ArticleThe AAPS journal2011
Development of a complex parent-metabolite joint population pharmacokinetic model.
Article in The AAPS journal, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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The trial behind it
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Who cites it
23 citing papers in PubMed.
- Population Pharmacokinetics Analysis of Talazoparib and Enzalutamide Combination Therapy for Patients With Metastatic Castration-Resistant Prostate Cancer.Journal of clinical pharmacology · 2026Trial
- Population Pharmacokinetic and Exposure-Efficacy Analyses of Valbenazine in Patients with Huntington's Disease: Supporting Dose Selection for Chorea Management.Journal of clinical pharmacology · 2025Trial
- Dextromethorphan Versus Dextrorphan: A Quantitative Comparison of Antitussive Potency Following Separate Administration of Metabolite.Journal of clinical pharmacology · 2025Trial
- Population pharmacokinetic analysis of quizartinib in patients with newly diagnosed FLT3-internal-tandem-duplication-positive acute myeloid leukemia.Clinical and translational science · 2024Trial
- Simultaneous Ivabradine Parent-Metabolite PBPK/PD Modelling Using a Bayesian Estimation Method.The AAPS journal · 2020Trial
- Population Pharmacokinetics of AL-335 and Its Two Main Metabolites (ALS-022399, ALS-022227) in Monotherapy and in Combination with Odalasvir and/or Simeprevir.The AAPS journal · 2018Trial
- Simultaneous pharmacokinetic model for rolofylline and both M1-trans and M1-cis metabolites.The AAPS journal · 2013Trial
- Development of Integrated Parent-Metabolite Pharmacokinetic Model With Apparent Presystemic Metabolism to Characterize the Disposition of Alverine.CPT: pharmacometrics & systems pharmacology · 2026Article
- Semi-Mechanistic Joint Population Pharmacokinetic Modeling of the Novel Antituberculosis Drug Sorfequiline and Its Metabolite M3 in Healthy Volunteers.CPT: pharmacometrics & systems pharmacology · 2026Article
- Population Pharmacokinetics of Ticagrelor during Veno-Arterial ECMO in Acute Coronary Syndrome: Model-Informed Dosing Simulations.Clinical pharmacology and therapeutics · 2026Observational
- Population Pharmacokinetics of Levosimendan and its Metabolites OR-1855 and OR-1896 in Critically Ill Adults, Neonates and Infants on Veno-Arterial ECMO.Clinical pharmacokinetics · 2026Observational
- Donepezil Brain and Blood Pharmacokinetic Modeling after Nasal Film and Oral Solution Administration in Mice.Pharmaceutics · 2023Article
- Effect of autoinduction and food on the pharmacokinetics of furmonertinib and its active metabolite characterized by a population pharmacokinetic model.Acta pharmacologica Sinica · 2022Article
- Population Pharmacokinetics of Busulfan and Its Metabolite Sulfolane in Patients with Myelofibrosis Undergoing Hematopoietic Stem Cell Transplantation.Pharmaceutics · 2022Article
- Population Pharmacokinetic Model for Tramadol and O-desmethyltramadol in Older Patients.European journal of drug metabolism and pharmacokinetics · 2022Article
- Population Pharmacokinetic Analysis of Quizartinib in Healthy Volunteers and Patients With Relapsed/Refractory Acute Myeloid Leukemia.Journal of clinical pharmacology · 2020Article
- Population pharmacokinetics of regorafenib in solid tumours: Exposure in clinical practice considering enterohepatic circulation and food intake.British journal of clinical pharmacology · 2020Article
- Population Pharmacokinetics of Ibrutinib and Its Dihydrodiol Metabolite in Patients with Lymphoid Malignancies.Clinical pharmacokinetics · 2020Observational
- Population pharmacokinetics of oxcarbazepine and its monohydroxy derivative in epileptic children.British journal of clinical pharmacology · 2017Article
- Using sensitivity equations for computing gradients of the FOCE and FOCEI approximations to the population likelihood.Journal of pharmacokinetics and pharmacodynamics · 2015Article
Corrections and comments
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
This study aimed to develop a joint population pharmacokinetic model for an antipsychotic agent in development (S33138) and its active metabolite (S35424) produced by reversible metabolism. Because such a model leads to identifiability problems and numerical difficulties, the model building was performed using the FOCE-I and the Stochastic Approximation Expectation Maximization (SAEM) estimation algorithms in NONMEM and MONOLIX, respectively. Four different structural models were compared based on Bayesian information criteria. Models were first written as ordinary differential equations systems and then in closed form (CF) to facilitate further analyses. The impact of polymorphisms on genes coding for the CYP2C19 and CYP2D6 enzymes, respectively involved in the parent drug and the metabolite elimination were investigated using permutation Wald test. The parent drug and metabolite plasma concentrations of 101 patients were analyzed on two occasions after 4 and 8 weeks of treatment at 1, 3, 6, and 24 h following daily oral administration. All configurations led to a two compartment model with back-transformation of the metabolite into the parent drug and a first-pass effect. The elimination clearance of the metabolite through other processes than back-transformation was decreased by 35% [9-53%] in CYP2D6 poor metabolizer. Permutation tests were performed to ensure the robustness of the analysis, using SAEM and CF. In conclusion, we developed a complex joint pharmacokinetic model adequately predicting the impact of CYP2D6 polymorphisms on the parent drug and its metabolite concentrations through the back-transformation mechanism.
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