Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, Dept. R4PK, Bldg. AP31-3, North Chicago, IL, 60064, USA.
Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Cancer Chemother Pharmacol. 2021 Apr;87(4):465-474. doi: 10.1007/s00280-020-04179-w. Epub 2021 Jan 4.
Venetoclax, a targeted anticancer agent approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, is a substrate of cytochrome P450 (CYP) 3A enzyme (CYP3A4). Posaconazole, commonly used to prevent invasive fungal infections in neutropenic patients with hematological malignancies, potently inhibits CYP3A4. The purpose of this evaluation was to predict venetoclax exposures following co-administration of posaconazole at doses not previously studied clinically.
Two physiologically based pharmacokinetic (PBPK) models were developed for posaconazole based on published parameters, one for an oral suspension and another for delayed released tablets. Parameter optimization, guided by sensitivity analyses, was conducted such that the models could replicate clinical exposures of posaconazole and drug-drug interactions with sensitive CYP3A substrates including venetoclax. The clinically verified posaconazole PBPK models were then utilized to predict DDI with a previously published venetoclax PBPK model at clinically relevant dosing scenarios.
The posaconazole PBPK models predicted posaconazole exposure and DDI related fold changes with acceptable prediction errors for both posaconazole formulations. The model predicted exposures of venetoclax, when co-administered with a 300 mg QD dose of delayed release tablets of posaconazole, were in concordance with observed data. Increasing the posaconazole dose to 500 mg QD increased venetoclax exposures by about 12% relative to 300 mg QD, which were still within the venetoclax safe exposure range.
The posaconazole PBPK models were developed and clinically verified. Predictions using the robust PBPK model confirmed the venetoclax label recommendation of 70 mg in the presence of posaconazole at doses up to 500 mg QD.
维奈托克是一种靶向抗癌药物，已获批用于治疗慢性淋巴细胞白血病和急性髓系白血病，是细胞色素 P450（CYP）3A 酶（CYP3A4）的底物。泊沙康唑常用于预防血液恶性肿瘤中性粒细胞减少患者的侵袭性真菌感染，可强效抑制 CYP3A4。本评估的目的是预测在未临床研究剂量下联合使用泊沙康唑时维奈托克的暴露情况。
根据已发表的参数，开发了两种泊沙康唑的基于生理的药代动力学（PBPK）模型，一种是口服混悬液，另一种是延迟释放片剂。通过敏感性分析指导参数优化，以使模型能够复制泊沙康唑的临床暴露和与敏感 CYP3A 底物（包括维奈托克）的药物相互作用。然后，利用经过临床验证的泊沙康唑 PBPK 模型，在临床相关给药方案下预测与先前发表的维奈托克 PBPK 模型的药物相互作用。
泊沙康唑 PBPK 模型预测了泊沙康唑暴露和与药物相互作用的相关折叠变化，两种制剂的预测误差都在可接受范围内。该模型预测，当与 500mg QD 剂量的延迟释放片剂的泊沙康唑联合使用时，维奈托克的暴露量与观察到的数据一致。与 300mg QD 相比，当泊沙康唑剂量增加至 500mg QD 时，维奈托克的暴露量增加了约 12%，但仍在维奈托克的安全暴露范围内。
开发并临床验证了泊沙康唑 PBPK 模型。使用稳健的 PBPK 模型进行预测，证实了在剂量高达 500mg QD 的情况下，维奈托克标签推荐在泊沙康唑存在的情况下使用 70mg。
