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Twice-Daily Darunavir/Ritonavir in Regimens for Pregnant Women
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Third International Workshop on HIV and Women, January 14-15, 2013, Toronto
Mark Mascolini
Darunavir levels attained with lopinavir/ritonavir at a twice-daily dose 600/100 mg as part of an antiretroviral regimen were lower during pregnancy than after delivery in an 11-woman study [1]. But because darunavir levels unbound by protein were similar during pregnancy and after delivery, the US investigators concluded that plasma concentrations "seem adequate to suppress HIV and prevent mother-to-child transmission."
Use of lopinavir/ritonavir during pregnancy is informed only by a handful of case reports, some of which did not examine pharmacokinetics of the protease inhibitors (PIs). Pharmacokinetic studies of other PIs have found lower concentrations during pregnancy than after delivery or in populations of nonpregnant people.
With support from Janssen, darunavir's maker, US investigators planned this phase 3 nonrandomized multicenter study of darunavir/ritonavir at a dose of 600/100 mg twice daily plus a background regimen. All women were 18 to 26 years old and receiving darunavir/ritonavir, etravirine, and/or rilpivirine for at least 2 weeks before entering the study. All had a normal obstetric exam. The protocol called for 12-hour pharmacokinetic sampling once in the second trimester, once in the third trimester, and once 6 to 12 weeks after delivery.
The 16 study participants included 10 blacks, 4 Hispanics, and 2 whites, only 2 of them in their first pregnancy. Median age at screening stood at 24 and median body mass index at 29 kg/m(2) (range 20 to 59). Median CD4 count measured 421 (range 104 to 793) and median viral load 83 copies (range 49 to 45,200).
The investigators analyzed all samples collected during the study, even from women who did not complete all visits. Full pharmacokinetic profiles for darunavir were available for 10 women in the second trimester, 11 in the third, and 11 after delivery. For measurement of unbound darunavir, samples were available from 6, 7, and 11 women in the three study periods. Full profiles for ritonavir were available for 11 women in all three periods. Five women stopped treatment, 2 because of HIV-related adverse events, 2 because of virologic failure, and 1 because of ineligibility to continue the trial. Poor adherence appeared to explain the virologic failures.
For total darunavir, minimum concentrations were 43% higher in the second trimester than after delivery and 86% higher in the third trimester than after delivery. But 12-hour area under the concentration-time curve (AUC) was 24% lower in the second trimester and 17% lower in the third trimester than after delivery. Maximum concentration was 28% lower in the second trimester than postpartum and 19% lower in the third trimester.
Minimum concentrations of unbound darunavir were similar in the second and third trimester and postpartum (least square mean ratios 1.10 and 1.14), and the same was true for 12-hour AUC (least square mean ratios 0.92 and 0.93). Maximum unbound concentrations were moderately lower in the second and third trimester than postpartum (least square mean ratios 0.78 and 0.82). Albumin concentrations fell 22% during pregnancy, while alpha-acid glycoprotein levels fell 28% during pregnancy.
In 9 women and infants with samples available, average maternal plasma total darunavir concentrations were higher than cord blood concentrations (2324 versus 383 ng/mL). Median cord/maternal blood ratio percentage was 14.5%.
Most women had a viral load below 400 or 50 copies in the third trimester (100% and 90%), in postpartum weeks 2 to 5 (80% and 100%), and in postpartum weeks 6 to 12 (80% and 80%).
Infections arose in 44% of women and gastrointestinal disorders in 25%. One serious adverse event occurred, increased transaminase. Four of 12 infants were born prematurely. All 12 infants were HIV-negative by PCR within 16 weeks of delivery.
The researchers concluded that total darunavir plasma concentrations with a dose of 600/100 mg twice daily were lower during pregnancy than after delivery. But unbound darunavir concentrations--in other words, active drug--remained nearly unchanged during pregnancy. As a result, the investigators see no need for dose adjustment when women take darunavir/ritonavir at this dose.
This ongoing trial will collect pharmacokinetic data on 800/100 mg of darunavir/ritonavir once daily, 200 mg of etravirine twice daily, and 25 mg of rilpivirine once daily.
Reference
1. Osiyemi OO, Zorrilla CD, Wright R, et al. Total and unbound darunavir pharmacokinetics in HIV-1-infected pregnant women. Third International Workshop on HIV and Women, January 14-15, 2013, Toronto. Abstract O_16.
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