Management of Drug Interactions with Inducers: Onset and Disappearance of Induction on Cytochrome P450 3A4 and Uridine Diphosphate Glucuronosyltransferase 1A1 Substrates.

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY European Journal of Drug Metabolism and Pharmacokinetics Pub Date : 2023-07-01 DOI:10.1007/s13318-023-00833-9
Sara Bettonte, Mattia Berton, Felix Stader, Manuel Battegay, Catia Marzolini
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引用次数: 1

Abstract

Background: People living with HIV may present co-morbidities requiring the initiation and subsequently the discontinuation of medications with inducing properties. The time to reach maximal enzyme induction and to return to baseline enzyme levels has not been thoroughly characterized.

Objective: The aim of this study was to evaluate the onset and disappearance of dolutegravir [uridine diphosphate glucuronosyltransferase (UGT) 1A1 and cytochrome P450 (CYP) 3A4 substrate] and raltegravir (UGT1A1 substrate) induction with strong and moderate inducers using physiologically based pharmacokinetic (PBPK) modeling.

Methods: The predictive performance of the PBPK model to simulate dolutegravir and raltegravir pharmacokinetics and to reproduce the strength of induction was verified using clinical drug-drug interaction studies (steady-state induction) and switch studies (residual induction). The model was considered verified when the predictions were within 2-fold of the observed data. One hundred virtual individuals (50% female) were generated to simulate the unstudied scenarios. The results were used to calculate the fold-change in CYP3A4 and UGT1A1 enzyme levels upon initiation and discontinuation of strong (rifampicin) or moderate (efavirenz or rifabutin) inducers.

Results: The time for reaching maximal induction and subsequent disappearance of CYP3A4 induction was 14 days for rifampicin and efavirenz but 7 days for rifabutin. The distinct timelines for the moderate inducers relate to their different half-lives and plasma concentrations. The induction and de-induction processes were more rapid for UGT1A1.

Conclusions: Our simulations support the common practice of maintaining the adjusted dosage of a drug for another 2 weeks after stopping an inducer. Furthermore, our simulations suggest that an inducer should be administered for at least 14 days before conducting interaction studies to reach maximal induction.

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药物与诱导剂相互作用的管理:细胞色素P450 3A4和尿苷二磷酸葡萄糖醛基转移酶1A1底物诱导的开始和消失。
背景:艾滋病毒感染者可能出现合并症,需要开始并随后停止使用具有诱导特性的药物。达到最大酶诱导和返回到基线酶水平的时间还没有完全表征。目的:本研究的目的是通过基于生理的药代动力学(PBPK)模型,评估多替格拉韦[尿苷二磷酸葡萄糖醛基转移酶(UGT) 1A1和细胞色素P450 (CYP) 3A4底物]和雷替格拉韦(UGT1A1底物)在强和中等诱导剂诱导下的起效和消失。方法:通过临床药物相互作用研究(稳态诱导)和切换研究(残留诱导)验证PBPK模型在模拟多替格拉韦和雷替格拉韦药代动力学和再现诱导强度方面的预测性能。当预测与观测数据的误差在2倍以内时,认为模型得到了验证。100个虚拟个体(50%为女性)被生成来模拟未研究的场景。结果被用来计算CYP3A4和UGT1A1酶水平在强(利福平)或中等(依非韦伦或利福布汀)诱导剂起始和停药后的倍增变化。结果:利福平、依非韦伦组达到最大诱导时间为14 d,利福布汀组为7 d。中等诱导剂的不同时间线与它们不同的半衰期和血浆浓度有关。UGT1A1的诱导和去诱导过程更为迅速。结论:我们的模拟支持在停止使用诱导剂后再维持调整剂量2周的常规做法。此外,我们的模拟表明,在进行相互作用研究之前,诱导剂应至少使用14天以达到最大诱导。
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来源期刊
CiteScore
3.70
自引率
0.00%
发文量
64
审稿时长
>12 weeks
期刊介绍: Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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