Total and unbound darunavir pharmacokinetics in pregnant women infected with HIV‐1: results of a study of darunavir/ritonavir 600/100 mg administered twice daily

Abstract

ObjectivesAntiretroviral therapy during pregnancy is recommended to reduce the risk of mother-to-child transmission of HIV and for maternal care management. Physiological changes during pregnancy can affect pharmacokinetics, potentially altering pharmacological activity. We therefore evaluated the pharmacokinetics of twice-daily (bid) darunavir in HIV-1-infected pregnant women.MethodsHIV-1-infected pregnant women receiving an antiretroviral regimen containing darunavir/ritonavir 600/100 mg bid were enrolled in this study. Total and unbound darunavir and total ritonavir plasma concentrations were obtained over 12 h during the second and third trimesters and postpartum. Total darunavir and ritonavir plasma concentrations were determined using a validated high-performance liquid chromatography tandem mass spectrometry assay and unbound darunavir was determined using 14C-darunavir-fortified plasma. Pharmacokinetic parameters were derived using noncompartmental analysis.ResultsData were available for 14 women. The area under the plasma concentration–time curve from 0 to 12 h (AUC12h) for total darunavir was 17–24% lower during pregnancy than postpartum. The AUC12h for unbound darunavir was minimally reduced during pregnancy vs. postpartum. The minimum plasma concentration (Cmin) of total and unbound darunavir was on average 43–86% and 10–14% higher, respectively, during pregnancy vs. postpartum. The antiviral response (< 50 HIV-1 RNA copies/mL) was 33% at baseline and increased to 73–90% during treatment; the percentage CD4 count increased over time. One serious adverse event was reported (increased transaminase). All 12 infants born to women remaining in the study at delivery were HIV-1-negative; four of these infants were premature.ConclusionsTotal darunavir exposure decreased during pregnancy. No clinically relevant change in unbound (active) darunavir occurred during pregnancy, suggesting that no dose adjustment is required for darunavir/ritonavir 600/100 mg bid in pregnant women.

Adverse drug reactions associated with antiretroviral therapy during pregnancy

“…There are few published papers about the safety of fosamprenavir [162,163] and darunavir [164] during pregnancy, all reporting infrequent adverse drug reactions in both mothers and infants. These studies all included a small number of volunteers and short follow-up period.…”

HIV and Pregnancy

“…Perhaps, as in the previously cited study of LPV/r, maintenance of the unbound fractions of drug allow for therapeutic antiviral effect. Although total DRV exposure decreased during pregnancy, no clinically relevant change in unbound (active) darunavir occurred, suggesting that no dose adjustment is required for DRV/RTV 600/100 mg bid in pregnant women [43,48].…”

Placental Transfer of Darunavir in an Ex Vivo Human Cotyledon Perfusion Model

“…Clinical data on darunavir use in pregnant women are still limited to small case series, but the available pharmacological data are compatible with our findings. In matched maternal and cord plasma samples at delivery, the median cord/maternal plasma ratios of the darunavir concentrations were, respectively, 0.18 (range, 0.10 to 0.24) (23), 0.11 (24), 0.24 (25), and 0.15 (26).…”

“…Interestingly, among the protease inhibitors, those which are more lipophilic than darunavir and highly protein bound have lower placental transfer rates (17,31). The protein binding rate for darunavir is 95%, which is considerably less than that for lopinavir or ritonavir and somewhat more than that for atazanavir (26). Darunavir is a substrate of efflux transporters expressed in the placenta, as are the HIV protease inhibitors, in general (32), and some other antiretroviral drugs (18), resulting in decreased fetal exposure (33).…”

“…The maternal plasma concentration decreases for darunavir, as for other protease inhibitors, in the third trimester of pregnancy (23,26), although Zorrilla et al (26) observed that the plasma concentrations of unbound darunavir do not decrease. Twicedaily dosing is now recommended during pregnancy (3).…”