 years, with incremental dose escalation with each subsequent cohort, until achievement of target exposures or safety concerns. Cohort 1 opened with a rifampicin dose of 15 mg/kg for 14 days, with a single higher dose (35 mg/kg) on day 15. Pharmacokinetic data from days 14 and 15 were analysed using population modelling and safety data reviewed. Incrementally increased rifampicin doses for the next cohort (days 1-14 and day 15) were simulated from the updated model, up to the dose expected to achieve the target exposure [235 mg/L.h, the geometric mean area under the concentration-time curve from 0 to 24h (AUC(0-24)) among adults receiving a 35mg/kg dose]. Results: Sixty-two children were enrolled in three cohorts. The median age overall was 2.1 years (range=0.4-11.7). Evaluated doses were similar to 35 mg/kg (days 1-14) and similar to 50 mg/kg (day 15) for cohort 2 and similar to 60 mg/kg (days 1-14) and similar to 75mg/kg (day 15) for cohort 3. Approximately half of participants had an adverse event related to study rifampicin; none was grade 3 or higher. A 65-70 mg/kg rifampicin dose was needed in children to reach the target exposure. Conclusions: High rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks.
27.	Haas, David W., et al. (författare) Pharmacogenetics of Between-Individual Variability in Plasma Clearance of Bedaquiline and Clofazimine in South Africa 2022 Ingår i: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 226:1, s. 147-156 Tidskriftsartikel (refereegranskat)abstract In a cohort of patients treated for drug-resistant tuberculosis in South Africa, CYP3A53was associated with slower plasma bedaquiline clearance. Different CYP3A53minor allele frequencies among populations may help explain the more rapid bedaquiline clearance previously reported with African ancestry.Background Plasma bedaquiline clearance is reportedly more rapid with African ancestry. Our objective was to determine whether genetic polymorphisms explained between-individual variability in plasma clearance of bedaquiline, its M2 metabolite, and clofazimine in a cohort of patients treated for drug-resistant tuberculosis in South Africa.Methods Plasma clearance was estimated with nonlinear mixed-effects modeling. Associations between pharmacogenetic polymorphisms, genome-wide polymorphisms, and variability in clearance were examined using linear regression models.Results Of 195 cohort participants, 140 were evaluable for genetic associations. Among 21 polymorphisms selected based on prior genome-wide significant associations with any drug, rs776746 (CYP3A53) was associated with slower clearance of bedaquiline (P = .0017) but not M2 (P = .25). CYP3A53 heterozygosity and homozygosity were associated with 15% and 30% slower bedaquiline clearance, respectively. The lowest P value for clofazimine clearance was with VKORC1 rs9923231 (P = .13). In genome-wide analyses, the lowest P values for clearance of bedaquiline and clofazimine were with RFX4 rs76345012 (P = 6.4 x 10(-7)) and CNTN5 rs75285763 (P = 2.9 x 10(-8)), respectively.Conclusions Among South Africans treated for drug-resistant tuberculosis, CYP3A53 was associated with slower bedaquiline clearance. Different CYP3A53 frequencies among populations may help explain the more rapid bedaquiline clearance reported in Africans. Associations with RFX4 and CNTN5 are likely by chance alone.
28.	Iandolo, Beniamino, 1985, et al. (författare) Tailoring Charge Recombination in Photoelectrodes Using Oxide Nanostructures 2016 Ingår i: Nano Letters. - : American Chemical Society (ACS). - 1530-6992 .- 1530-6984. ; 16:4, s. 2381-2386 Tidskriftsartikel (refereegranskat)abstract Optimizing semiconductor devices for solar energy conversion requires an explicit control of the recombination of photogenerated electron hole pairs. Here we show how the recombination of charge carriers can be controlled in semiconductor thin films by surface patterning with oxide nanodisks. The control mechanism relies on the formation of dipole-like electric fields at the interface that, depending on the field direction, attract or repel minority carriers from underneath the disks. The charge recombination rate can be controlled through the choice of oxide material and the surface coverage of nanodisks. We provide proof-of-principle demonstration of this approach by patterning the surface of Fe2O3, one of the most studied semiconductors for light-driven water splitting, with TiO2 and Cu2O nanodisks. We expect this method to be generally applicable to a range of semiconductor-based solar energy conversion devices.
29.	Jacobs, Tom G., et al. (författare) Pharmacokinetics of antiretroviral and tuberculosis drugs in children with HIV/TB co-infection : a systematic review 2020 Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 75:12, s. 3433-3457 Forskningsöversikt (refereegranskat)abstract Introduction: Management of concomitant use of ART and TB drugs is difficult because of the many drug-drug interactions (DDIs) between the medications. This systematic review provides an overview of the current state of knowledge about the pharmacokinetics (PK) of ART and TB treatment in children with HIV/TB co-infection, and identifies knowledge gaps. Methods: We searched Embase and PubMed, and systematically searched abstract books of relevant conferences, following PRISMA guidelines. Studies not reporting PK parameters, investigating medicines that are not available any Longer or not including children with HIV/TB co-infection were excluded. ALL studies were assessed for quality. Results: In total, 47 studies met the inclusion criteria. No dose adjustments are necessary for efavirenz during concomitant first-Line TB treatment use, but intersubject PK variability was high, especially in children <3 years of age. Super-boosted Lopinavir/ritonavir (ratio 1:1) resulted in adequate Lopinavir trough concentrations during rifampicin co-administration. Double-dosed raltegravir can be given with rifampicin in children >4 weeks old as well as twice-daily dolutegravir (instead of once daily) in children older than 6 years. Exposure to some TB drugs (ethambutol and rifampicin) was reduced in the setting of HIV infection, regardless of ART use. Only Limited PK data of second-Line TB drugs with ART in children who are HIV infected have been published. Conclusions: Whereas integrase inhibitors seem favourable in older children, there are Limited options for ART in young children (<3 years) receiving rifampicin-based TB therapy. The PK of TB drugs in HIV-infected children warrants further research.
30.	Janssen, Mathias, 1973, et al. (författare) Environmental assessment of a biorefinery concept for production of bulk and fine chemicals 2019 Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract Moving from a fossil-based to a bio-based economy requires the development of new technologies and process concepts for the production of bio-based energy, chemicals and materials. Biorefinery concepts can be designed by integrating such technologies in order to provide environmentally and economically attractive alternatives to produce bulk and fine chemicals. This paper presents life cycle and techno-economic assessments of a novel biorefinery concept, in its early stages of development, for the combined production of adipic acid from forest residues and of lutein from micro-algae. Adipic acid is a bulk chemical with a yearly production of approximately 2.3 million tonnes, and is primarily used for the production of nylon-6,6. Conventional adipic acid production from fossil resources causes significant emissions of N2O due to the use of nitric acid as an oxidizing agent. This conventional production can thus lead to a significant climate impact if these emissions are not sufficiently mitigated. Lutein is a high added-value chemical used in the food and pharmaceutical industries, and is conventionally produced from marigold flowers. The biorefinery concept in this work consists of the pretreatment of forest residues, the separation of lignin (which is an important by-product), and the hydrolysis and fermentation of the pretreated forest residues to adipic acid which is then separated and purified. Water, nutrients and CO2 flows from the adipic acid production can be connected to the algae production. The lutein is extracted from the micro-algae using methanol. Anaerobic digestion is used in this concept to produce biogas (another important by-product) from waste streams. The biorefinery concept thus comprises technologies that are at different technology readiness levels (TRLs), from as low as a TRL of 2 for the fermentation process, to a TRL of 9 for the anaerobic digestion process. Twelve design variants of the biorefinery concept were modelled and simulated based on experimental and literature data. These variants aimed at narrowing down uncertainties about, for instance, the performance of the fermentation process. The data and information resulting from the simulations of the design variants were used 1) to compile the life cycle inventories for the LCA of each of these variants, and to do the subsequent life cycle impact assessment, and 2) to determine the capital and operating costs in order to calculate the economic feasibility of the biorefinery design variants. The assessment of all variants provides a range for the environmental and economic performance of the biorefinery concept based on design choices and process conditions. Furthermore, scenarios for future energy systems were considered in order to assess the influence of the background system on the performance of the biorefinery concept. The results show that there is a large variation in the performance among the different design variants, where some designs can significantly improve the prospects for the bio-based adipic acid production. However, the results are strongly dependent on the foreground and background energy systems. The results provide valuable insights to industry and policy decision makers in order to guarantee an environmentally benign and economically feasible production of bulk and fine chemicals in a biorefinery.
31.	Janssen, Mathias, 1973, et al. (författare) Prospective LCA of a biorefinery concept for production of bulk and fine chemicals 2018 Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract The move from a fossil-based to a bio-based economy requires the development of new technologies and process concepts for the production of bio-based energy, chemicals and materials. A biorefinery concept can be designed by integrating such technologies, and can thus provide a viable alternative to produce bulk and fine chemicals. This paper presents a prospective life cycle assessment (LCA) of a novel biorefinery concept, in its early stages of development, for the combined production of adipic acid from forest residues (GROT) and of lutein from micro-algae. Adipic acid is a high-volume chemical (yearly production of approx. 2.3 million tonnes) and is primarily used for the production of nylon-6,6. Conventional adipic acid production from fossil resources is characterized by significant emissions of N2O. Lutein is a high added-value chemical used in the food and pharmaceutical industries, and is conventionally produced from marigold flowers. Furthermore, lignin is an important by-product. The biorefinery concept in this work consists of the pretreatment of GROT, the separation of lignin, and the hydrolysis and fermentation of the pretreated GROT to adipic acid which is then separated and purified. Water, nutrients and CO2 flows from the adipic acid production can be connected to the algae production. Anaerobic digestion is used in this concept to produce biogas from waste streams. Multiple design variants of the biorefinery concept, which is the foreground system, were modelled and simulated based on both experimental and literature data. These variants aimed at narrowing down uncertainties about, for instance, the most suitable GROT pretreatment options, available technologies for anaerobic digestion, and possible routes for further processing of lignin. The data and information resulting from the simulations of the design variants were used to compile the life cycle inventories of each of these variants. The assessment of these variants provides a range for the future environmental performance of the biorefinery concept based on design choices and process conditions. Furthermore, scenarios for future energy systems were considered in order to assess the influence of the background system on the environmental performance of the biorefinery concept. The results provide more relevant information and valuable insight to industry and policy decision makers in order to guarantee an environmentally benign future production of bulk and fine chemicals.
32.	Keutzer, Lina, et al. (författare) Machine Learning and Pharmacometrics for Prediction of Pharmacokinetic Data : Differences, Similarities and Challenges Illustrated with Rifampicin 2022 Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 14:8 Tidskriftsartikel (refereegranskat)abstract Pharmacometrics (PM) and machine learning (ML) are both valuable for drug development to characterize pharmacokinetics (PK) and pharmacodynamics (PD). Pharmacokinetic/pharmacodynamic (PKPD) analysis using PM provides mechanistic insight into biological processes but is time- and labor-intensive. In contrast, ML models are much quicker trained, but offer less mechanistic insights. The opportunity of using ML predictions of drug PK as input for a PKPD model could strongly accelerate analysis efforts. Here exemplified by rifampicin, a widely used antibiotic, we explore the ability of different ML algorithms to predict drug PK. Based on simulated data, we trained linear regressions (LASSO), Gradient Boosting Machines, XGBoost and Random Forest to predict the plasma concentration-time series and rifampicin area under the concentration-versus-time curve from 0-24 h (AUC(0-24h)) after repeated dosing. XGBoost performed best for prediction of the entire PK series (R-2: 0.84, root mean square error (RMSE): 6.9 mg/L, mean absolute error (MAE): 4.0 mg/L) for the scenario with the largest data size. For AUC(0-24h) prediction, LASSO showed the highest performance (R-2: 0.97, RMSE: 29.1 h center dot mg/L, MAE: 18.8 h center dot mg/L). Increasing the number of plasma concentrations per patient (0, 2 or 6 concentrations per occasion) improved model performance. For example, for AUC(0-24h) prediction using LASSO, the R-2 was 0.41, 0.69 and 0.97 when using predictors only (no plasma concentrations), 2 or 6 plasma concentrations per occasion as input, respectively. Run times for the ML models ranged from 1.0 s to 8 min, while the run time for the PM model was more than 3 h. Furthermore, building a PM model is more time- and labor-intensive compared with ML. ML predictions of drug PK could thus be used as input into a PKPD model, enabling time-efficient analysis.
33.	Koele, Simon E., et al. (författare) Early bactericidal activity studies for pulmonary tuberculosis : A systematic review of methodological aspects 2023 Ingår i: International Journal of Antimicrobial Agents. - : Elsevier. - 0924-8579 .- 1872-7913. ; 61:5 Forskningsöversikt (refereegranskat)abstract A milestone in the development of novel antituberculosis drugs is the demonstration of early bactericidal activity (EBA) in a phase IIa clinical trial. The significant variability in measurements of bacterial load complicates data analysis in these trials.A systematic review and evaluation of methods for determination of EBA in pulmonary tuberculosis studies was undertaken. Bacterial load quantification biomarkers, reporting intervals, calculation methods, statistical testing, and handling of negative culture results were extracted. In total, 79 studies were identi-fied in which EBA was determined. Colony-forming units on solid culture media and/or time-to-positivity in liquid media were the biomarkers used most often, reported in 72 (91%) and 34 (43%) studies, respec-tively. Twenty-two different reporting intervals were presented, and 12 different calculation methods for EBA were identified. Statistical testing for a significant EBA compared with no change was performed in 54 (68%) studies, and between-group testing was performed in 32 (41%) studies. Negative culture result handling was discussed in 34 (43%) studies.Notable variation was found in the analysis methods and reporting of EBA studies. A standardized and clearly reported analysis method, accounting for different levels of variability in the data, could aid the generalization of study results and facilitate comparison between drugs/regimens.
34.	Koele, Simon E., et al. (författare) Optimized Loading Dose Strategies for Bedaquiline When Restarting Interrupted Drug-Resistant Tuberculosis Treatment 2022 Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 66:3 Tidskriftsartikel (refereegranskat)abstract Interruption of treatment is common in drug-resistant tuberculosis patients. Bedaquiline has a long terminal half-life; therefore, restarting after an interruption without a loading dose could increase the risk of suboptimal treatment outcome and resistance development. Interruption of treatment is common in drug-resistant tuberculosis patients. Bedaquiline has a long terminal half-life; therefore, restarting after an interruption without a loading dose could increase the risk of suboptimal treatment outcome and resistance development. We aimed to identify the most suitable loading dose strategies for bedaquiline restart after an interruption. A model-based simulation study was performed. Pharmacokinetic profiles of bedaquiline and its metabolite M2 (associated with QT prolongation) were simulated for 5,000 virtual patients for different durations and starting points of treatment interruption. Weekly bedaquiline area under the concentration-time curve (AUC) and M2 maximum concentration (C-max) deviation before interruption and after reloading were assessed to evaluate the efficacy and safety, respectively, of the reloading strategies. Bedaquiline weekly AUC and M2 C-max deviation were mainly driven by the duration of interruption and only marginally by the starting point of interruption. For interruptions with a duration shorter than 2 weeks, no new loading dose is needed. For interruptions with durations between 2 weeks and 1 month, 1 month and 1 year, and longer than 1 year, reloading periods of 3 days, 1 week, and 2 weeks, respectively, are recommended. This reloading strategy results in an average bedaquiline AUC deviation of 1.88% to 5.98% compared with -16.4% to -59.8% without reloading for interruptions of 2 weeks and 1 year, respectively, without increasing M2 C-max. This study presents easy-to-implement reloading strategies for restarting a patient on bedaquiline treatment after an interruption.
35.	Koele, Simon E, et al. (författare) Power to identify exposure-response relationships in phase IIa pulmonary tuberculosis trials with multi-dimensional bacterial load modeling. 2023 Ingår i: CPT. - 2163-8306. Tidskriftsartikel (refereegranskat)abstract Adequate power to identify an exposure-response relationship in a phase IIa clinical trial for pulmonary tuberculosis (TB) is important for dose selection and design of follow-up studies. Currently, it is not known what response marker provides the pharmacokinetic-pharmacodynamic (PK-PD) model more power to identify an exposure-response relationship. We simulated colony-forming units (CFU) and time-to-positivity (TTP) measurements for four hypothetical drugs with different activity profiles for 14 days. The power to identify exposure-response relationships when analyzing CFU, TTP, or combined CFU + TTP data was determined at 60 total participants, or with 25 out of 60 participants in the lowest and highest dosing groups (unbalanced design). For drugs with moderate bactericidal activity, power was low (<59%), irrespective of the data analyzed. Power was 1.9% to 29.4% higher when analyzing TTP data compared to CFU data. Combined analysis of CFU and TTP further improved the power, on average by 4.2%. For a drug with a medium-high activity, the total sample size needed to achieve 80% power was 136 for CFU, 72 for TTP, and 68 for combined CFU + TTP data. The unbalanced design improved the power by 16% over the balanced design. In conclusion, the power to identify an exposure-response relationship is low for TB drugs with moderate bactericidal activity or with a slow onset of activity. TTP provides the PK-PD model with more power to identify exposure-response relationships compared to CFU, and combined analysis or an unbalanced dosing group study design offers modest further improvement.
36.	Litjens, Carlijn H. C., et al. (författare) Physiologically-Based Pharmacokinetic Modelling to Predict the Pharmacokinetics and Pharmacodynamics of Linezolid in Adults and Children with Tuberculous Meningitis 2023 Ingår i: Antibiotics. - : MDPI. - 2079-6382. ; 12:4 Tidskriftsartikel (refereegranskat)abstract Linezolid is used off-label for treatment of central nervous system infections. However, its pharmacokinetics and target attainment in cranial cerebrospinal fluid (CSF) in tuberculous meningitis patients is unknown. This study aimed to predict linezolid cranial CSF concentrations and assess attainment of pharmacodynamic (PD) thresholds (AUC:MIC of >119) in plasma and cranial CSF of adults and children with tuberculous meningitis. A physiologically based pharmacokinetic (PBPK) model was developed to predict linezolid cranial CSF profiles based on reported plasma concentrations. Simulated steady-state PK curves in plasma and cranial CSF after linezolid doses of 300 mg BID, 600 mg BID, and 1200 mg QD in adults resulted in geometric mean AUC:MIC ratios in plasma of 118, 281, and 262 and mean cranial CSF AUC:MIC ratios of 74, 181, and 166, respectively. In children using similar to 10 mg/kg BID linezolid, AUC:MIC values at steady-state in plasma and cranial CSF were 202 and 135, respectively. Our model predicts that 1200 mg per day in adults, either 600 mg BID or 1200 mg QD, results in reasonable (87%) target attainment in cranial CSF. Target attainment in our simulated paediatric population was moderate (56% in cranial CSF). Our PBPK model can support linezolid dose optimization efforts by simulating target attainment close to the site of TBM disease.
37.	Litjens, Carlijn H. C., et al. (författare) Prediction of Moxifloxacin Concentrations in Tuberculosis Patient Populations by Physiologically Based Pharmacokinetic Modeling 2022 Ingår i: Journal of clinical pharmacology. - : John Wiley & Sons. - 0091-2700 .- 1552-4604. ; 62:3, s. 385-396 Tidskriftsartikel (refereegranskat)abstract Moxifloxacin has an important role in the treatment of tuberculosis (TB). Unfortunately, coadministration with the cornerstone TB drug rifampicin results in suboptimal plasma exposure. We aimed to gain insight into the moxifloxacin pharmacokinetics and the interaction with rifampicin. Moreover, we provided a mechanistic framework to understand moxifloxacin pharmacokinetics. We developed a physiologically based pharmacokinetic model in Simcyp version 19, with available and newly generated in vitro and in vivo data, to estimate pharmacokinetic parameters of moxifloxacin alone and when administered with rifampicin. By combining these strategies, we illustrate that the role of P-glycoprotein in moxifloxacin transport is limited and implicate MRP2 as transporter of moxifloxacin-glucuronide followed by rapid hydrolysis in the gut. Simulations of multiple dose area under the plasma concentration-time curve (AUC) of moxifloxacin (400 mg once daily) with and without rifampicin (600 mg once daily) were in accordance with clinically observed data (predicted/observed [P/O] ratio of 0.87 and 0.80, respectively). Importantly, increasing the moxifloxacin dose to 600 mg restored the plasma exposure both in actual patients with TB as well as in our simulations. Furthermore, we extrapolated the single dose model to pediatric populations (P/O AUC ratios, 1.04-1.52) and the multiple dose model to children with TB (P/O AUC ratio, 1.51). In conclusion, our combined approach resulted in new insights into moxifloxacin pharmacokinetics and accurate simulations of moxifloxacin exposure with and without rifampicin. Finally, various knowledge gaps were identified, which may be considered as avenues for further physiologically based pharmacokinetic refinement.
38.	Litjens, Carlijn H. C., et al. (författare) Protein binding of rifampicin is not saturated when using high-dose rifampicin 2019 Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 74:4, s. 986-990 Tidskriftsartikel (refereegranskat)abstract Background Higher doses of rifampicin are being investigated as a means to optimize response to this pivotal TB drug. It is unknown whether high-dose rifampicin results in saturation of plasma protein binding and a relative increase in protein-unbound (active) drug concentrations. Objectives To assess the free fraction of rifampicin based on an in vitro experiment and data from a clinical trial on high-dose rifampicin. Methods Protein-unbound rifampicin concentrations were measured in human serum spiked with increasing total concentrations (up to 64mg/L) of rifampicin and in samples obtained by intensive pharmacokinetic sampling of patients who used standard (10mg/kg daily) or high-dose (35mg/kg) rifampicin up to steady-state. The performance of total AUC(0-24) to predict unbound AUC(0-24) was evaluated. Results The in vitro free fraction of rifampicin remained unaltered (approximate to 9%) up to 21mg/L and increased up to 13% at 41mg/L and 17% at 64mg/L rifampicin. The highest (peak) concentration in vivo was 39.1mg/L (high-dose group). The arithmetic mean percentage unbound to total AUC(0-24)in vivo was 13.3% (range=8.1%-24.9%) and 11.1% (range=8.6%-13.6%) for the standard group and the high-dose group, respectively (P=0.214). Prediction of unbound AUC(0-24) based on total AUC(0-24) resulted in a bias of -0.05% and an imprecision of 13.2%. Conclusions Plasma protein binding of rifampicin can become saturated, but exposures after high-dose rifampicin are not high enough to increase the free fraction in TB patients with normal albumin values. Unbound rifampicin exposures can be predicted from total exposures, even in the higher dose range.
39.	Lopez-Varela, Elisa, et al. (författare) Drug concentration at the site of disease in children with pulmonary tuberculosis 2022 Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 77:6, s. 1710-1719 Tidskriftsartikel (refereegranskat)abstract Background Current TB treatment for children is not optimized to provide adequate drug levels in TB lesions. Dose optimization of first-line antituberculosis drugs to increase exposure at the site of disease could facilitate more optimal treatment and future treatment-shortening strategies across the disease spectrum in children with pulmonary TB. Objectives To determine the concentrations of first-line antituberculosis drugs at the site of disease in children with intrathoracic TB. Methods We quantified drug concentrations in tissue samples from 13 children, median age 8.6 months, with complicated forms of pulmonary TB requiring bronchoscopy or transthoracic surgical lymph node decompression in a tertiary hospital in Cape Town, South Africa. Pharmacokinetic models were used to describe drug penetration characteristics and to simulate concentration profiles for bronchoalveolar lavage, homogenized lymph nodes, and cellular and necrotic lymph node lesions. Results Isoniazid, rifampicin and pyrazinamide showed lower penetration in most lymph node areas compared with plasma, while ethambutol accumulated in tissue. None of the drugs studied was able to reach target concentration in necrotic lesions. Conclusions Despite similar penetration characteristics compared with adults, low plasma exposures in children led to low site of disease exposures for all drugs except for isoniazid.
40.	Ngwalero, Precious, et al. (författare) Relationship between Plasma and Intracellular Concentrations of Bedaquiline and Its M2 Metabolite in South African Patients with Rifampin-Resistant Tuberculosis 2021 Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 65:11 Tidskriftsartikel (refereegranskat)abstract Bedaquiline is recommended for the treatment of all patients with rifampin-resistant tuberculosis (RR-TB). Bedaquiline accumulates within cells, but its intracellular pharmacokinetics have not been characterized, which may have implications for dose optimization. We developed a novel assay using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the intracellular concentrations of bedaquiline and its primary metabolite M2 in patients with RR-TB in South Africa. Twenty-one participants were enrolled and underwent sparse sampling of plasma and peripheral blood mononuclear cells (PBMCs) at months 1, 2, and 6 of treatment and at 3 and 6 months after bedaquiline treatment completion. Intensive sampling was performed at month 2. We used noncompartmental analysis to describe plasma and intracellular exposures and a population pharmacokinetic model to explore the relationship between plasma and intracellular pharmacokinetics and the effects of key covariates. Bedaquiline concentrations from month 1 to month 6 of treatment ranged from 94.7 to 2,540 ng/ml in plasma and 16.2 to 5,478 ng/ml in PBMCs, and concentrations of M2 over the 6-month treatment period ranged from 34.3 to 496 ng/ml in plasma and 109.2 to 16,764 ng/ml in PBMCs. Plasma concentrations of bedaquiline were higher than those of M2, but intracellular concentrations of M2 were considerably higher than those of bedaquiline. In the pharmacokinetic modeling, we estimated a linear increase in the intracellular-plasma accumulation ratio for bedaquiline and M2, reaching maximum effect after 2 months of treatment. The typical intracellular-plasma ratios 1 and 2 months after start of treatment were 0.61 (95% confidence interval [CI]: 0.42 to 0.92) and 1.10 (95% CI: 0.74 to 1.63) for bedaquiline and 12.4 (95% CI: 8.8 to 17.8) and 22.2 (95% CI: 15.6 to 32.3) for M2. The intracellular-plasma ratios for both bedaquiline and M2 were decreased by 54% (95% CI: 24 to 72%) in HIV-positive patients compared to HIV-negative patients. Bedaquiline and M2 were detectable in PBMCs 6 months after treatment discontinuation. M2 accumulated at higher concentrations intracellularly than bedaquiline, supporting in vitro evidence that M2 is the main inducer of phospholipidosis.
41.	Pieterman, E. D., et al. (författare) Higher Dosing of Rifamycins Does Not Increase Activity against Mycobacterium tuberculosis in the Hollow-Fiber Infection Model 2021 Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 65:4 Tidskriftsartikel (refereegranskat)abstract Improvements in the translational value of preclinical models can allow more-successful and more-focused research on shortening the duration of tuberculosis treatment. Although the hollow-fiber infection model (HFIM) is considered a valuable addition to the drug development pipeline, its exact role has not been fully determined yet. Since the strategy of increasing the dose of rifamycins is being evaluated for its treatment-shortening potential, additional in vitro modeling is important. Therefore, we assessed increased dosing of rifampin and rifapentine in our HFIM in order to gain more insight into the place of the HFIM in the drug development pipeline. Total and free-fraction concentrations corresponding to daily dosing of 2.7, 10, and 50 mg of rifampin/kg of body weight, as well as 600 mg and 1,500 mg rifapentine, were assessed in our HFIM using the Mycobacterium tuberculosis H37Rv strain. Drug activity and the emergence of drug resistance were assessed by CFU counting and subsequent mathematical modeling over 14 days, and pharmacokinetic exposures were checked. We found that increasing rifampin exposure above what is expected with the standard dose did not result in higher antimycobacterial activity. For rifapentine, only the highest concentration showed increased activity, but the clinical relevance of this observation is questionable. Moreover, for both drugs, the emergence of resistance was unrelated to exposure. In conclusion, in the simplest experimental setup, the results of the HFIM did not fully correspond to preexisting clinical data. The inclusion of additional parameters and readouts in this preclinical model could be of interest for proper assessment of the translational value of the HFIM.
42.	Prins, H. A. B., et al. (författare) Exposure and virologic outcomes of dolutegravir combined with ritonavir boosted darunavir in treatment-naive individuals enrolled in the Netherlands Cohort Study on Acute HIV infection (NOVA) 2023 Ingår i: International Journal of Antimicrobial Agents. - : Elsevier. - 0924-8579 .- 1872-7913. ; 61:1 Tidskriftsartikel (refereegranskat)abstract To the authors' knowledge, there is currently no literature or guidance recommendation regard-ing whether the dose of dolutegravir (DTG) should be increased when co-administered with darunavir/ritonavir (DRV/r) in patients with acute human immunodeficiency virus infection (AHI). This study assessed the pharmacokinetics (PK) of twice-daily (BID) DTG and once-daily (QD) DRV/r, and com-pared this with DTG QD without DRV/r in patients with AHI. Forty-six participants initiated antiretro-viral therapy within < 24 h of enrolment: DTG 50 mg BID, DRV/r 80 0/10 0 mg QD, and two nucleoside reverse transcriptase inhibitors (NRTIs) for 4 weeks (Phase I); and DTG 50 mg QD with two NRTIs there-after (Phase II: reference). Total DTG trough concentration (Ctrough) and area under the concentration-time profile of 0-24 h (AUC0-24h) were predicted using a population PK model. DTG glucuronidation metabolic ratio (MR) and DTG free fraction were determined and compared per treatment phase using geometric mean ratio (GMR) and 90% confidence interval (CI). Participants had a predicted geometric mean steady-state DTG Ctrough of 2.83 [coefficient of variation (CV%) 30.3%] mg/L (Phase I) and 1.28 (CV% 52.4%) mg/L (Phase II), with GMR of 2.20 (90% CI 1.90-2.55). Total exposure during DTG BID increased but did not double [AUC0-24h GMR 1.65 (90% CI 1.50-1.81) h.mg/L]. DTG glucuronidation MR increased by approxi-mately 29% during Phase I. DTG Ctrough was above in-vivo EC90 (0.32 mg/L) during both phases, except in one participant during Phase I. At Week 8, 84% of participants had viral loads <= 40 copies/mL. The drug-drug interaction between DTG (BID) and DRV/r (QD) was due to induced glucuronidation, and is not clinically relevant in patients with AHI.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )
43.	Radtke, Kendra K., et al. (författare) Emerging data on rifampicin pharmacokinetics and approaches to optimal dosing in children with tuberculosis 2022 Ingår i: Expert Review of Clinical Pharmacology. - : Informa UK Limited. - 1751-2433 .- 1751-2441. ; 15:2, s. 161-174 Forskningsöversikt (refereegranskat)abstract Introduction Despite its longstanding role in tuberculosis (TB) treatment, there continues to be emerging rifampicin research that has important implications for pediatric TB treatment and outstanding questions about its pharmacokinetics and optimal dose in children. Areas covered This review aims to summarize and discuss emerging data on the use of rifampicin for: 1) routine treatment of drug-susceptible TB; 2) special subpopulations such as children with malnutrition, HIV, or TB meningitis; 3) treatment shortening. We also highlight the implications of these new data for child-friendly rifampicin formulations and identify future research priorities. Expert opinion New data consistently show low rifampicin exposures across all pediatric populations with 10-20 mg/kg dosing. Although clinical outcomes in children are generally good, rifampicin dose optimization is needed, especially given a continued push to shorten treatment durations and for specific high-risk populations of children who have worse outcomes. A pooled analysis of existing data using applied pharmacometrics would answer many of the important questions remaining about rifampicin pharmacokinetics needed to optimize doses, especially in special populations. Targeted clinical studies in children with TB meningitis and treatment shortening with high-dose rifampicin are also priorities.
44.	Ruth, Mike Marvin, et al. (författare) A bedaquiline/clofazimine combination regimen might add activity to the treatment of clinically relevant non-tuberculous mycobacteria 2019 Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 74:4, s. 935-943 Tidskriftsartikel (refereegranskat)abstract Background: Non-tuberculous mycobacteria (NTM) infections are hard to treat. New antimicrobial drugs and smarter combination regimens are needed.Objectives: Our aim was to determine the in vitro activity of bedaquiline against NTM and assess its synergy with established antimycobacterials.Methods: We determined MICs of bedaquiline for clinically relevant NTM species and Mycobacterium tuberculosis by broth microdilution for 30 isolates. Synergy testing was performed using the chequerboard method for 22 reference strains and clinical isolates of Mycobacterium abscessus (MAB) and Mycobacterium avium complex (MAC). Time-kill kinetics (TK) assays with resistance monitoring of bedaquiline alone and combined with clofazimine were performed for MAB CIP 104536 and M. avium ATCC 700898; bedaquiline/clarithromycin combinations were evaluated against M. avium ATCC 700898. Interactions were assessed for TK experiments based on Bliss independence.Results: Bedaquiline had modest activity against tested NTM, with MICs between <0.007and 1mg/L. Bedaquiline showed no interaction with tested drugs against MAB or MAC. Lowest mean fractional inhibitory concentration index (FICI) values were 0.79 with clofazimine for MAB and 0.97 with clofazimine and 0.82 with clarithromycin for MAC. In TK assays, bedaquiline showed a bacteriostatic effect. Clofazimine extended the bacteriostatic activity of bedaquiline against MAB and yielded a slight bactericidal effect against M. avium. The bedaquiline/clofazimine combination slowed emergence of bedaquiline resistance for M. avium but promoted it for MAB. Relative to Bliss independence, bedaquiline/clofazimine showed synergistic interaction over time for MAB and no interaction for M. avium and bedaquiline/clarithromycin showed antagonistic interaction for M. avium.Conclusions: Following these in vitro data, a bedaquiline/clofazimine combination might add activity to MAB and MAC treatment. The bedaquiline/clarithromycin combination might have lower activity compared with bedaquiline alone for MAC treatment.
45.	Ruth, Mike Marvin, et al. (författare) Auranofin Activity Exposes Thioredoxin Reductase as a Viable Drug Target in Mycobacterium abscessus 2019 Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 63:9 Tidskriftsartikel (refereegranskat)abstract Nontuberculous mycobacteria (NTM) are highly drug-resistant, opportunistic pathogens that can cause pulmonary disease. The outcomes of the currently recommended treatment regimens are poor, especially for Mycobacterium abscessus. New or repurposed drugs are direly needed. Auranofin, a gold-based antirheumatic agent, was investigated for Mycobacterium tuberculosis. Here, we test auranofin against NTM in vitro and ex vivo. We tested the susceptibility of 63 NTM isolates to auranofin using broth microdilution. Next, we assessed synergy between auranofin and antimycobacterial drugs using the checkerboard method and calculated the fractional inhibition concentration index (FICI). Using time-kill kinetics assays (TK), we assessed pharmacodynamics of auranofin alone and in combination with drug combinations showing the lowest FICIs for M. abscessus CIP 104536. A response surface analysis was used to assess synergistic interactions over time in TKs. Primary isolated macrophages were infected with M. abscessus and treated with auranofin. Finally, using KEGG Orthology, we looked for orthologues to auranofins drug target in M. tuberculosis. M. abscessus had the lowest auranofin MIC50 (2 mu g/ml) among the tested NTM. The lowest average FICIs were observed between auranofin and amikacin (0.45) and linezolid (0.50). Auranofin exhibited concentration-dependent killing of M. abscessus, with >1-log killing at concentrations of >2x MIC. Only amikacin was synergistic with auranofin according to Bliss independence. Auranofin could not lower the intracellular bacterial load in macrophages. Auranofin itself may not be feasible for M. abscessus treatment, but these data point toward a promising, unutilized drug target.
46.	Ruth, Mike Marvin, et al. (författare) Is there a role for tedizolid in the treatment of non-tuberculous mycobacterial disease? 2020 Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 75:3, s. 609-617 Tidskriftsartikel (refereegranskat)abstract Background: Pulmonary infections caused by non-tuberculous mycobacteria (NTM) are hard to treat and have low cure rates despite intensive multidrug therapy.Objectives: To assess the feasibility of tedizolid, a new oxazolidinone, for the treatment of Mycobacterium avium and Mycobacterium abscessus.Methods: We determined MICs of tedizolid for 113 isolates of NTM. Synergy with key antimycobacterial drugs was assessed using the chequerboard method and calculation of the FIC index (FICI). We performed time-kill kinetics assays of tedizolid alone and combined with amikacin for M. abscessus and with ethambutol for M. avium. Human macrophages were infected with M. abscessus and M. avium and subsequently treated with tedizolid; intracellular and extracellular cfu were quantified over time.Results: NTM isolates generally had a lower MIC of tedizolid than of linezolid. FICIs were lowest between tedizolid and amikacin for M. abscessus (FICI = 0.75) and between tedizolid and ethambutol for M. avium (FICI = 0.72). Clarithromycin and tedizolid showed initial synergy, which was abrogated by erm(41)-induced macrolide resistance (FICI = 0.53). Tedizolid had a weak bacteriostatic effect on M. abscessus and combination with amikacin slightly prolonged its effect. Tedizolid had concentration-dependent activity against M. avium and its efficacy was enhanced by ethambutol. Both combinations had a concentration-dependent synergistic effect. Tedizolid could inhibit the intracellular bacterial population of both M. avium and M. abscessus.Conclusions: Tedizolid should be further investigated in pharmacodynamic studies and clinical trials for M. avium complex pulmonary disease. It is less active against M. abscessus, but still promising.
47.	Ruth, Mike Marvin, et al. (författare) Standard therapy of Mycobacterium avium complex pulmonary disease shows limited efficacy in an open source hollow fibre system that simulates human plasma and epithelial lining fluid pharmacokinetics 2022 Ingår i: Clinical Microbiology and Infection. - : Elsevier. - 1198-743X .- 1469-0691. ; 28:3, s. 448.e1-448.e7 Tidskriftsartikel (refereegranskat)abstract Objectives: Mycobacterium avium complex (MAC) bacteria can cause chronic pulmonary disease (PD). Current treatment regimens of azithromycin, ethambutol and rifampicin have culture conversion rates of around 65%. Dynamic, preclinical models to assess the efficacy of treatment regimens are important to guide clinical trial development. The hollow fibre system (HFS) has been applied but reports lack experimental details.Methods: We simulated the human pharmacokinetics of azithromycin, ethambutol and rifampicin both in plasma and epithelial lining fluid (ELF) in a HFS, exposing THP-1 cells infected with M. avium to the triple-drug regimen for 3 weeks. We accounted for drug-drug interactions and protein-binding and provide all laboratory protocols. We differentiated the effects on the intracellular and extracellular mycobacterial population.Results: The antibiotic concentrations in the HFS accurately reflected the time to peak concentration (T-max), the peak concentration (C-max) and half-life of azithromycin, rifampicin and ethambutol in plasma and ELF reported in literature. We find that plasma drug concentrations fail to hold the MAC bacterial load static (Delta Log10 CFU/ml(Control:Regimen) = 0.66 +/- 0.76 and 0.45 +/- 0.28 at 3 and 21 days); ELF concentrations do hold the bacterial load static for 3 days and inhibit bacterial growth for the duration of the experiment (Delta Log10 CFU/ml(Control:Regimen) = 1.1 +/- 0.1 and 1.64 +/- 0.59 at 3 and 21 days).Discussion: In our model, the current therapy against MAC is ineffective, even when accounting for antibiotic accumulation at the site of infection and intracellularly. New treatment regimens need to be developed and be compared with currently recommended regimens in dynamic models prior to clinical evaluation. With the publication of all protocols we aim to open this technology to new users.
48.	Ryeznik, Yevgen, et al. (författare) Pharmacometrics meets statistics-A synergy for modern drug development 2021 Ingår i: CPT. - : John Wiley & Sons. - 2163-8306. ; 10:10, s. 1134-1149 Tidskriftsartikel (refereegranskat)abstract Modern drug development problems are very complex and require integration of various scientific fields. Traditionally, statistical methods have been the primary tool for design and analysis of clinical trials. Increasingly, pharmacometric approaches using physiology-based drug and disease models are applied in this context. In this paper, we show that statistics and pharmacometrics have more in common than what keeps them apart, and collectively, the synergy from these two quantitative disciplines can provide greater advances in clinical research and development, resulting in novel and more effective medicines to patients with medical need.
49.	Sasaki, Tomohiro, et al. (författare) Population Pharmacokinetic and Concentration-QTc Analysis of Delamanid in Pediatric Participants with Multidrug-Resistant Tuberculosis 2022 Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 66:2 Tidskriftsartikel (refereegranskat)abstract A population pharmacokinetic analysis of delamanid and its major metabolite DM-6705 was conducted to characterize the pharmacokinetics of delamanid and DM-6705 in pediatric participants with multidrug-resistant tuberculosis (MDR-TB). Data from participants between the ages of 0.67 and 17 years, enrolled in 2 clinical trials, were utilized for the analysis. The final data set contained 634 delamanid and 706 DM-6705 valid plasma concentrations from 37 children. A transit model with three compartments best described the absorption of delamanid. Two-compartment models for each component with linear elimination were selected to characterize the dispositions of delamanid and DM-6705, respectively. The covariates included in the model were body weight on the apparent volume of distribution and apparent clearance (for both delamanid and DM-6705); formulation (dispersible versus film-coated tablet) on the mean absorption time; age, formulation, and dose on the bioavailability of delamanid; and age on the fraction of delamanid metabolized to DM-6705. Based on the simulations, doses for participants within different age/weight groups that result in delamanid exposure comparable to that in adults following the approved adult dose were calculated. By concentration-QTc (QTcB [QT corrected by Bazett's formula]) analysis, a significant positive correlation was detected with concentrations of DM-6705. However, the modelpredicted upper bounds of the 90% confidence intervals of Delta QTc values were <10 ms at the simulated maximum concentration (C-max) of DM-6705 following the administration of the maximum doses simulated. This suggests that the effect on the QT interval following the proposed dosing is unlikely to be clinically meaningful in children with MDRTB who receive delamanid.
50.	Singh, K. P., et al. (författare) Clinical standards for the management of adverse effects during treatment for TB 2023 Ingår i: The International Journal of Tuberculosis and Lung Disease. - : International Union Against Tuberculosis and Lung Disease. - 1027-3719 .- 1815-7920. ; 27:7, s. 506-519 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE.METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitiv-ity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research.CONCLUSION: These standards provide a person -centred, consensus-based approach to minimise the impact of AE TB treatment.

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Författare/redaktör: Svensson, Elin, 1985 ... (55); Aarnoutse, Rob E. (17); Diacon, Andreas H. (15); Svensson, Elin M., 1 ... (15); Simonsson, Ulrika S. ... (12); Denti, Paolo (11); visa fler...; Boeree, Martin J. (10); Maartens, Gary (9); van Ingen, Jakko (9); Dawson, Rodney (8); Wiesner, Lubbe (7); Abulfathi, Ahmed A. (7); Dooley, Kelly E. (7); Hesseling, Anneke C. (7); Hoefsloot, Wouter (7); te Brake, Lindsey H. ... (7); Karlsson, Mats (6); Garcia-Prats, Anthon ... (6); Burger, David M. (6); Upton, Caryn M. (6); Magis-Escurra, Cecil ... (6); Brust, James C. M. (5); Reuter, Helmuth (5); Karlsson, Mats O. (5); Wertheim, Heiman F. ... (5); McIlleron, Helen (5); Ter Heine, Rob (5); Aarnoutse, Rob (5); Pennings, Lian J. (5); Wasserman, Sean (4); Gandhi, Neel R. (4); Meintjes, Graeme (4); de Jager, Veronique (4); Janssen, Mathias, 19 ... (4); Papadokonstantakis, ... (4); Svensson, Robin J. (4); Badr, Sara, 1985 (4); Svensson, Elin, 1980 (4); Kuipers, Saskia (4); Wasmann, Roeland E. (4); Abdelwahab, Mahmoud ... (3); Donald, Peter R. (3); Alffenaar, Jan-Wille ... (3); Savic, Radojka M. (3); Schaaf, H. Simon (3); Gillespie, Stephen H ... (3); Te Brake, Lindsey (3); van der Laan, Louvin ... (3); Heinrich, Norbert (3); Ruslami, Rovina (3); visa färre...

Lärosäte: Uppsala universitet (71); Chalmers tekniska högskola (5); Karolinska Institutet (2); Linköpings universitet (1)

Språk: Engelska (76)

Forskningsämne (UKÄ/SCB): Medicin och hälsovetenskap (70); Teknik (4); Naturvetenskap (1)

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