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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Physiologically Based Pharmacokinetic Modeling of Doravirine and Its Major Metabolite to Support Dose Adjustment With Rifabutin
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Physiologically Based Pharmacokinetic Modeling of Doravirine and Its Major Metabolite to Support Dose Adjustment With Rifabutin

机译：基于生理基于Doravirine的药代动力学建模及其主要代谢产物与利福布脲支持剂量调整

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摘要

Doravirine, a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV-1), is predominantly cleared by cytochrome P450 (CYP) 3A4 and metabolized to an oxidative metabolite (M9). Coadministration with rifabutin, a moderate CYP3A4 inducer, decreased doravirine exposure. Based on nonparametric superposition modeling, a doravirine dose adjustment from 100 mg once daily to 100 mg twice daily during rifabutin coadministration was proposed. However, M9 exposure may also be impacted by induction, in addition to the dose adjustment. As M9 concentrations have not been quantified in previous clinical studies, a physiologically based pharmacokinetic model was developed to investigate the change in M9 exposure when doravirine is coadministered with CYP3A inducers. Simulations demonstrated that although CYP3A induction increases doravirine clearance by up to 4.4-fold, M9 exposure is increased by only 1.2-fold relative to exposures for doravirine 100 mg once daily in the absence of CYP3A induction. Thus, a 2.4-fold increase in M9 exposure relative to the clinical dose of doravirine is anticipated when doravirine 100 mg twice daily is coadministered with rifabutin. In a subsequent clinical trial, doravirine and M9 exposures, when doravirine 100 mg twice daily was coadministered with rifabutin, were found to be consistent with model predictions using rifampin and efavirenz as representative inducers. These findings support the dose adjustment to doravirine 100 mg twice daily when coadministered with rifabutin.
机译：多拉维林是一种用于治疗人类免疫缺陷病毒1型（HIV-1）的新型非核苷逆转录酶抑制剂，主要被细胞色素P450（CYP）3A4清除并代谢为氧化代谢物（M9）。与中度CYP3A4诱导剂利福布丁合用可减少多拉维林的暴露。基于非参数叠加模型，建议在利福平联合用药期间，将多拉维林的剂量从每天一次100mg调整为每天两次100mg。然而，除了剂量调整外，M9暴露也可能受到诱导的影响。由于M9浓度在之前的临床研究中尚未量化，因此开发了一个基于生理学的药代动力学模型，以研究多拉维林与CYP3A诱导剂合用时M9暴露的变化。模拟表明，虽然CYP3A诱导可使多拉维林清除率增加4.4倍，但在没有CYP3A诱导的情况下，M9暴露仅比每天一次100 mg多拉维林的暴露增加1.2倍。因此，当多拉维林100 mg每日两次与利福平合用时，预计M9暴露量相对于多拉维林的临床剂量增加2.4倍。在随后的临床试验中，当多拉维林100 mg每日两次与利福平合用时，发现多拉维林和M9暴露与使用利福平和依法韦伦作为代表性诱导剂的模型预测一致。这些发现支持在与利福平合用时，每天两次将多拉维林的剂量调整为100 mg。

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