Comparative Clinical Pharmacokinetics and Pharmacodynamics of HIV-1 Integrase Strand Transfer Inhibitors: An Updated Rev
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REVIEW ARTICLE
Comparative Clinical Pharmacokinetics a1 nd Pharmacodynamics of HIV‑1 Integrase Strand Transfer Inhibitors: An Updated Review Anthony T. Podany1 · Kimberly K. Scarsi1 · Michelle M. Pham1 · Courtney V. Fletcher1
© Springer Nature Switzerland AG 2020
Abstract Bictegravir, cabotegravir, dolutegravir, elvitegravir, and raltegravir are members of the latest class of antiretrovirals available to treat human immunodeficiency virus (HIV) infection, the integrase strand transfer inhibitors. Integrase strand transfer inhibitors are potent inhibitors of the HIV integrase enzyme with IC90/95 values in the low nanogram per milliliter range and they retain antiviral activity against strains of HIV with acquired resistance to other classes of antiretrovirals. Each of the integrase strand transfer inhibitors have unique pharmacokinetic/pharmacodynamic properties, influencing their role in clinical use in specific subsets of patients. Cabotegravir, approved for use in Canada but not yet by the US Food and Drug Administration, is formulated in both oral and intramuscular formulations; the latter of which has shown efficacy as a long-acting extended-release formulation. Cabotegravir, raltegravir, and dolutegravir have minimal drug–drug interaction profiles, as their metabolism has minimal cytochrome P450 involvement. Conversely, elvitegravir metabolism occurs primarily via cytochrome P450 3A4 and requires pharmacokinetic boosting to achieve systemic exposures amenable to once-daily dosing. Bictegravir metabolism has similar contributions from both cytochrome P450 3A4 and uridine 5ʹ-diphospho-glucuronosyltransferase 1A1. Bictegravir, dolutegravir, and raltegravir are recommended components of initial regimens for most people with HIV in the US adult and adolescent HIV treatment guidelines. This review summarizes and compares the pharmacokinetics and pharmacodynamics of the integrase strand transfer inhibitor agents, and describes specific pharmacokinetic considerations for persons with hepatic impairment, renal dysfunction, pregnancy, and co-infections. Key Points Integrase strand transfer inhibitors (INSTIs) represent the newest class of antiretrovirals to treat human immunodeficiency virus infection The five currently approved INSTIs have unique pharmacokinetic and pharmacodynamic profiles, providing advantages for certain individuals and in special populations such as those with renal and hepatic impairment or who are pregnant INSTIs achieve high inhibitory quotients in vivo, rapidly decrease viral load, and are safe and well tolerated There are accumulating data to support that the use of INSTIs has improved viral suppression rates in the USA * Anthony T. Podany [email protected] 1
Antiviral Pharmacology Laboratory, College of Pharmacy, University of Nebraska Medical Center, PDD Rm 3019, 986145 Nebraska Medical Center, Omaha, NE 68198‑6145, USA
1 Introduction There are an estimated 36 million people living with human immunodeficiency virus (HIV) infection globally. With the advent of antiretroviral therapy
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