S-warfarin limited sampling strategy with a population pharmacokinetic approach to estimate exposure and cytochrome P450 (CYP) 2C9 activity in healthy adults

• Published in: European journal of clinical pharmacology Vol. 77; no. 9; pp. 1349 - 1356
• Main Authors: Tran, Lana, Nikanjam, Mina, Capparelli, Edmund V., Bertino, Joseph S., Nafziger, Anne N., Kashuba, Angela D.M., Turpault, Sandrine, Ma, Joseph D.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2021; Springer Nature B.V
• Subjects: Age Factors; Anticoagulants; Antiretroviral drugs; Area Under Curve; Bayes Theorem; Bayesian analysis; Biomedical and Life Sciences; Biomedicine; Cytochrome; Cytochrome P-450 CYP2C9 - genetics; Cytochrome P-450 CYP2C9 - metabolism; Cytochrome P-450 CYP2C9 Inducers - pharmacology; Cytochrome P450; Dose-Response Relationship, Drug; Drug Combinations; Female; Genotype; Healthy Volunteers; Humans; Lopinavir; Lopinavir - pharmacology; Male; Mathematical models; Metabolic Clearance Rate; Models, Biological; Pharmacokinetics; Pharmacokinetics and Disposition; Pharmacology/Toxicology; Phenotype; Phenotypes; Phenotyping; Population; Ritonavir; Ritonavir - pharmacology; Sampling; Sex Factors; Warfarin; Warfarin - administration & dosage; Warfarin - pharmacology; Cytochrome P450 2C9; Warfarin; Drug-drug interaction; Limited sampling; Phenotyping
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-021-03123-y

Purpose S-warfarin is used to phenotype cytochrome P450 (CYP) 2C9 activity. This study evaluated S-warfarin limited sampling strategy with a population pharmacokinetic (PK) approach to estimate CYP2C9 activity in healthy adults. Methods In 6 previously published studies, a single oral dose of warfarin 10 mg was administered alone or with a CYP2C9 inducer to 100 healthy adults. S-warfarin concentrations were obtained from adults during conditions when subjects were not on any prescribed medications. A population PK model was developed using non-linear mixed effects modeling. Limited sampling models (LSMs) using single- or 2-timepoint concentrations were compared with full PK profiles from intense sampling using empiric Bayesian post hoc estimations of S-warfarin AUC derived from the population PK model. Preset criterion for LSM selection and validation were a correlation coefficient ( R 2 ) > 0.9, relative percent mean prediction error (%MPE) > −5 to < 5%, relative percent mean absolute error (%MAE) ≤ 10%, and relative percent root mean squared error (%RMSE) ≤ 15%. Results S-warfarin concentrations ( n =2540) were well described with a two-compartment model. Mean apparent oral clearance was 0.56 L/hr and volume of distribution was 35.5 L. Clearance decreased 33% with the CYP2C9 *3 allele and increased 42% with lopinavir/ritonavir co-administration. During CYP2C9 constitutive conditions, LSMs at 48 hr and at 72 hr as well as 2-timepoint LSMs were within acceptable limits for R 2 , %MPE, %MAE, and %RMSE. During CYP2C9 induction, S-warfarin LSMs had unacceptable %MPE, %MAE, and %RMSE. Conclusions Phenotyping studies with S-warfarin in healthy subjects can utilize a single- and/or a 2-timepoint LSM with a population PK approach to estimate constitutive CYP2C9 activity.