| 1. |
- Haas, David W., et al.
(author)
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Pharmacogenetics of Between-Individual Variability in Plasma Clearance of Bedaquiline and Clofazimine in South Africa
- 2022
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In: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 226:1, s. 147-156
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Journal article (peer-reviewed)abstract
- In a cohort of patients treated for drug-resistant tuberculosis in South Africa, CYP3A5*3was associated with slower plasma bedaquiline clearance. Different CYP3A5*3minor 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 (CYP3A5*3) was associated with slower clearance of bedaquiline (P = .0017) but not M2 (P = .25). CYP3A5*3 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, CYP3A5*3 was associated with slower bedaquiline clearance. Different CYP3A5*3 frequencies among populations may help explain the more rapid bedaquiline clearance reported in Africans. Associations with RFX4 and CNTN5 are likely by chance alone.
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| 2. |
- Koele, Simon E., et al.
(author)
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Optimized Loading Dose Strategies for Bedaquiline When Restarting Interrupted Drug-Resistant Tuberculosis Treatment
- 2022
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In: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 66:3
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Journal article (peer-reviewed)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.
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| 3. |
- Ngwalero, Precious, et al.
(author)
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Relationship between Plasma and Intracellular Concentrations of Bedaquiline and Its M2 Metabolite in South African Patients with Rifampin-Resistant Tuberculosis
- 2021
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In: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 65:11
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Journal article (peer-reviewed)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.
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| 4. |
- Stemkens, Ralf, et al.
(author)
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Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis
- 2023
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In: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 67:10
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Journal article (peer-reviewed)abstract
- Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1–15), followed by RIF40 (days 16–30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%–115%); tolbutamide, 80% (74%–86%); omeprazole, 55% (47%–65%); dextromethorphan, 77% (68%–86%); midazolam, 62% (49%–78%), and 117% (105%–130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.
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| 5. |
- van Beek, Stijn W., et al.
(author)
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A Model-Informed Method for the Purpose of Precision Dosing of Isoniazid in Pulmonary Tuberculosis
- 2021
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In: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 60:7, s. 943-953
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Journal article (peer-reviewed)abstract
- Background and ObjectiveThis study aimed to develop and evaluate a population pharmacokinetic model and limited sampling strategy for isoniazid to be used in model-based therapeutic drug monitoring.MethodsA population pharmacokinetic model was developed based on isoniazid and acetyl-isoniazid pharmacokinetic data from seven studies with in total 466 patients from three continents. Three limited sampling strategies were tested based on the available sampling times in the dataset and practical considerations. The tested limited sampling strategies sampled at 2, 4, and 6 h, 2 and 4 h, and 2 h after dosing. The model-predicted area under the concentration–time curve from 0 to 24 h (AUC24) and the peak concentration from the limited sampling strategies were compared to predictions using the full pharmacokinetic curve. Bias and precision were assessed using the mean error (ME) and the root mean square error (RMSE), both expressed as a percentage of the mean model-predicted AUC24 or peak concentration on the full pharmacokinetic curve.ResultsPerformance of the developed model was acceptable and the uncertainty in parameter estimations was generally low (the highest relative standard error was 39% coefficient of variation). The limited sampling strategy with sampling at 2 and 4 h was determined as most suitable with an ME of 1.1% and RMSE of 23.4% for AUC24 prediction, and ME of 2.7% and RMSE of 23.8% for peak concentration prediction. For the performance of this strategy, it is important that data on both isoniazid and acetyl-isoniazid are used. If only data on isoniazid are available, a limited sampling strategy using 2, 4, and 6 h can be employed with an ME of 1.7% and RMSE of 20.9% for AUC24 prediction, and ME of 1.2% and RMSE of 23.8% for peak concentration prediction.ConclusionsA model-based therapeutic drug monitoring strategy for personalized dosing of isoniazid using sampling at 2 and 4 h after dosing was successfully developed. Prospective evaluation of this strategy will show how it performs in a clinical therapeutic drug monitoring setting.
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| 6. |
- van Beek, Stijn W., et al.
(author)
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Model-based assessment of the safety of community interventions with primaquine in sub-Saharan Africa
- 2021
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In: Parasites & Vectors. - : BioMed Central (BMC). - 1756-3305. ; 14:1
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Journal article (peer-reviewed)abstract
- Background Single low-dose primaquine (SLD-PQ) is recommended in combination with artemisinin-based combination therapy to reduce Plasmodium falciparum transmission in areas threatened by artemisinin resistance or aiming for malaria elimination. SLD-PQ may be beneficial in mass drug administration (MDA) campaigns to prevent malaria transmission but uptake is limited by concerns of hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. The aim of this study was to improve the evidence on the safety of MDA with SLD-PQ in a sub-Saharan African setting. Methods A nonlinear mixed-effects model describing the pharmacokinetics and treatment-induced hemolysis of primaquine was developed using data from an adult (n = 16, G6PD deficient) and pediatric study (n = 38, G6PD normal). The relationship between primaquine pharmacokinetics and hemolysis was modeled using an established erythrocyte lifespan model. The safety of MDA with SLD-PQ was explored through Monte Carlo simulations for SLD-PQ at 0.25 or 0.4 mg/kg using baseline data from a Tanzanian setting with detailed information on hemoglobin concentrations and G6PD status. Results The predicted reduction in hemoglobin levels following SLD-PQ was small and returned to pre-treatment levels after 25 days. G6PD deficiency (African A- variant) was associated with a 2.5-fold (95% CI 1.2-8.2) larger reduction in hemoglobin levels. In the Tanzanian setting where 43% of the population had at least mild anemia (hemoglobin < 11-13 g/dl depending on age and sex) and 2.73% had severe anemia (hemoglobin < 7-8 g/dl depending on age and sex), an additional 3.7% and 6.0% of the population were predicted to develop at least mild anemia and 0.25% and 0.41% to develop severe anemia after 0.25 and 0.4 mg/kg SLD-PQ, respectively. Children < 5 years of age and women >= 15 years of age were found to have a higher chance to have low pre-treatment hemoglobin. Conclusions This study supports the feasibility of MDA with SLD-PQ in a sub-Saharan African setting by predicting small and transient reductions in hemoglobin levels. In a setting where a substantial proportion of the population had low hemoglobin concentrations, our simulations suggest treatment with SLD-PQ would result in small increases in the prevalence of anemia which would most likely be transient.
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| 7. |
- van Beek, Stijn W., et al.
(author)
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Model-Predicted Impact of ECG Monitoring Strategies During Bedaquiline Treatment
- 2022
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In: OPEN FORUM INFECTIOUS DISEASES. - : Oxford University Press. - 2328-8957. ; 9:8
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Journal article (peer-reviewed)abstract
- Background: The M2 metabolite of bedaquiline causes QT-interval prolongation, making electrocardiogram (ECG) monitoring of patients receiving bedaquiline for drug-resistant tuberculosis necessary. The objective of this study was to determine the relationship between M2 exposure and Fridericia-corrected QT (QTcF)-interval prolongation and to explore suitable ECG monitoring strategies for 6-month bedaquiline treatment.Methods: Data from the PROBeX study, a prospective observational cohort study, were used to characterize the relationship between M2 exposure and QTcF. Established nonlinear mixed-effects models were fitted to pharmacokinetic and ECG data. In a virtual patient population, QTcF values were simulated for scenarios with and without concomitant clofazimine. ECG monitoring strategies to identify patients who need to interrupt treatment (QTcF > 500 ms) were explored.Results: One hundred seventy patients were included, providing 1131 bedaquiline/M2 plasma concentrations and 1702 QTcF measurements; 2.1% of virtual patients receiving concomitant clofazimine had QTcF > 500 ms at any point during treatment (0.7% without concomitant clofazimine). With monthly monitoring, almost all patients with QTcF > 500 ms were identified by week 12; after week 12, patients were predominantly falsely identified as QTcF > 500 ms due to stochastic measurement error. Following a strategy with monitoring before treatment and at weeks 2, 4, 8, and 12 in simulations with concomitant clofazimine, 93.8% of all patients who should interrupt treatment were identified, and 26.4% of all interruptions were unnecessary (92.1% and 32.2%, respectively, without concomitant clofazimine).Conclusions: Our simulations enable an informed decision for a suitable ECG monitoring strategy by weighing the risk of missing patients with QTcF > 500 ms and that of interrupting bedaquiline treatment unnecessarily. We propose ECG monitoring before treatment and at weeks 2, 4, 8, and 12 after starting bedaquiline treatment.
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| 8. |
- van Beek, Stijn W., et al.
(author)
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Personalized Tuberculosis Treatment Through Model-Informed Dosing of Rifampicin
- 2019
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In: Clinical Pharmacokinetics. - : ADIS INT LTD. - 0312-5963 .- 1179-1926. ; 58:6, s. 815-826
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Journal article (peer-reviewed)abstract
- Background and objective: Thisstudy proposes a model-informed approach for therapeutic drug monitoring (TDM) of rifampicin to improve tuberculosis (TB) treatment.Methods: Two datasets from pulmonary TB patients were used: a pharmacokinetic study (34 patients, 373 samples), and TDM data (96 patients, 391 samples) collected at Radboud University Medical Center, The Netherlands. Nine suitable population pharmacokinetic models of rifampicin were identified in the literature and evaluated on the datasets. A model developed by Svensson et al. was found to be the most suitable based on graphical goodness of fit, residual diagnostics, and predictive performance. Prediction of individual area under the concentration-time curve from time zero to 24h (AUC(24)) and maximum concentration (C-max) employing various sampling strategies was compared with a previously established linear regression TDM strategy, using sampling at 2, 4, and 6h, in terms of bias and precision (mean error [ME] and root mean square error [RMSE]).Results: A sampling strategy using 2- and 4-h blood collection was selected to be the most suitable. The bias and precision of the two strategies were comparable, except that the linear regression strategy was more biased in prediction of the AUC(24)than the model-informed approach (ME of 9.9% and 1.5%, respectively). A comparison of resulting dose advice, using predictions on a simulated dataset, showed no significant difference in sensitivity or specificity between the two methods. The model was successfully implemented in the InsightRX precision dosing platform.Conclusion: Blood sampling at 2 and 4h, combined with model-based prediction, can be used instead of the currently used linear regression strategy, shortening the sampling by 2h and one sampling point without performance loss while simultaneously offering flexibility in sampling times.
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