| 1. |
- van Beek, Stijn W., et al.
(författare)
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A Model-Informed Method for the Purpose of Precision Dosing of Isoniazid in Pulmonary Tuberculosis
- 2021
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Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 60:7, s. 943-953
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Tidskriftsartikel (refereegranskat)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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| 2. |
- van Beek, Stijn W., et al.
(författare)
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Personalized Tuberculosis Treatment Through Model-Informed Dosing of Rifampicin
- 2019
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Ingår i: Clinical Pharmacokinetics. - : ADIS INT LTD. - 0312-5963 .- 1179-1926. ; 58:6, s. 815-826
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Tidskriftsartikel (refereegranskat)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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| 3. |
- Boosman, René J, et al.
(författare)
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Toxicity of pemetrexed during renal impairment explained-Implications for safe treatment
- 2021
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 149:8, s. 1576-1584
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Tidskriftsartikel (refereegranskat)abstract
- Pemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: <45 mL/min) the approved dose of 500 mg/m2 would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20 mg for patients (eGFR: 20 mL/min) is shown to be neutropenic-equivalent to the approved dose in patients with adequate renal function (eGFR: 90 mL/min), but would result in an approximately 13-fold lower area under the concentration-time curve. The pemetrexed exposure-toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment.
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| 4. |
- Centanni, Maddalena, 1994-
(författare)
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Model-based evaluation of biomarkers for dose-individualization in oncology
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In contemporary cancer care, several issues are garnering increasing attention. First, significant inter-individual variability among patients challenges the effectiveness of a uniform dosing approach. Second, the escalating costs of treatments necessitate careful consideration when selecting doses and other clinical modalities, including biomarkers, while balancing economic constraints. The objective of this thesis was to evaluate techniques for tailoring doses and guiding clinical decisions for cancer patients through the development and implementation of various models, with the aim of improving treatment outcomes in terms of both efficacy and safety. Through a model-based framework integrating sunitinib pharmacokinetics (PK), adverse events, biomarkers, tumor dynamics and their correlation with overall survival, different treatment schedules and biomarkers for dose individualization were explored. Based on the proposed threshold values, neutrophil count (ANC) and the biomarker sVEGFR-3 were identified as offering the best balance between safety and efficacy for sunitinib in gastro-intestinal stromal tumors (GIST) and could thus serve as viable guides for dose individualization in clinical practice. Given its routine measurement, dose adjustments guided by ANC may be preferable in clinical settings. The feasibility of utilizing diastolic blood pressure (dBP) for personalized dose optimization of tyrosine-kinase inhibitors in clinical settings is constrained due to its reliance on repeated measurements taken at consistent intervals. For axitinib and sunitinib, model-based predictions using multiple clinical measurements were more accurate than single sample measurements. For drugs with high unexplained inter-individual variability (IIV), low residual variability (RUV), and low inter-occasional variability (IOV), therapeutic drug monitoring (TDM) provided a more accurate measure of exposure. Conversely, for drugs with low IIV and high RUV and IOV, pharmacogenetic profiling was more suitable. However, the prevalence of pharmacogenetic subtypes and the challenge of measuring exposure metrics like AUC through limited sampling also influence these approaches.This research further emphasizes how model structure affects the outcomes of cost-effectiveness analyses and consequently the potential implications for regulatory decisions. Although creating mechanistic models for these analyses demands substantial initial effort, the growing need for model-based analyses in drug approval is likely to make these models more accessible for future compounds. Moreover, such models are expected to be more biologically plausible and therefore more reflective of reality and offer flexibility for exploring alternative dosages with limited additional effort.Using model-based assessments, the relationship between the PK and PK-pharmacodynamic (PKPD) profiles of adverse events arising from therapies for acute lymphocytic leukemia were established. For PEG-asparaginase, the PK model categorized 93% of patients who experienced inactivation against PEG-asparaginase as having an increased clearance, and 86% of patients who did not experience hypersensitivity as maintaining stable clearance throughout their asparaginase treatment. This approach marks a potential method for predicting inactivation by identifying early changes in clearance. For vincristine, model-informed precision dosing was shown to reduce the incidence of vincristine-induced peripheral neuropathy (VIPN) from 62.1% to 53.9%, though the clinical impact remains modest.
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| 5. |
- de Rouw, Nikki, et al.
(författare)
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Rethinking the Application of Pemetrexed for Patients with Renal Impairment : A Pharmacokinetic Analysis
- 2021
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Ingår i: Clinical Pharmacokinetics. - : ADIS INT LTD. - 0312-5963 .- 1179-1926. ; 60:5, s. 649-654
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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.
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| 6. |
- Schalkwijk, Stein, et al.
(författare)
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Evaluating darunavir/ritonavir dosing regimens for HIV-positive pregnant women using semi-mechanistic pharmacokinetic modelling
- 2019
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Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 74:5, s. 1348-1356
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Tidskriftsartikel (refereegranskat)abstract
- Background: Darunavir 800mg once (q24h) or 600 mg twice (q12h) daily combined with low-dose ritonavir is used to treat HIV-positive pregnant women. Decreased total darunavir exposure (17%-50%) has been reported during pregnancy, but limited data on unbound exposure are available. Objectives: To evaluate total and unbound darunavir exposures following standard darunavir/ritonavir dosing and to explore the value of potential optimized darunavir/ritonavir dosing regimens for HIV-positive pregnant women. Patients and methods: A population pharmacokinetic analysis was conducted based on data from 85 women. The final model was used to simulate total and unbound darunavir AUC(0-tau) and C-trough during the third trimester of pregnancy, as well as to assess the probability of therapeutic exposure. Results: Simulations predicted that total darunavir exposure (AUC(0-tau)) was 24% and 23% lower in pregnancy for standard q24h and q12h dosing, respectively. Unbound darunavir AUC(0-tau) was 5% and 8% lower compared with post-partum for standard q24h and q12h dosing, respectively. The probability of therapeutic exposure (unbound) during pregnancy was higher for standard q12h dosing (99%) than for q24h dosing (94%). Conclusions: The standard q12h regimen resulted in maximal and higher rates of therapeutic exposure compared with standard q24h dosing. Darunavir/ritonavir 600/100 mg q12h should therefore be the preferred regimen during pregnancy unless (adherence) issues dictate q24h dosing. The value of alternative dosing regimens seems limited.
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| 7. |
- van Beek, Stijn W., et al.
(författare)
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Model-based assessment of the safety of community interventions with primaquine in sub-Saharan Africa
- 2021
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Ingår i: Parasites & Vectors. - : BioMed Central (BMC). - 1756-3305. ; 14:1
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Tidskriftsartikel (refereegranskat)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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| 8. |
- Wasmann, Roeland E., et al.
(författare)
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Normal fat mass cannot be reliably estimated in typical pharmacokinetic studies
- 2021
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Ingår i: European Journal of Clinical Pharmacology. - : Springer. - 0031-6970 .- 1432-1041. ; 77, s. 727-733
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: An influential covariate for pharmacokinetics is (body) size. Recently, the method of estimation of normal fat mass (NFM) has been advocated. Here, the relative contribution of fat mass, estimated as a fraction fat (Ffat), is used to explain differences in pharmacokinetic parameters. This concept is more and more applied. However, it remains unclear whether NFM can be reliably estimated in these typical studies.Methods: We performed an evaluation of the reliability of NFM estimation in a typical study size (n = 30), otherwise best-case scenario, by means of a pharmacokinetic simulation study. Several values of Ffat were investigated.Results: In a typical pharmacokinetic study, high imprecision was observed for NFM parameter estimates over a range of scenarios. For example, in a scenario where the true value of Ffat on clearance was 0.5, we found a 95% confidence interval of - 0.1 to 2.1, demonstrating a low precision. The implications for practice are that one could conclude that fat-free mass best describes the relationship of the pharmacokinetics with body size, while the true relationship was between fat-free mass and total body weight. Consequently, this could lead to incorrect extrapolation of pharmacokinetics to extreme body sizes.Conclusion: In typical pharmacokinetic studies, NFM should be used with caution because the Ffat estimates have low precision. The estimation of Ffat should always be preceded by careful study design evaluation before planning a study, to ensure that the design and sample size is sufficient to apply this potentially useful methodology.
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