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Elvitegravir/cobicistat pharmacokinetics in pregnant and postpartum women with HIV

Momper, Jeremiah D.a; Best, Brookie M.a; Wang, Jiajiab; Capparelli, Edmund V.a; Stek, Alicec; Barr, Emilyd; Badell, Martina L.e; Acosta, Edward P.f; Purswani, Murlig; Smith, Elizabethh; Chakhtoura, Nahidai; Park, Kyunghuna; Burchett, Sandraj; Shapiro, David E.b; Mirochnick, Markk for the IMPAACT P1026s Protocol Team

doi: 10.1097/QAD.0000000000001992
CLINICAL SCIENCE
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Objective: To evaluate elvitegravir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery.

Design: Nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women and their children in the United States.

Methods: Intensive steady-state 24-h pharmacokinetic profiles after 150 mg of elvitegravir and 150 mg of cobicistat given orally in fixed dose combination once-daily were performed during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Elvitegravir and cobicistat were measured in plasma by a validated liquid chromatography with tandem mass spectrometry assay with a lower quantitation limit of 10 ng/ml. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-participant comparisons.

Results: Thirty pregnant women taking elvitegravir and cobicistat once-daily enrolled in the study. Compared with paired postpartum data, elvitegravir AUC0–24 was 24% lower in the second trimester [n = 14, P = 0.058, geometric mean ratios (GMR) = 0.76, 90% confidence interval (CI) 0.57–1.0] and 44% lower in the third trimester (n = 24, P = 0.0001, GMR = 0.56, 90% CI 0.42–0.73), while cobicistat AUC0–24 was 44% lower in the second trimester (n = 14, P = 0.0085, GMR = 0.56, 90% CI 0.37–0.85) and 59% lower in the third trimester (n = 24, P < 0.0001, GMR = 0.41, 90% CI 0.30–0.57). Median cord blood elvitegravir concentration was 540.6 ng/ml and the median ratio of cord blood to maternal plasma elvitegravir concentrations was 0.91.

Conclusion: Standard elvitegravir and cobicistat dosing during pregnancy results in significantly lower exposure which may increase the risk of virologic failure and mother-to-child transmission. Additional studies are needed to optimize elvitegravir and cobicistat dosing regimens in pregnant women.

aSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California

bCenter for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, Massachusetts

cUniversity of Southern California School of Medicine, Los Angeles, California

dUniversity of Colorado, Children's Hospital Colorado, Aurora, Colorado

eEmory University School of Medicine, Atlanta, Georgia

fUniversity of Alabama at Birmingham, Birmingham, Alabama

gBronx-Lebanon Hospital Center, Icahn School of Medicine at Mount Sinai, New York, New York

hMaternal, Adolescent, and Pediatric Research Branch, National Institute of Allergy and Infectious Diseases (NIAID)

iMaternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, Maryland

jChildren's Hospital Boston

kBoston University School of Medicine, Boston, Massachusetts, USA.

Correspondence to Jeremiah D. Momper, PharmD, PhD, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, MC 0657, La Jolla, CA 92093-0719, USA. Tel: +1 858 822 0913; fax: +1 858 822 5591; e-mail: jmomper@ucsd.edu

Received 30 March, 2018

Accepted 12 June, 2018

Copyright © 2018 Wolters Kluwer Health, Inc.