Medicine Design Pharmacokinetics, Pharmacodynamics, and Metabolism, Worldwide Research, Development and Medical, Pfizer Inc., Groton, Connecticut, USA.
Clinical Pharmacology, Early Clinical Development, Worldwide Research, Development and Medical, Pfizer Inc., Cambridge, Massachusetts, USA.
Clin Transl Sci. 2022 Sep;15(9):2184-2194. doi: 10.1111/cts.13352. Epub 2022 Jul 2.
PF-05251749 is a dual inhibitor of casein kinase 1 δ/ε under clinical development to treat disruption of circadian rhythm in Alzheimer's and Parkinson's diseases. In vitro, PF-05251749 (0.3-100 μM) induced CYP3A in cryopreserved human hepatocytes, demonstrating non-saturable, dose-dependent CYP3A mRNA increases, with induction slopes in the range 0.036-0.39 μM . In a multiple-dose study (B8001002) in healthy participants, CYP3A activity was explored by measuring changes in 4β-hydroxycholesterol/cholesterol ratio. Following repeated oral administration of PF-05251749, up to 400 mg q.d., no significant changes were observed in 4β-hydroxycholesterol/cholesterol ratio; this ratio increased significantly (~1.5-fold) following administration of PF-05251749 at 750 mg q.d., suggesting potential CYP3A induction at this dose. Physiologically based pharmacokinetic (PBPK) models were developed to characterize the observed clinical pharmacokinetics (PK) of PF-05251749 at 400 and 750 mg q.d.; the PBPK induction model was calibrated using the in vitro linear fit induction slope, with rifampin as reference compound (Ind = 8, EC = 0.32 μM). Clinical trial simulation following co-administration of PF-05251749, 400 mg q.d. with oral midazolam 2 mg, predicted no significant drug interaction risk. PBPK model predicted weak drug interaction following co-administration of PF-05251749, 750 mg q.d. with midazolam 2 mg. In conclusion, good agreement was obtained between CYP3A drug interaction risk predicted using linear-slope PBPK model and exploratory biomarker trends. This agreement between two orthogonal approaches enabled assessment of drug interaction risks of PF-05251749 in early clinical development, in the absence of a clinical drug-drug interaction study.
PF-05251749 是一种正在临床开发中用于治疗阿尔茨海默病和帕金森病中昼夜节律紊乱的双重酪蛋白激酶 1δ/ε抑制剂。在体外，PF-05251749（0.3-100μM）在冷冻保存的人原代肝细胞中诱导 CYP3A，表现出非饱和、剂量依赖性的 CYP3A mRNA 增加，诱导斜率在 0.036-0.39μM 范围内。在健康受试者的一项多剂量研究（B8001002）中，通过测量 4β-羟胆固醇/胆固醇比值的变化来探索 CYP3A 活性。在重复口服 PF-05251749 后，高达 400mg，qd，4β-羟胆固醇/胆固醇比值无明显变化；qd 给予 PF-05251749 750mg 后，该比值显著增加（~1.5 倍），提示该剂量下可能存在 CYP3A 诱导。建立了基于生理的药代动力学（PBPK）模型，以描述 PF-05251749 在 400 和 750mg，qd 时的观察到的临床药代动力学（PK）；使用体外线性拟合诱导斜率和利福平作为参考化合物（Ind=8，EC=0.32μM）对 PBPK 诱导模型进行了校准。在 PF-05251749 400mg，qd 与口服咪达唑仑 2mg 联合给药的临床试验模拟中，预测没有显著的药物相互作用风险。PBPK 模型预测 PF-05251749 750mg，qd 与咪达唑仑 2mg 联合给药时存在较弱的药物相互作用。总之，使用线性斜率 PBPK 模型预测的 CYP3A 药物相互作用风险与探索性生物标志物趋势之间具有良好的一致性。这两种正交方法之间的一致性使我们能够在没有临床药物相互作用研究的情况下，评估 PF-05251749 在早期临床开发中的药物相互作用风险。
