Pharmacokinetics of Once Versus Twice Daily Darunavir in Pregnant HIV-Infected Women

Abstract

Objective To describe darunavir pharmacokinetics with once and twice daily dosing during pregnancy and postpartum in HIV-infected women. Design Women were enrolled in International Maternal Pediatric Adolescent AIDS Clinical Trials Network Protocol P1026s, a prospective, non-blinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included separate cohorts receiving darunavir/ritonavir dosed at either 800 mg/100 mg once daily or 600 mg/100 mg twice daily. Methods Intensive steady-state 12 or 24 hour pharmacokinetic profiles were performed during the second trimester, third trimester and postpartum. Darunavir was measured using high performance liquid chromatography (detection limit: 0.09 μg/mL). Results Pharmacokinetic data were available for 64 women (30 once daily and 34 twice daily dosing). Median darunavir area under the concentration-time curve (AUC) and maximum concentration (Cmax) were significantly reduced during pregnancy with both dosing regimens compared to postpartum, while the last measurable concentration (Clast) was also reduced during pregnancy with once daily darunavir. Darunavir AUC with once daily dosing was reduced by 38% during the second trimester and by 39% during the third trimester. With twice daily dosing, darunavir AUC was reduced by 26% in both trimesters. The median (range) ratio of cord blood/maternal delivery darunavir concentration in 32 paired samples was 0.18 (range: 0 – 0.82). Conclusion Darunavir exposure is reduced by pregnancy. In order to achieve darunavir plasma concentrations during pregnancy equivalent to those seen in non-pregnant adults, an increased twice daily dose may be necessary. This may be especially important for treatment-experienced women who may have developed antiretroviral resistance mutations.

Pharmacokinetics of once‐daily darunavir/ritonavir in HIV‐1–infected pregnant women

“…Similar findings were demonstrated in two previous trials that evaluated data for women who received darunavir/ritonavir 800/100 mg qd . Data for 12 pregnant women in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1026s trial showed a reduction of 23% in AUC 24h during the third trimester vs .…”

“…Data for 12 pregnant women in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1026s trial showed a reduction of 23% in AUC 24h during the third trimester vs . postpartum . Another study of 18 women who received darunavir/ritonavir 800/100 mg qd showed a reduction of 34% in AUC 24h during the third trimester vs .…”

Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition

“…Similar drug concentration declines in pregnancy have also been reported for other CYP3A4 substrates,14, 15 and also in a previous case report for quetiapine 8. In that publication, trough serum levels of quetiapine in the first, second, and third trimester were 42%, 55%, and 53% lower than the nonpregnant levels, respectively.…”

British HIV Association guidelines for the management of HIV in pregnancy and postpartum 2018

“…For darunavir, a study from the USA showed reduced troughs and 24‐h AUC values with daily dosing in pregnancy, whereas twice daily dosing produced levels more comparable to those in non‐pregnant individuals . The authors concluded that twice daily dosing should be used in pregnancy and higher doses may be required.…”