Reduced exposure to darunavir and cobicistat in HIV‐1‐infected pregnant women receiving a darunavir/cobicistat‐based regimen

Abstract

ObjectivesThe aim of the study was to evaluate darunavir and cobicistat pharmacokinetics in pregnant women with HIV-1 infection. MethodsThis phase 3b, open-label study enrolled HIV-1-infected pregnant women (18-26 weeks of gestation) receiving combination antiretroviral therapy with once-daily darunavir/cobicistat 800/ 150 mg. The plasma pharmacokinetics of darunavir (total and unbound) and cobicistat were assessed over 24 h during the second and third trimesters (24-28 and 34-38 weeks of gestation, respectively) and 6-12 weeks postpartum. Pharmacokinetic parameters [area under the plasma concentration-time curve over 24 h (AUC 24 h ), maximum plasma concentration (C max ) and minimum plasma concentration (C min )] were derived using noncompartmental analysis and compared using linear mixed effects modelling (pregnancy versus postpartum). Antiviral activity and safety were evaluated. ResultsSeven women were enrolled in the study; six completed it. Total darunavir exposure was lower during pregnancy than postpartum (AUC 24 h , 50-56% lower; C max , 37-49% lower; C min , 89-92% lower); unbound darunavir exposure was also reduced (AUC 24 h , 40-45% lower; C max , 32-41% lower; C min , 88-92% lower). Cobicistat exposure was also lower during pregnancy than postpartum (AUC 24 h , 49-63% lower; C max , 27-50% lower; C min , 83% lower). At study completion, five of six (83%) women were virologically suppressed (HIV-1 RNA < 50 copies/mL). There was one virological failure (the patient was nonadherent; no emerging genotypic resistance was observed and susceptibility to antiretrovirals was maintained). No mother-to-child transmission was detected among six infants born to the six women who completed the study. Overall, darunavir/cobicistat was well tolerated in women and infants. ConclusionsIn view of markedly reduced darunavir and cobicistat exposures during pregnancy, this combination is not recommended in HIV-1-infected pregnant women.

Pharmacokinetic Enhancement of HIV Antiretroviral Therapy During Pregnancy

“…8,55,66 Darunavir and cobicistat trough concentrations were reduced by approximately 80% to 90% in the second and third trimesters of pregnancy compared to postpartum. 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.…”

“…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. 66 Cobicistat Adequately Boosts Tenofovir Alafenamide During Pregnancy but Not Protease Inhibitors/Integrase Inhibitors Several studies have been conducted to characterize the plasma pharmacokinetics of TAF during pregnancy versus postpartum, one of which was conducted to evaluate TAF 10 mg with 150 mg of cobicistat (n = 27 women).…”

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

“…Physiological changes in pregnancy seem to have a different effect on ritonavir- and cobicistat-boosted regimens, as shown in Table 1 . 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 – 24 , 35 – 38 ].…”

“…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 ].…”

Cobicistat: A case of mislabelled drug‐drug interaction risk?

“…As an example, product labels for cobicistat with either atazanavir, darunavir, and elvitegravir were recently updated to state that these combinations were not recommended during pregnancy, although ritonavir‐boosted protease inhibitors remained viable treatment options during pregnancy. The reason of these changes was based on pharmacokinetic data demonstrating a marked reduction in mean steady‐state minimum concentrations in the second and third trimester versus postpartum of cobicistat, darunavir, and elvitegravir …”