Medicine Design - Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research and Development, Pfizer Inc., Groton, CT, USA.
Clinical Pharmacology and Bioanalytics, Pfizer Inc., La Jolla, CA, USA.
J Clin Pharmacol. 2024 Jan;64(1):80-93. doi: 10.1002/jcph.2348. Epub 2023 Oct 18.
Glasdegib (DAURISMO) is a hedgehog pathway inhibitor approved for the treatment of acute myeloid leukemia (AML). Cytochrome P450 3A4 (CYP3A4) has been identified as a major metabolism and clearance pathway for glasdegib. The role of CYP3A4 in the clearance of glasdegib has been confirmed with clinical drug-drug interaction (DDI) studies following the coadministration of glasdegib with the strong CYP3A4 inhibitor ketoconazole and the strong inducer rifampin. To evaluate potential drug interactions with CYP3A4 modulators, the coadministration of glasdegib with a moderate CYP3A4 inducer, efavirenz, was evaluated using physiologically based pharmacokinetic (PBPK) modeling using the Simcyp simulator. The glasdegib compound file was developed using measured physicochemical properties, data from human intravenous and oral pharmacokinetics, absorption, distribution, metabolism, and excretion studies, and in vitro reaction phenotyping results. The modeling assumptions, model parameters, and assignments of fractional CYP3A4 metabolism were verified using results from clinical pharmacokinetics (PK) and DDI studies with ketoconazole and rifampin. The verified glasdegib and efavirenz compound files, the latter of which was available in the Simcyp simulator, were used to estimate the potential impact of efavirenz on the PK of glasdegib. PBPK modeling predicted a glasdegib area under the concentration-time curve ratio of 0.45 and maximum plasma concentration ratio of 0.75 following coadministration with efavirenz. The PBPK results, in lieu of a formal clinical study, informed the drug label, with the recommendation to double the clinical dose of glasdegib when administered in conjunction with a moderate CYP3A4 inducer, followed by a resumption of the original dose 7 days post-discontinuation.
吉拉西布（DAURISMO）是一种已获批用于治疗急性髓系白血病（AML）的 Hedgehog 通路抑制剂。细胞色素 P450 3A4（CYP3A4）已被确定为吉拉西布的主要代谢和清除途径。通过吉拉西布与强 CYP3A4 抑制剂酮康唑和强诱导剂利福平联合给药后的临床药物相互作用（DDI）研究，证实了 CYP3A4 在吉拉西布清除中的作用。为了评估与 CYP3A4 调节剂的潜在药物相互作用，使用 Simcyp 模拟器中的基于生理学的药代动力学（PBPK）模型评估了吉拉西布与中度 CYP3A4 诱导剂依非韦伦联合给药的情况。吉拉西布化合物文件是使用测量的物理化学性质、人体静脉内和口服药代动力学、吸收、分布、代谢和排泄研究以及体外反应表型结果开发的。使用酮康唑和利福平的临床药代动力学（PK）和 DDI 研究的结果验证了建模假设、模型参数和分数 CYP3A4 代谢的分配。经过验证的吉拉西布和依非韦伦化合物文件，后者可在 Simcyp 模拟器中使用，用于估计依非韦伦对吉拉西布 PK 的潜在影响。PBPK 模型预测，依非韦伦联合给药后，吉拉西布的 AUC0-t 比值为 0.45，最大血浆浓度比值为 0.75。PBPK 结果代替了正式的临床研究，为药物标签提供了信息，建议在与中度 CYP3A4 诱导剂联合给药时将吉拉西布的临床剂量增加一倍，然后在停药后 7 天恢复原剂量。
