Clinically Significant Lower Elvitegravir Exposure During the Third Trimester of Pregnant Patients Living With Human Immunodeficiency Virus: Data From the Pharmacokinetics of ANtiretroviral agents in HIV-infected pregNAnt women (PANNA) Network

Abstract

This phase-IV study investigated the influence of pregnancy on the pharmacokinetics of elvitegravir/cobicistat in 14 HIV-1-positive women. The results support the recommendation against elvitegravir/cobicistat use during pregnancy, as the elvitegravir Ctrough was reduced by 77%, with 85% of pregnant women having a Ctrough below the EC90.

Anti‐Infective Dosing in Special Populations: Pregnancy

“…Concentrations of cobicistat and cobicistat‐boosted elvitegravir and darunavir were significantly lower during pregnancy 30,31 . This finding was reiterated in an additional study published in 2020 32 . Cobicistat is a potent cytochrome P450 3A4 (CYP3A4) inhibitor used in combination with darunavir and elvitegravir to increase their plasma concentrations 9 .…”

“…30,31 This finding was reiterated in an additional study published in 2020. 32 Cobicistat is a potent cytochrome P450 3A4 (CYP3A4) inhibitor used in combination with darunavir and elvitegravir to increase their plasma concentrations. 9 The progesterone-mediated induction of CYP3A4 during pregnancy accelerates cobicistat clearance, resulting in lower concentrations of itself and the partner drugs.…”

Dexamethasone is a dose-dependent perpetrator of drug–drug interactions: implications for use in people living with HIV

“…Differences in pharmacokinetics relating to the two boosters are also seen in the presence of efavirenz or in pregnancy. 34 , 35 Thus, co-administration of boosted PIs, in particular by cobicistat, with high-dose dexamethasone warrants caution with recommended monitoring of ARV efficacy and symptoms of hypercortisolism. The risk of developing a Cushing syndrome, due to inhibition of dexamethasone metabolism by PIs, is less likely to occur when using low-dose and short-term treatment courses of the corticosteroid.…”

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].…”

“…First, the decrease in cobicistat AUC and especially the C trough seems larger compared to the decrease in ritonavir AUC and C trough (Table 1 ). Cobicistat concentrations in pregnant women largely drop below the half maximal inhibitory concentration for CYP3A4 inhibition (i.e., 0.11 mg/L) to trough concentrations < 0.05 mg/L during the dosing interval [ 33 , 35 , 38 , 61 ]. Cobicistat exposure is significantly decreased in the third trimester compared with non-pregnant women resulting in a decreased cobicistat-boosting effect [ 36 ].…”