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

Abstract

Objective: To describe darunavir (DRV) 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 nonblinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included separate cohorts receiving DRV/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. DRV 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 DRV area under the concentration-time curve (AUC) and maximum concentration were significantly reduced during pregnancy with both dosing regimens compared with postpartum, whereas the last measurable concentration (Clast) was also reduced during pregnancy with once daily DRV. DRV AUC with once daily dosing was reduced by 38% during the second trimester and by 39% during the third trimester. With twice daily dosing, DRV AUC was reduced by 26% in both trimesters. The median (range) ratio of cord blood/maternal delivery DRV concentration in 32 paired samples was 0.18 (range: 0-0.82).

Conclusions: DRV exposure is reduced by pregnancy. To achieve DRV plasma concentrations during pregnancy equivalent to those seen in nonpregnant 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.

Figures

Figure 1

Semilog plots of median darunavir (DRV) concentration–time curves during the 2nd trimester, third trimester, postpartum and the estimated 50th percentile for non-pregnant HIV-infected historical adult controls with once daily (QD) and twice daily (BID) dosing.,

Figure 2

Darunavir (DRV) Clast (C12 or C24) across sampling times.

Figure 3

Maternal darunavir concentrations at delivery and cord blood darunavir concentrations plotted against the time interval between maternal dosing and delivery. Circles present data for twice daily subjects and triangles present data for once daily subjects. Maternal plasma darunavir concentrations at delivery are represented with filled symbols, cord blood darunavir concentrations with open symbols. BQL = below quantitation limit of assay.