Pharmacokinetics of darunavir and cobicistat in pregnant and postpartum women with HIV

Abstract

Objective: To evaluate darunavir 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 darunavir and cobicistat pharmacokinetics in pregnant women with HIV and their children in the United States.

Methods: Intensive steady-state 24-h pharmacokinetic profiles were performed after administration of 800 mg of darunavir 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. Darunavir and cobicistat were measured in plasma by validated HPLC-UV and liquid chromatography with tandem mass spectrometry detection (LC-MS)/MS assays, respectively. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-participant comparisons.

Results: A total of 29 pregnant women receiving darunavir and cobicistat once-daily enrolled in the study. Compared with paired postpartum data, darunavir AUC0--24 was 53% lower in the second trimester [n = 12, P = 0.0024, geometric mean of ratio (GMR)=0.47, 90% confidence interval (CI) 0.33 - 0.68] and 56% lower in the third trimester (n = 18, P < 0.0001, GMR = 0.44, 90% CI 0.36 - 0.54), whereas cobicistat AUC0--24 was 50% lower in the second trimester (n = 12, P = 0.0024, GMR = 0.50, 90% CI 0.36-0.69) and 56% lower in the third trimester (n = 18, P < 0.0001, GMR = 0.44, 90% CI 0.35-0.55). Placental transfer of darunavir and cobicistat was limited.

Conclusion: Standard darunavir/cobicistat dosing during pregnancy results in significantly lower exposure during pregnancy, which may increase the risk of virologic failure and perinatal transmission.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Figures

Figure 1.

Median antepartum and postpartum plasma darunavir (a) and cobicistat (b) concentration versus time profiles at steady state following once-daily dosing of 800/150 mg darunavir/cobicistat. The shaded area displays the 10th to 90th percentile concentrations of darunavir in non-pregnant adults.

Figure 2.

Scatter plot of darunavir plasma concentrations in cord blood and in infants after birth. Concentrations below the limit of quantitation (BLQ; 0.09 μg/mL) are displayed as 1/2 the lower limit of quantitation (0.045 μg/mL). Darunavir was BLQ in 15 of 19 available cord blood samples. A total of 85 washout samples were obtained from 26 infants over the first 9 days of life. In 17 infants all samples were BLQ for darunavir.