| 1. |
- Delattre, Isabelle K., et al.
(författare)
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Population Pharmacokinetic Modeling and Optimal Sampling Strategy for Bayesian Estimation of Amikacin Exposure in Critically Ill Septic Patients
- 2010
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Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 32:6, s. 749-756
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Tidskriftsartikel (refereegranskat)abstract
- Because the sepsis-induced pharmacokinetic (PK) modifications need to be considered in aminoglycoside dosing, the present study aimed to develop a population PK model for amikacin (AMK) in severe sepsis and to subsequently propose an optimal sampling strategy suitable for Bayesian estimation of the drug PK parameters. Concentration-time profiles for AMK were obtained from 88 critically ill septic patients during the first 24 hours of antibiotic treatment. The population PK model was developed using a nonlinear mixed effects modeling approach. Covariate analysis included demographic data, pathophysiological characteristics, and comedication. Optimal sampling times were selected based on a robust Bayesian design criterion. Taking into account clinical constraints, a two-point sampling approach was investigated. A two-compartment model with first-order elimination best fitted the AMK concentrations. Population PK estimates were 19.2 and 9.34 L for the central and peripheral volume of distribution and 4.31 and 2.21 L/h for the intercompartmental and total body clearance. Creatinine clearance estimated using the Cockcroft-Gault equation was retained in the final model. The two optimal sampling times were 1 hour and 6 hours after onset of the drug infusion. Predictive performance of individual Bayes estimates computed using the proposed optimal sampling strategy was reported: mean prediction errors were less than 5% and root mean square errors were less than 30%. The present study confirmed the significant influence of the creatinine clearance on the PK disposition of AMK during the first hours of treatment in critically ill septic patients. Based on the population estimates, an optimal sampling strategy suitable for Bayesian estimation of the drug PK parameters was developed, meeting the need of clinical practice.
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| 2. |
- Haglund, Sofie, et al.
(författare)
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The Role of Inosine-5'-Monophosphate Dehydrogenase in Thiopurine Metabolism in Patients With Inflammatory Bowel Disease.
- 2011
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Ingår i: Therapeutic Drug Monitoring. - : Lippincott Williams & Wilkins. - 0163-4356 .- 1536-3694. ; 33:2, s. 200-208
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:: There is a large interindividual variability in thiopurine metabolism. High concentrations of methylthioinosine-5'-monophosphate (meTIMP) and low concentrations of 6-thioguanine nucleotides (6-TGNs) have been associated with a lower response rate and an increased risk of adverse events. In this study, the role of inosine-5'-monophosphate dehydrogenase (IMPDH) for differences in metabolite patterns of thiopurines was investigated. METHODS:: IMPDH activity and thiopurine metabolite concentrations were determined in patients with inflammatory bowel disease and a normal thiopurine methyltransferase (TPMT) phenotype and meTIMP/6-TGN concentration ratio > 20 (n = 26), in patients with a metabolite ratio ≤20 (n = 21), in a subgroup with a metabolite ratio <4 (n = 6), and in 10 patients with reduced TPMT activity. In vitro studies were conducted on human embryonic kidney cells (HEK293) with genetically engineered IMPDH and TPMT activities. RESULTS:: Patients with metabolite ratios >20 had lower IMPDH activity than those with ratios ≤20 (P < 0.001). Metabolic ratios >20 were only observed in patients with normal TPMT activity. Downregulation of IMPDH activity in HEK293 cells was associated with an increase in the concentration of meTIMP (fold change: 17 up to 93, P < 0.001) but, unexpectedly, also of 6-thioguanosine monophosphate (fold change: 2.6 up to 5.0, P < 0.001). CONCLUSIONS:: These data question the general view of IMPDH as the rate-limiting enzyme in the phosphorylation of thiopurines. Investigations of other mechanisms are needed to more fully explain the various metabolite patterns and outcomes in patients under treatment.
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| 3. |
- Johansson, Åsa M., et al.
(författare)
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A Population Pharmacokinetic/Pharmacodynamic Model of Methotrexate and Mucositis Scores in Osteosarcoma
- 2011
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Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 33:6, s. 711-718
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Tidskriftsartikel (refereegranskat)abstract
- Methotrexate, when used in high doses (12 g/m(2)) in the treatment of osteosarcoma, shows wide between-subject variability (BSV) in its pharmacokinetics. High-dose methotrexate is associated with severe toxicity; therefore, therapeutic drug monitoring (TDM) is carried out to guide rescue therapy and monitor for nephrotoxicity. Mucositis is a commonly encountered dose-limiting toxicity that often leads to delays in subsequent courses of chemotherapy. This, in turn, results in a reduction in the dosing intensity, which is essential in the treatment of osteosarcoma. The aims of this study were to develop a population pharmacokinetic (PK) model from TDM using physiologically relevant covariates and to investigate the correlation between mucositis scores and methotrexate pharmacokinetics. In total, 46 osteosarcoma patients (30 men and 16 women; age, 4-51 years) were recruited, and blood samples were collected for routine TDM once every 24 hours. Mucositis scores, graded according to the National Cancer Institute Common Toxicity Criteria, were recorded for 28 of the patients (18 men and 10 women; age, 8-51 years) predose and postdose. A population PK model was developed in NONMEM VI. A 2-compartment PK model was chosen, and clearance (CL) was divided into filtration and secretion/metabolism components. All parameters were scaled with body weight, and, in addition, total CL was scaled with age-and sex-adjusted serum creatinine. Between-subject variability was modeled for all parameters, and betweenoccasion variability was included in CL. For a typical 70 kg man of 18 years or older, the parameter estimates for the final model were CL(filt) = 2.69 L/h/70 kg, CL(sec) = 10.9 L/h/70 kg, V(1) = 74.3 L/70 kg, Q = 0.110 L/h/70 kg, and V(2) = 4.10 L/70 kg. Sequential pharmacodynamic modeling consisted of mucositis scores as 5-point ordered categorical data. A significant linear relationship between individual area under the curve (AUC) and mucositis score probability was found, and the probability of having mucositis score >= 1 increased with increasing AUC and was almost 50% at the average cumulative AUC after 2 consecutive methotrexate doses.
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| 4. |
- Kronstrand, Robert, et al.
(författare)
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A Screening Method for 30 Drugs in Hair Using Ultrahigh-Performance Liquid Chromatography Time-of-Flight Mass Spectrometry
- 2013
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Ingår i: Therapeutic Drug Monitoring. - : Lippincott, Williams and Wilkins. - 0163-4356 .- 1536-3694. ; 35:3, s. 288-295
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The objectives of this study were to develop and to validate a qualitative screening method that met the new Society of Hair Testing (SoHT) guideline criteria for thresholds. less thanbrgreater than less thanbrgreater thanMethods: Extraction of 20 mg hair was performed by a previously validated procedure using overnight incubation in a mixture of methanol:acetonitrile:formiate buffer pH 3 (10:10:80). Analysis was performed on an Agilent 6540 quadrupole time-of-flight mass spectrometer in combination with an Agilent 1290 Infinity ultrahigh-performance liquid chromatography system. Separation was achieved with a 12-minute linear gradient chromatography on a high-strength silica T3 column at acidic conditions. An in-house database containing 30 compounds from the groups amphetamines, opiates, opioids, cocaine, benzodiazepines, and other sedatives including 6 deuterated internal standards was built by analyzing solutions from certified standards. Data were extracted using mass accuracy of +/- 10 ppm, retention time deviation of +/- 0.15 minutes, and area of andgt;= 30,000 counts. Identification was based on scoring of retention time, accurate mass measurement, and isotopic pattern. Validation included selectivity, repeatability of analyte area, and the scoring parameters at the proposed thresholds and a method comparison with the present liquid chromatography-mass spectrometry-mass spectrometry method using 50 authentic hair samples. A daily cutoff calibrator was used to identify positive samples. less thanbrgreater than less thanbrgreater thanResults: All cutoffs could be met with imprecisions of less than 5% for most parameters and analytes. Hair from drug-free subjects did not produce any positive results and the method comparison agreed in more than 90% of the cases. less thanbrgreater than less thanbrgreater thanConclusions: We conclude that the developed method meets the criteria of the new SoHT guidelines for screening cutoffs. Even though no thresholds have been suggested for benzodiazepines, we conclude that thresholds between 0.05 and 0.1 ng/mg should be sufficient to determine regular use of these substances.
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| 5. |
- von Euler, Mia, 1967-, et al.
(författare)
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Differential diagnosis of central nervous system involvement in a patient treated with acyclovir
- 2013
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Ingår i: Therapeutic Drug Monitoring. - : Lippincott Williams & Wilkins. - 0163-4356 .- 1536-3694. ; 35:4, s. 417-419
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Tidskriftsartikel (refereegranskat)abstract
- Acyclovir-induced neuropsychiatric symptoms (AINSs) may resemble several diseases of the central nervous system. Laboratory testing of acyclovir may be critical in supporting the diagnosis of AINSs when there is doubt. We present a case of suspected herpes encephalitis in which the diagnosis of AINSs was supported by therapeutic drug monitoring of plasma and cerebrospinal fluid concentrations of acyclovir and its main metabolite 9-carboxymethoxymethylguanine.
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| 6. |
- Wallin, Johan E, et al.
(författare)
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Population pharmacokinetics of tacrolimus in pediatric liver transplantation : early posttransplantation clearance
- 2011
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Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 33:6, s. 663-672
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Tacrolimus is an immunosuppressant with a narrow therapeutic window, with considerable pharmacokinetic variability. Getting sufficient concentrations in pediatric liver transplantation is imperative, but it has proven difficult in the immediate posttransplantation period in particular. A predictive pharmacokinetic model could be the basis for development of a novel initial dose schedule, and therapeutic drug monitoring with Bayesian methodology. METHODS: The predictive capacity of 2 previously developed population pharmacokinetic models of tacrolimus in pediatric liver transplant recipients was tested in 20 new patients using Bayesian forecasting. Predictive performance was poor in the immediate posttransplant period with tacrolimus pharmacokinetics changing rapidly. A new population pharmacokinetic model, focusing on the immediate posttransplant period, was subsequently developed in 73 patients. RESULTS: An increase in the apparent clearance of tacrolimus in the first few weeks after transplant was evident. Typical apparent clearance of tacrolimus was 0.148 L·h·kg immediately after transplantation, increasing to a maximum of 1.37 L·h·kg. Typical apparent distribution volume was 27.2 L/kg. Internal and external validation studies confirmed the predictive capabilities of the developed model. Simulation studies reveal that in 60% of subjects the current initial standard dose without subsequent dosage adjustments overshoot the desired trough concentration range of 10-20 ng/mL. An alternative dosing schedule was developed based on allometric scaling with an initial loading dose followed by a maintenance dose increasing with time. CONCLUSIONS: A population pharmacokinetic model for tacrolimus was developed, to better describe the early posttransplantation phase. This model has the potential to aid therapeutic drug monitoring and was also used to suggest a revised dosing scheme in the intended population.
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| 7. |
- Zhang, Chao, et al.
(författare)
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Population Pharmacokinetic Model for Adherence Evaluation Using Lamivudine Concentration Monitoring
- 2012
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Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 34:4, s. 481-484
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Tidskriftsartikel (refereegranskat)abstract
- Background: Interpretation of antiretroviral drug concentration measurements could be aided by information about adherence to recent doses. We developed a population pharmacokinetic model of lamivudine in young children to propose reference lamivudine concentrations for evaluation of adherence to recent treatment doses.Methods: The steady state pharmacokinetics of lamivudine were evaluated in 68 young HIV-infected children receiving antiretroviral treatment twice daily. A population pharmacokinetic analysis was conducted using NONMEM 7.Results: A 2-compartment model with transit absorption best described lamivudine pharmacokinetics. After adjustment for maturation and body weight (using allometric scaling), the variability of clearance was small, hence simulations could accurately predict lamivudine concentrations. Higher lamivudine trough concentrations were detected before the morning dose, possibly owing to slower overnight clearance. Reference values for lamivudine concentrations that can be used to evaluate adherence to recent doses are proposed.Conclusions: Lamivudine concentration measurement can be used to assess recent treatment adherence.
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