Comprehensive Physiologically Based Pharmacokinetic Model to Assess Drug–Drug Interactions of Phenytoin

Abstract

Regulatory agencies worldwide expect that clinical pharmacokinetic drug–drug interactions (DDIs) between an investigational new drug and other drugs should be conducted during drug development as part of an adequate assessment of the drug’s safety and efficacy. However, it is neither time nor cost efficient to test all possible DDI scenarios clinically. Phenytoin is classified by the Food and Drug Administration as a strong clinical index inducer of CYP3A4, and a moderate sensitive substrate of CYP2C9. A physiologically based pharmacokinetic (PBPK) platform model was developed using GastroPlus® to assess DDIs with phenytoin acting as the victim (CYP2C9, CYP2C19) or perpetrator (CYP3A4). Pharmacokinetic data were obtained from 15 different studies in healthy subjects. The PBPK model of phenytoin explains the contribution of CYP2C9 and CYP2C19 to the formation of 5-(4′-hydroxyphenyl)-5-phenylhydantoin. Furthermore, it accurately recapitulated phenytoin exposure after single and multiple intravenous and oral doses/formulations ranging from 248 to 900 mg, the dose-dependent nonlinearity and the magnitude of the effect of food on phenytoin pharmacokinetics. Once developed and verified, the model was used to characterize and predict phenytoin DDIs with fluconazole, omeprazole and itraconazole, i.e., simulated/observed DDI AUC ratio ranging from 0.89 to 1.25. This study supports the utility of the PBPK approach in informing drug development.

Applying Physiologically Based Pharmacokinetic Modeling to Interpret Carbamazepine’s Nonlinear Pharmacokinetics and Its Induction Potential on Cytochrome P450 3A4 and Cytochrome P450 2C9 Enzymes

“…The quinidine and dolutegravir PBPK models in GastroPlus ® could successfully capture the corresponding drug baselines, whereas the in-house PHT model tended to overpredict PHT exposure, particularly in the initial stages ( Figure 4 a,b,d, Supplementary Material Table S6 ). Nevertheless, the PK parameters for PHT are still within a two-fold range of the observed values, a standard in PHT model development and verification [ 45 ]. The predicted DDI AUC last and DDI C max ratios for dolutegravir, phenytoin, and tolbutamide are within the prediction success limits proposed by Guest ( Figure 4 f,g).…”

“…The CBZ P-M PBPK model was coupled with the built-in PBPK models of victim drugs in GastroPlus ® to assess CBZ DDI potentials on enzyme CYP3A4 and CYP2C9. Specifically, dolutegravir and quinidine model versions 1 and midazolam model version 2 were used as CYP3A4 victim drugs, while tolbutamide model version 1 and phenytoin (in-house model [ 45 ]) were used as CYP2C9 victim drugs (illustrated in Figure 2 , part C). In these clinical studies, CBZ was first titrated to a steady state, resulting in full induction of CYP3A4 and CYP2C9 before the co-administration of a single dose of victim drugs.…”