Elvitegravir/cobicistat pharmacokinetics in pregnant and postpartum women with HIV

Abstract

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.

Figures

Figure 1.

Maternal median plasma concentration versus time profiles for (a) elvitegravir and (b) cobicistat. Inset displays data plotted on a semilog scale.

Figure 2.

Scatter plot of individual infant elvitegravir plasma concentrations in cord blood and post-delivery. The horizontal line represents the median concentration at each time point. No plasma samples had quantifiable elvitegravir concentrations at the final washout sample (between 5–9 days of life). Samples below the lower limit of quantitation of the assay (LLOQ; 10 ng/mL) are shown as 1/2 LLOQ (5 ng/mL).

Figure 3.

Elvitegravir apparent oral clearance (CL/F) versus cobicistat AUC. The dotted line represents the combined data fit to a non-linear power model. 2T, second trimester; 3T, third trimester; PP, postpartum.