Clinical Pharmacokinetics of the Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Doravirine: An Assessment of
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REVIEW ARTICLE
Clinical Pharmacokinetics of the Novel HIV‑1 Non‑Nucleoside Reverse Transcriptase Inhibitor Doravirine: An Assessment of the Effect of Patient Characteristics and Drug–Drug Interactions Sauzanne Khalilieh1 · Ka Lai Yee2 · Rosa Sanchez2 · S. Aubrey Stoch2 · Larissa Wenning2 · Marian Iwamoto2
© The Author(s) 2020
Abstract Doravirine (MK-1439) is a novel non-nucleoside reverse transcriptase inhibitor indicated for the combination treatment of human immunodeficiency virus type-1 (HIV-1) infection. The recommended dose is 100 mg once daily. This review summarizes the pharmacokinetics of doravirine, the influence of intrinsic factors, and its drug–drug interaction (DDI) profile. Following oral administration, doravirine is rapidly absorbed (median time to maximum plasma concentration, 1–4 h) and undergoes cytochrome P450 (CYP)3A-mediated oxidative metabolism. Steady-state geometric means for AUC0–24, C24, and Cmax in individuals with HIV-1 following administration of doravirine 100 mg once daily are 37.8 μM·h, 930 nM, and 2260 nM, respectively. Age, gender, severe renal impairment, and moderate hepatic impairment have no clinically meaningful effect on doravirine pharmacokinetics, and there is limited potential for DDIs. No dose adjustment is necessary when doravirine is co-administered with strong CYP3A inhibitors. However, doravirine is contraindicated with strong CYP3A inducers (e.g., rifampin), and dose adjustment of doravirine is recommended for co-administration with the moderate CYP3A inducer, rifabutin. Included in this review are clinical trial data from phase I pharmacokinetic trials, including DDI trials and trials in participants with renal and hepatic disease but without HIV-1 infection (N = 326), as well as phase I, II, and III safety and efficacy trials in participants living with HIV-1 (N = 991). Based on these data, the pharmacokinetic profile of doravirine supports its use in diverse populations living with HIV-1 and allows co-administration with various antiretroviral agents and treatments for commonly occurring co-morbidities.
1 Introduction Human immunodeficiency virus (HIV) infection continues to be a global concern. In 2017, nearly 37 million people worldwide were living with HIV, and 1.8 million people were newly diagnosed with the virus [1]. Current guidelines recommend that all individuals with HIV infection be treated with antiretroviral therapy [2, 3]. First-line threedrug regimens generally consist of two nucleoside reverse Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40261-020-00934-2) contains supplementary material, which is available to authorized users. Sauzanne Khalilieh and Ka Lai Yee contributed equally. * Sauzanne Khalilieh [email protected] 1
Merck & Co., Inc., Galloping Hill Road, Kenilworth, NJ 07033, USA
Merck & Co., Inc., Kenilworth, NJ, USA
2
transcriptase inhibitors (NRTIs) in combination with a third drug from another class, usually an integrase strand transfer inhibitor (InSTI)
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