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Comparative Clinical Pharmacokinetics and Pharmacodynamics of HIV-1 Integrase Strand Transfer Inhibitors

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Abstract

Dolutegravir (DTG), elvitegravir (EVG) and raltegravir (RAL) are members of the latest class of antiretrovirals (ARVs) that have become available to treat human immunodeficiency virus (HIV) infection: integrase strand transfer inhibitors (INSTIs). INSTIs are potent inhibitors of the HIV integrase enzyme, with protein binding–adjusted concentration inhibiting viral replication by 90/95 % [IC90/95] values in the low nanogram per millilitre range, and they retain antiviral activity against strains of HIV with acquired resistance to other classes of ARVs. Each of the INSTIs has unique pharmacokinetic/pharmacodynamic properties, influencing its role in clinical use in specific subsets of patients. RAL and DTG have minimal drug–drug interaction profiles, as their metabolism has minimal cytochrome P450 (CYP) involvement. Conversely, EVG metabolism occurs primarily via CYP3A4 and requires pharmacokinetic boosting to achieve systemic exposures amenable to once-daily dosing. EVG and DTG have the added benefit of availability of fixed-dose combination tablets, allowing for convenient and simplified ARV regimens. RAL is the only INSTI to be listed as a preferred agent in the current US perinatal treatment guidelines. All three INSTIs are recommended regimens for treatment-naïve individuals in the US adult and adolescent HIV treatment guidelines. This review summarizes and compares the pharmacokinetics and pharmacodynamics of the INSTIs, and describes specific pharmacokinetic considerations for special patient conditions: hepatic impairment, renal dysfunction, pregnancy and co-infections.

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Authors and Affiliations

  1. Antiviral Pharmacology Laboratory, College of Pharmacy, University of Nebraska Medical Center, 986000 Nebraska Medical Center, Omaha, NE, 68198-6000, USA

    Anthony T. Podany, Kimberly K. Scarsi & Courtney V. Fletcher

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  1. Anthony T. Podany
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  2. Kimberly K. Scarsi
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  3. Courtney V. Fletcher
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Correspondence to Courtney V. Fletcher.

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Funding

The authors acknowledge support from the following grants from the National Institutes of Health: 1R01HD085887-01A1 (to Kimberly K. Scarsi) and RO1 AI124965-01 and UM1AI06701 (to Courtney V. Fletcher).

Conflict of interest

Anthony T. Podany, Kimberly K. Scarsi and Courtney V. Fletcher have no conflicts of interest that are directly relevant to the content of this review.

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Podany, A.T., Scarsi, K.K. & Fletcher, C.V. Comparative Clinical Pharmacokinetics and Pharmacodynamics of HIV-1 Integrase Strand Transfer Inhibitors. Clin Pharmacokinet 56, 25–40 (2017). https://doi.org/10.1007/s40262-016-0424-1

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  • DOI: https://doi.org/10.1007/s40262-016-0424-1

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