Pharmacokinetics in pregnancy: darunavir/r and etravirine

Physiologic changes during pregnancy can affect pharmacokinetics (PK). Two small studies presented at the 5th International Workshop on HIV & Women evaluated the PK of darunavir/ritonavir (DRV/r) and etravirine (ETR) respectively in pregnancy. [1,2] In both studies drug exposure was altered – lower for DRV and higher for ETR.

The DRV/r evaluation compared PK in pregnancy that with post partum. The study was open label, multicentre, phase 3b. Women were enrolled in the 2nd trimester of pregnancy and received DRV/r (600/100 mg twice daily or 800/100 mg once daily), ETR (see below) or rilpivirine plus optimised background regimen.

PK evaluations were performed in the 2nd and 3rd trimesters and 6 to 12 weeks post partum. Total and unbound DRV plasma concentrations and total ritonavir plasma concentrations were evaluated predose and 1, 2, 3, 4, 6, 9, 12 and 24 hours postdose. Data for participants receiving DRV/r 800/100 mg were reported.

Seventeen women were enrolled: 5 black, 2 Latina, 7 white and 3 other. Sixteen had evaluable PK data.

The PK evaluation revealed reductions in total DRV AUC24h, Cmin and Cmax of: 34% (LS mean ratio, 90% CI: 0.66, 0.60 to 0.74), 32% (0.68, 0.56 to 0.83) and 34% (0.66, 0.59 to 0.75) in the 2nd trimester, compared with post partum. The respective values were: 35% (0.65, 0.57 to 0.74), 50% (0.50, 0.35 to 0.73) and 31% (0.69, 0.63 to 0.77) in the 3rd trimester.

Unbound DRV concentrations were also lower during pregnancy but to a lesser extent. Compared with postpartum, DRV AUC24h, Cmin and Cmax were decreased by: 24% (0.76, 0.67 to 0.85), 13% (0.87, 0.69 to 1.10) and 25% (0.75, 0.65 to 0.87) in the 2nd trimester; and 20% (0.80, 0.71 to 0.89), 38% (0.62, 0.43 to 0.90) and 16% (0.84, 0.74 to 0.96) in the 3rd trimester.

Ritonavir parameters decreased by approximately 45-50% overall in pregnancy compared with post partum.

Viral suppression <50 copies/mL increased and was maintained over time: 59%, 87%, 100% and 93% at baseline, 2nd trimester, 3rd trimester and postpartum respectively.

There were no deaths and 6 serious adverse events. All the events were considered to be pregnancy-related; only 1 (gestational diabetes) was considered possibly related to DRV/r. There were 3/16 infants born before week 37. All infants were HIV negative.

The PK (total concentrations) of ETR 200 mg twice daily was evaluated in a study of the same design. For this assessment 11/15 women had evaluable data.

ETR AUC24h, Cmin and Cmax were higher by: 46% (LS mean ratio, 90% CI: 1.46, 1.12 to 1.90), 131% (2.31, 1.26 to 4.22) and 39% (1.39, 1.15 to 1.67) during the 2nd trimester compared with postpartum. For the third trimester the increases were: 28% (1.28, 0.98 to 1.69), 93% (1.93, 1.03 to 3.61) and 31% (1.31, 1.08 to 1.59).

Higher exposures of ETR did not result in increased occurrence of adverse events. Four participants had serious adverse events, none of which were considered related to ETR. One participant had grade 1 treatment emergent atopic dermatitis that was considered possibly related to ETR. All infants were HIV negative.

The investigators noted that caution might be warranted with concomitant medicine or situations that could further increase ETR exposure.