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

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 warfar...

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Veröffentlicht in:European journal of clinical pharmacology 2021-09, Vol.77 (9), p.1349-1356
Hauptverfasser: Tran, Lana, Nikanjam, Mina, Capparelli, Edmund V., Bertino, Joseph S., Nafziger, Anne N., Kashuba, Angela D.M., Turpault, Sandrine, Ma, Joseph D.
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Sprache:eng
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Zusammenfassung: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.
ISSN:0031-6970
1432-1041
DOI:10.1007/s00228-021-03123-y