Abstract and Introduction
Background: This study evaluated atazanavir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples.
Setting: A nonrandomized, open-label, parallel-group, multicenter prospective study of atazanavir and cobicistat pharmacokinetics in pregnant women with HIV and their children.
Methods: Intensive steady-state 24-hour pharmacokinetic profiles were performed after administration of 300 mg of atazanavir and 150 mg of cobicistat orally in fixed-dose combination once daily during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Atazanavir and cobicistat were measured in plasma by validated high-performance liquid chromatography-ultraviolet and liquid chromatography-tandem mass spectrometry assays, respectively. A 2-tailed Wilcoxon signed-rank test (α = 0.10) was used for paired within-participant comparisons.
Results: A total of 11 pregnant women enrolled in the study. Compared with paired postpartum data, atazanavir AUC0–24 was 26% lower in the second trimester [n = 5, P = 0.1875, geometric mean of ratio (GMR) = 0.739, 90% CI: 0.527 to 1.035] and 54% lower in the third trimester (n = 6, GMR = 0.459, P = 0.1563, 90% CI: 0.190 to 1.109), whereas cobicistat AUC0–24 was 35% lower in the second trimester (n = 5, P = 0.0625, GMR = 0.650, 90% CI: 0.493 to 0.858) and 52% lower in the third trimester (n = 7, P = 0.0156, GMR = 0.480, 90% CI: 0.299 to 0.772). The median (interquartile range) 24-hour atazanavir trough concentration was 0.21 μg/mL (0.16–0.28) in the second trimester, 0.21 μg/mL (0.11–0.56) in the third trimester, and 0.61 μg/mL (0.42–1.03) in postpartum. Placental transfer of atazanavir and cobicistat was limited.
Conclusions: Standard atazanavir/cobicistat dosing during pregnancy results in lower exposure which may increase the risk of virologic failure and perinatal transmission.
Antiretroviral treatment is recommended for all pregnant individuals with HIV to optimize their health and to prevent perinatal HIV transmission. The use of potent antiretroviral regimens and other strategies by pregnant individuals living with HIV has reduced the rate of perinatal HIV transmission to 1% or less in the United States and Europe. Although the availability of safe and effective antiretroviral treatment options for use during pregnancy has increased, pharmacokinetic and safety data on newer agents during pregnancy remain limited.
A variety of physiological changes during pregnancy alter the absorption, distribution, metabolism, and excretion of drugs.[2,3] For example, the activity of hepatic cytochrome P450 3A (CYP3A) is increased by approximately 35% during all stages of pregnancy.[4–9] For individuals living with HIV, altered pharmacokinetics during pregnancy often leads to subtherapeutic antiretroviral exposure, which may result in increased risk of treatment failure, perinatal transmission, and drug resistance.[10,11]
Atazanavir is a protease inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. The US Department of Health and Human Services Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission recommends atazanavir as a preferred agent for pregnant women who require a protease inhibitor–based regimen during pregnancy. Atazanavir has a higher barrier to resistance than nonnucleoside reverse transcriptase inhibitors (NNRTIs). Atazanavir is metabolized and eliminated primarily by CYP3A-mediated hepatic metabolism and is typically boosted by coadministration with either ritonavir or cobicistat. Atazanavir boosted with ritonavir has been studied in pregnancy; however, the pharmacokinetics of atazanavir boosted with cobicistat has not yet been reported. Previous pharmacokinetic studies of darunavir and elvitegravir boosted with cobicistat have shown that cobicistat is an inadequate pharmacokinetic booster during pregnancy for antiretroviral drugs that are primarily eliminated by CYP3A-mediated hepatic metabolism.[15–17] The primary objective of this study was to evaluate the pharmacokinetics and safety of atazanavir and cobicistat in pregnant women with HIV-1.
J Acquir Immune Defic Syndr. 2022;89(3):303-309. © 2022 Lippincott Williams & Wilkins