Total and unbound darunavir (DRV) pharmacokinetics (PK) in HIV‐1‐infected pregnant women

Antiretroviral (ARV) therapy during pregnancy is recommended to reduce the risk of mother‐to‐child transmission (MTCT). Physiologic changes during pregnancy can affect PK. We present the PK of total and unbound (pharmacologically active) DRV in HIV‐1‐infected pregnant women receiving twice‐daily (bid) DRV/ritonavir (rtv). This Phase IIIb study enrolled HIV‐1‐infected pregnant women≥18 years old in the 2 nd trimester of pregnancy receiving DRV/rtv 600/100 mg bid and other ARVs. DRV (total and unbound) and rtv (total) plasma concentrations were obtained predose and 1, 2, 3, 4, 6, 9 and 12 hours postdose during the 2 nd and 3 rd trimesters and postpartum. Total DRV and rtv plasma concentrations were determined using a previously validated HPLC‐MS/MS assay (lower limit of quantification 5.00 ng/mL). Unbound DRV was determined by fortifying plasma samples with 14‐C DRV and separating total and unbound DRV using ultrafiltration. Total and unbound 14‐C DRV were measured using liquid scintillation counting. Total and unbound PK parameters were derived using a noncompartmental analysis. Safety and efficacy were investigated at each visit and summarized using descriptive statistics. Sixteen women (10 black, 4 Hispanic, 2 white) were enrolled; 11 had evaluable PK data. Total DRV AUC 12h was 24% and 17% lower during 2 nd and 3 rd trimesters, respectively, vs postpartum (Table). Unbound DRV AUC 12h was unchanged during 2 nd and 3 rd trimesters vs postpartum. Total and unbound DRV C min increased by 43% and 10%, respectively, during 2 nd trimester and by 86% and 14%, respectively, during 3 rd trimester vs postpartum. Unbound DRV was above the EC 50 (27.5 ng/mL) for PI‐resistant HIV in all patients. Albumin and α 1 ‐acid glycoprotein (AAG) concentrations were 22%–29% lower during pregnancy vs postpartum. Viral load decreased and CD4+ count increased over time. One serious adverse event was reported (increased transaminase). Three of 12 infants were born prior to 37 weeks (30, 36 and 36 weeks), and all 12 infants were HIV‐1‐negative by standard PCR testing. Total DRV and rtv PK decreased during pregnancy likely due to pregnancy‐related dilution of albumin and/or AAG. No clinically relevant change in unbound DRV AUC 12h and C min occurred during pregnancy, and there was no MTCT; therefore no dose adjustment is required for DRV/rtv 600/100mg bid in pregnant women. This ongoing trial will further evaluate the effects of pregnancy on DRV/rtv once daily, etravirine and rilpivirine PK.Pharmacokinetic parameters a LS mean ratio, (90% CI) 2 nd trimester vs postpartum 3 rd trimester vs postpartumDarunavir (total)N 11 b vs 11 11 vs 11C min 1.43 (0.39, 5.22) 1.86 (0.49, 7.04)C max 0.72 (0.61, 0.86) 0.81 (0.69, 0.96)AUC 12h 0.76 (0.63, 0.90) 0.83 (0.72, 0.97)Darunavir (unbound)N 6 d vs 11 7 e vs 11C min c 1.10 (0.59, 2.06) 1.14 (0.59, 2.20)C max 0.78 (0.52, 1.18) 0.82 (0.57, 1.16)AUC 12h 0.92 (0.66, 1.30) 0.93 (0.69, 1.24)Ritonavir (total)N 11 f vs 11 11 g vs 11C min 1.08 (0.31, 3.81) 1.22 (0.41, 3.59)C max 0.66 (0.41, 1.08) 0.63 (0.40, 0.98)AUC 12h 0.72 (0.44, 1.17) 0.67 (0.43, 1.04)Efficacy parameters Parameter Baseline, n=15 h2 nd trimester, n=14 3 rd trimester, n=11Log 10 viral load, mean (SD) 2.17 (0.770) 1.99 (0.514) 1.88 (0.598) CD4+ cell count, cells/mm 3 ,  median (range) 419 (104, 793) 429 (81, 933) 470 (103, 960) Virologic response (HIV RNA  <50 copies/mL), n (%) 5 (33.3) 9 (64.3) 9 i (81.8)a One patient was excluded from the PK analysis due to low adherence; b n=10 for AUC 12h ; c n=10 for postpartum; d n=9 for C min and n=7 for C max ; e n=8 for C min and C max ; f n=12 for C max ; g n=10 for C min ; h n=14 for CD4+ cell count; i 1 patient had VL 50–<400 copies/mL and 1 patient had VL≥1000 copies/mL; LS, least squares; CI, confidence interval; C min , minimum plasma concentration; C max , maximum plasma concentration; AUC 12h , area under the plasma concentration‐time curve over 12 hours; SD, standard deviation; PK, pharmacokinetic.