Cheng Shen, Flora Darcy R, Rettie Allan E, Brundage Richard C, Tracy Timothy S
Metrum Research Group, United States.
Present Affiliation: GRYT Health Inc., United States.
Drug Metab Dispos. 2022 Jul 7;50(9):1287-301. doi: 10.1124/dmd.122.000876.
The objective of this study is to characterize the impact of genotype on warfarin drug-drug interactions when warfarin is taken together with fluconazole, a cytochrome P450 (CYP) inhibitor, or rifampin, a CYP inducer with a nonlinear mixed effect modeling approach. A target mediated drug disposition model with a urine compartment was necessary to characterize both S-warfarin and R-warfarin plasma and urine pharmacokinetic profiles sufficiently. Following the administration of fluconazole, our study found subjects with or alleles experience smaller changes in S-warfarin CL compared with subjects without these alleles (69.5%, 64.8%, 59.7% and 47.8% decrease in subjects with , , and respectively). Whereas, following the administration of rifampin, subjects with or experience larger changes in S-warfarin CL compared with subjects with at least one copy of or (115%, 111%, 119%, 198% and 193% increase in subjects with , , , and respectively). The results suggest different dose adjustments are potentially required for patients with different genotypes if warfarin is administered together with CYP inhibitors or inducers. The present study found a target mediated drug disposition model is needed to sufficiently characterize the clinical pharmacokinetic profiles of warfarin racemates under different co-treatments in subjects with various genotypes, following a single dose of warfarin administration. The study also found S-warfarin, the pharmacologically more active ingredient in warfarin, exhibits genotype-dependent drug-drug interactions, which indicates the dose of warfarin may need to be adjusted differently in subjects with different genotypes in the presence of drug-drug interactions.
本研究的目的是采用非线性混合效应建模方法，表征当华法林与细胞色素P450（CYP）抑制剂氟康唑或CYP诱导剂利福平合用时，基因型对华法林药物相互作用的影响。为了充分表征S-华法林和R-华法林的血浆及尿液药代动力学特征，需要一个带有尿液房室的靶点介导药物处置模型。在给予氟康唑后，我们的研究发现，与没有这些等位基因的受试者相比，携带或等位基因的受试者S-华法林清除率的变化较小（携带、、和等位基因的受试者分别下降69.5%、64.8%、59.7%和47.8%）。然而，在给予利福平后，与至少携带一个或拷贝的受试者相比，携带或等位基因的受试者S-华法林清除率的变化更大（携带、、、和等位基因的受试者分别增加115%、111%、119%、198%和193%）。结果表明，如果华法林与CYP抑制剂或诱导剂合用，不同基因型的患者可能需要进行不同的剂量调整。本研究发现，在单次给予华法林后，需要一个靶点介导药物处置模型来充分表征不同基因型受试者在不同联合治疗下华法林对映体的临床药代动力学特征。该研究还发现，华法林中药理活性更强的成分S-华法林表现出基因型依赖性药物相互作用，这表明在存在药物相互作用的情况下，不同基因型的受试者可能需要不同地调整华法林剂量。
