Glasdegib（DAURISMO™）是一种被批准用于治疗急性髓系白血病的Hedgehog途径抑制剂。Cytochrome P450 3A4（CYP3A4）已被确认为glasdegib的主要代谢和清除途径。通过与强CYP3A4抑制剂酮康唑和强诱导剂利福平联合给药进行的临床药物相互作用（DDI）研究证实了CYP3A4在glasdegib清除中的作用。为了评估与CYP3A4调节剂的药物相互作用，使用生理药动学（PBPK）模型和Simcyp®模拟器对glasdegib与中度CYP3A4诱导剂依法韦伦（efavirenz）联合给药进行了评估。glasdegib化合物文件是根据测得的理化性质、人体静脉和口服药代动力学、吸收、分布、代谢和排泄研究数据以及体外反应表型结果开发的。通过与酮康唑和利福平的临床药代动力学（PK）和DDI研究结果验证了建模假设、模型参数和CYP3A4代谢的分数分配。经验证的glasdegib和efavirenz化合物文件，后者可在Simcyp®模拟器中获得，用于估计efavirenz对glasdegib PK的潜在影响。PBPK模型预测，在与efavirenz联合给药后，glasdegib的药物浓度 - 时间曲线下面积比值为0.45，最大血浆浓度比值为0.75。PBPK结果未经正式临床研究而代替其，为药物标签提供了建议，在与中度CYP3A4诱导剂联合给药时将glasdegib的临床剂量加倍，之后在停药后的第7天恢复至原来的剂量。本文章受版权保护。保留所有权利。

Glasdegib (DAURISMO™) is a Hedgehog pathway inhibitor approved for treatment of acute myeloid leukemia. 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 co-administration of glasdegib with strong CYP3A4 inhibitor ketoconazole and strong inducer rifampin. To evaluate the potential drug interactions with CYP3A4 modulators, co-administration 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 co-administration 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 resumption of the original dose 7 days post discontinuation. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.