Janssen Research & Development, Beerse, Belgium.
Triple O Research Institute PA, West Palm Beach, FL, USA.
HIV Med. 2019 May;20(5):337-343. doi: 10.1111/hiv.12721. Epub 2019 Mar 14.
The aim of the study was to evaluate darunavir and cobicistat pharmacokinetics in pregnant women with HIV-1 infection.
This phase 3b, open-label study enrolled HIV-1-infected pregnant women (18-26 weeks of gestation) receiving combination antiretroviral therapy with once-daily darunavir/cobicistat 800/150 mg. The plasma pharmacokinetics of darunavir (total and unbound) and cobicistat were assessed over 24 h during the second and third trimesters (24-28 and 34-38 weeks of gestation, respectively) and 6-12 weeks postpartum. Pharmacokinetic parameters [area under the plasma concentration-time curve over 24 h (AUC ), maximum plasma concentration (C ) and minimum plasma concentration (C )] were derived using noncompartmental analysis and compared using linear mixed effects modelling (pregnancy versus postpartum). Antiviral activity and safety were evaluated.
Seven women were enrolled in the study; six completed it. Total darunavir exposure was lower during pregnancy than postpartum (AUC , 50-56% lower; C , 37-49% lower; C , 89-92% lower); unbound darunavir exposure was also reduced (AUC , 40-45% lower; C , 32-41% lower; C , 88-92% lower). Cobicistat exposure was also lower during pregnancy than postpartum (AUC , 49-63% lower; C , 27-50% lower; C , 83% lower). At study completion, five of six (83%) women were virologically suppressed (HIV-1 RNA < 50 copies/mL). There was one virological failure (the patient was nonadherent; no emerging genotypic resistance was observed and susceptibility to antiretrovirals was maintained). No mother-to-child transmission was detected among six infants born to the six women who completed the study. Overall, darunavir/cobicistat was well tolerated in women and infants.
In view of markedly reduced darunavir and cobicistat exposures during pregnancy, this combination is not recommended in HIV-1-infected pregnant women.
本研究旨在评估感染 HIV-1 的孕妇体内达芦那韦和考比司他的药代动力学。
这是一项 3b 期、开放性标签研究，共纳入了 18-26 孕周接受每日一次达芦那韦/考比司他 800/150mg 联合抗逆转录病毒治疗的 HIV-1 感染孕妇。在妊娠第二和第三个三个月（分别为 24-28 周和 34-38 周）以及产后 6-12 周时，通过非房室分析评估了 24 小时内达芦那韦（总达芦那韦和游离达芦那韦）和考比司他的血浆药代动力学。使用线性混合效应模型（怀孕期与产后期）比较药代动力学参数（24 小时时的血浆浓度-时间曲线下面积（AUC ）、最大血浆浓度（C ）和最小血浆浓度（C ））。评估了抗病毒活性和安全性。
本研究共纳入 7 名女性，其中 6 名完成了研究。与产后相比，妊娠期间总达芦那韦的暴露量更低（AUC 降低 50-56%；C 降低 37-49%；C 降低 89-92%）；游离达芦那韦的暴露量也降低（AUC 降低 40-45%；C 降低 32-41%；C 降低 88-92%）。妊娠期间考比司他的暴露量也低于产后（AUC 降低 49-63%；C 降低 27-50%；C 降低 83%）。研究结束时，6 名完成研究的女性中有 5 名（83%）病毒学抑制（HIV-1 RNA <50 拷贝/mL）。1 例发生病毒学失败（患者不依从；未观察到新的基因型耐药，且对抗病毒药物的敏感性保持）。6 名完成研究的女性所生的 6 名婴儿中均未检测到母婴传播。总的来说，达芦那韦/考比司他在女性和婴儿中均耐受良好。
鉴于妊娠期间达芦那韦和考比司他的暴露量明显减少，因此不建议将该联合方案用于感染 HIV-1 的孕妇。
