Dataset Information

Pharmacokinetics of Capecitabine and Four Metabolites in a Heterogeneous Population of Cancer Patients: A Comprehensive Analysis.

ABSTRACT: Capecitabine is an oral prodrug of the anticancer drug 5-fluorouracil (5-FU). The primary aim of this study was to develop a pharmacokinetic model for capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine (dFCR), 5'-deoxy-5-fluorouridine (dFUR), 5-FU, and fluoro-?-alanine (FBAL) using data from a heterogeneous population of cancer patients (n = 237) who participated in seven clinical studies. A four-transit model adequately described capecitabine absorption. Capecitabine, dFCR, and FBAL pharmacokinetics were well described by two-compartment models, and dFUR and 5-FU were subject to flip-flop pharmacokinetics. Partial and total gastrectomy were associated with a significantly faster capecitabine absorption resulting in higher capecitabine and metabolite peak concentrations. Patients who were heterozygous polymorphic for a genetic mutation encoding dihydropyrimidine dehydrogenase, the DPYD*2A mutation, demonstrated a 21.5% (relative standard error 11.2%) reduction in 5-FU elimination. This comprehensive population model gives an extensive overview of capecitabine and metabolite pharmacokinetics in a large and heterogeneous population of cancer patients.

SUBMITTER: Jacobs BAW

PROVIDER: S-EPMC6930859 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Pharmacokinetics of Capecitabine and Four Metabolites in a Heterogeneous Population of Cancer Patients: A Comprehensive Analysis.

Jacobs Bart A W BAW Deenen Maarten J MJ Joerger Markus M Rosing Hilde H de Vries Niels N Meulendijks Didier D Cats Annemieke A Beijnen Jos H JH Schellens Jan H M JHM Huitema Alwin D R ADR

CPT: pharmacometrics & systems pharmacology 20191120 12

Capecitabine is an oral prodrug of the anticancer drug 5-fluorouracil (5-FU). The primary aim of this study was to develop a pharmacokinetic model for capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine (dFCR), 5'-deoxy-5-fluorouridine (dFUR), 5-FU, and fluoro-β-alanine (FBAL) using data from a heterogeneous population of cancer patients (n = 237) who participated in seven clinical studies. A four-transit model adequately described capecitabine absorption. Capecitabine, dFCR, and FBAL ph ...[more]

PMID: 31652031

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Project description:PURPOSE:Etirinotecan pegol (EP), a long-acting topoisomerase-1 inhibitor, is a polyethylene glycol conjugate of irinotecan, with an intended indication for treatment of breast cancer with brain metastases. The objective of this study was to develop a population pharmacokinetic (popPK) model of EP and four of its metabolites (irinotecan, SN38, SN38-glucuronide, and APC) and determine covariates affecting their pharmacokinetics. METHODS:Data from 83 cancer patients enrolled in phase 1 studies were used. The model was developed in two stages: (1) concentration-time data were analyzed with a 3-analyte model for EP, irinotecan, and SN38; and (2) a 5-analyte model developed based on expansion of 3-analyte model to include concentration-time data for SN38 glucuronide and APC with parameter values from 3-analyte model fixed. Covariate relationships with parameters were selected based on Wald's test within the Wald's Approximation Method approach, first for the 3-analyte model then the 5-analyte model. RESULTS:The final integrated popPK model for the five analytes was a two-compartment per analyte model that followed the metabolic cascade of EP to irinotecan, followed by metabolism of irinotecan to the previously known metabolites, but with altered exposures as compared to administration of irinotecan. With the model developed based on total dose of EP, the population estimates of EP clearance and central volume were 0.237 L/h and 5.5 L, respectively. Patient age, body surface area (BSA), and estimated glomerular filtration rate were found to correlate with EP clearance and BSA with EP central volume. Individuals who were homozygous for UGT1A1*28 genotype had modestly reduced elimination capacity of SN38 compared to heterozygous and wild-type genotypes. Simulations evaluating the clinical importance of significant covariates indicated minimal change in areas under the curve and peak concentrations of EP and SN38. CONCLUSIONS:The pharmacokinetics of EP and four metabolites including the active metabolite SN38 were described by an integrated popPK model. Other than BSA, which was already accounted by a BSA-based dosing scheme, no other covariates were deemed to have clinical implications. No EP starting dose adjustment based on patient demographics and other covariates was deemed necessary.

Project description:Background and objectivesCariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist, is approved for the treatment of adults with schizophrenia (1.5-6 mg/day) and manic/mixed (3-6 mg/day) episodes associated with bipolar I disorder. This population pharmacokinetic analysis describes the concentration-time profiles of cariprazine and its two major active metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). Additionally, the potential impact of patient characteristics, creatinine clearance, and cytochrome P450 2D6 (CYP2D6) metabolizer status on the pharmacokinetics of cariprazine and its metabolites was evaluated.MethodsData from three phase 1 and ten phase 2/3 studies in adult patients with schizophrenia or bipolar mania were included. Nonlinear mixed-effects pharmacokinetic modeling was performed using the NONMEM software package. Compartmental modeling was performed sequentially with the cariprazine elimination rate used as the DCAR formation rate and likewise the elimination rate of DCAR used with a delay as the DDCAR formation rate.ResultsCariprazine pharmacokinetics were described by a three-compartment model with zero-order input of the dose to a depot compartment followed by first-order absorption and first-order elimination. DCAR and DDCAR pharmacokinetics were described by two-compartment models with linear elimination. Statistically significant predictors of pharmacokinetic parameters included weight, sex, and race, though differences in exposures were not large enough to require an adjustment in dose. Creatinine clearance was not a statistically significant predictor of drug clearance, and a post hoc analysis found that CYP2D6 metabolizer status was not associated with changes in exposure levels for cariprazine, DCAR, or DDCAR. The median time to 90% of steady state was approximately 1 week for cariprazine and DCAR and 3 weeks for DDCAR.ConclusionsPopulation pharmacokinetic modeling provided a quantitative description of the concentration-time profile of cariprazine and its metabolites.

Dataset Information

Pharmacokinetics of Capecitabine and Four Metabolites in a Heterogeneous Population of Cancer Patients: A Comprehensive Analysis.

Publications

Pharmacokinetics of Capecitabine and Four Metabolites in a Heterogeneous Population of Cancer Patients: A Comprehensive Analysis.

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