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

Objectives: Antiretroviral 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. Methods: HIV-1-infected pregnant women receiving an antiretroviral regimen containing darunavir/ritonavir 600/100mg bid were enrolled in this study. Total and unbound darunavir and total ritonavir plasma concentrations were obtained over 12h 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. Results: Data were available for 14 women. The area under the plasma concentration-time curve from 0 to 12h (AUC_12h) for total darunavir was 17-24% lower during pregnancy than postpartum. The AUC_12h for unbound darunavir was minimally reduced during pregnancy vs. postpartum. The minimum plasma concentration (C_min) 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. Conclusions: Total 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 600/100mg bid in pregnant women.