Laboratory of Biochemical Pharmacology, Emory Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
Department of Pathology and Laboratory Medicine and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia, USA.
J Clin Pharmacol. 2021 Dec;61(12):1555-1566. doi: 10.1002/jcph.1930. Epub 2021 Jul 23.
Ruxolitinib is a US Food and Drug Administration-approved orally administered Janus kinase (1/2) inhibitor that reduces cytokine-induced inflammation. As part of a randomized, phase 2, open-label trial, ruxolitinib (10 mg twice daily) was administered to HIV-positive, virologically suppressed individuals (33 men, 7 women) on antiretroviral therapy (ART) for 5 weeks. Herein, we report the population PK subsequently determined from this study. Plasma concentrations of ruxolitinib (294 samples) and antiretroviral agents were measured at week 1 (N = 39 participants) and week 4 or 5 (N = 37). Ruxolitinib PK was adequately described with a 2-compartment model with first-order absorption and elimination with distribution volumes normalized to mean body weight (91.5 kg) and a separate typical clearance for participants administered efavirenz (a known cytochrome P450 3A4 inducer). Participants administered an ART regimen with efavirenz had an elevated typical apparent oral clearance versus the integrase inhibitor regimen group (22.5 vs 12.9 L/hr; N = 14 vs 25). Post hoc predicted apparent oral clearance was likewise more variable and higher (P < .0001) in those administered efavirenz. There was an ≈25% variation in ruxolitinib plasma exposures between week 1 and week 4/5. ART plasma concentrations resembled those from PK studies without ruxolitinib. Therefore, integrase inhibitor-based ART regimens may be preferred over efavirenz-based regimens when ruxolitinib is administered to HIV-positive individuals.
芦可替尼是一种美国食品和药物管理局批准的口服 Janus 激酶（1/2）抑制剂，可减少细胞因子诱导的炎症。在一项随机、2 期、开放标签试验中，芦可替尼（每日 2 次，10 毫克）给予接受抗逆转录病毒治疗（ART）的 HIV 阳性、病毒抑制个体（33 名男性，7 名女性），疗程为 5 周。在此，我们报告了随后从该研究中确定的群体药代动力学。在第 1 周（N = 39 名参与者）和第 4 或第 5 周（N = 37）测量了芦可替尼（294 个样本）和抗逆转录病毒药物的血浆浓度。芦可替尼 PK 用 2 室模型充分描述，该模型具有 1 阶吸收和消除，分布体积归一化为平均体重（91.5 kg），并为接受依非韦伦（一种已知的细胞色素 P450 3A4 诱导剂）治疗的参与者单独设定典型清除率。接受含有依非韦伦的 ART 方案治疗的参与者的典型表观口服清除率高于整合酶抑制剂方案组（22.5 比 12.9 L/hr；N = 14 比 25）。事后预测的表观口服清除率在接受依非韦伦治疗的患者中也更具变异性和更高（P <.0001）。在第 1 周和第 4/5 周之间，芦可替尼的血浆暴露量有 ≈25%的差异。ART 血浆浓度与无芦可替尼的 PK 研究相似。因此，当给予 HIV 阳性个体芦可替尼时，基于整合酶抑制剂的 ART 方案可能优于基于依非韦伦的方案。
