Elvitegravir/cobicistat pharmacokinetics in pregnant and postpartum women with HIV

Abstract

Objective: To evaluate elvitegravir and cobicistat pharmacokinetics during pregnancy compared to postpartum and in infant washout samples after delivery. Design: Nonrandomized, open-label, parallel-group, multi-center phase-IV prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women and their children in the U.S. Methods: Intensive steady-state 24 hour 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 LC-MS/MS 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 to paired postpartum data, elvitegravir AUC0–24 was 24% lower in the second trimester (n=14, P=0.058, GMR=0.76, 90% 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<.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. Conclusions: 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.

Pharmacokinetic Enhancement of HIV Antiretroviral Therapy During Pregnancy

“…65 Comparably, second-and third-trimester concentrations of elvitegravir/cobicistat were also lower by approximately 50% to 60% compared to postpartum. 61 Reduced boosting by cobicistat may be associated with a higher risk of virologic failure, loss of virologic suppression, inadequate therapeutic effect, and possible development of drug resistance during pregnancy and postpartum. 65 The reproductive health policy implications of these findings for pregnant women with HIV are significant.…”

Effectiveness and safety of integrase inhibitors in HIV-infected pregnant women followed up in the Madrid Cohort

“…Currently, there is no information enough to recommend DTG or EVG during pregnancy [3,13,25]. EVG boosted with cobicistat has a great variability in pharmakokinetics during pregnancy leading commonly to subtherapeutic levels [27].…”

Drug–Drug Interactions with Antiretroviral Drugs in Pregnant Women Living with HIV: Are They Different from Non-Pregnant Individuals?

“…The darunavir (DRV) trough concentration (C trough ) seems to be particularly lower during pregnancy in cobicistat-compared to ritonavir-boosted DRV 800 mg once-daily regimens; boosting with cobicistat resulted in a 71-92% decrease in C trough vs 24-64% with ritonavir boosting [25, 26, 28-31, 33, 34]. Similarly, the ATV C trough is lower in cobicistat-compared to ritonavir-boosted regimens, and EVG C trough is also excessively decreased during pregnancy on average by 81-89% [17][18][19][20][21][22][23][24][35][36][37][38]. Because of the pronounced reduction in C trough, which is considered to be mostly related to efficacy, cobicistat-boosted regimens are no longer recommended during pregnancy [16].…”