A Randomized Phase 1 Study Evaluating Pharmacokinetics, Safety, and Tolerability of a High-Concentration, Long-Acting Cabotegravir Formulation in Adults Without HIV

IF 1.8 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Kelong Han, Paul Benn, Jörg Sievers, David Dorey, Michael Warwick-Sanders, Randa Hareedy, Louise Harkness, Claudia Leemereise, Kjersten Offenbecker, Christina Donatti, Darin B. Brimhall, Christian Schwabe, Craig Boyle, Michael A. Hassman, Steve Knowles, Ronald D'Amico, William R. Spreen
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Abstract

Long-acting (LA) cabotegravir 200-mg/mL (CAB200) injections are approved for HIV-1 prevention and as a complete LA HIV-1 treatment regimen with rilpivirine. A high-concentration suspension formulation, cabotegravir 400 mg/mL (CAB400-D), was developed to enable less frequent dosing and self-administration. This phase 1, double-blind, randomized study (NCT04484337) evaluated intramuscular (IM) gluteal, subcutaneous (SC) abdominal, and IM thigh CAB400-D injections (200-800 mg [0.5-2.0 mL]) in adults without HIV, using CAB200 injections as active control. Co-administration with recombinant human hyaluronidase (rHuPH20), topical nonsteroidal anti-inflammatory drug, or topical steroid was evaluated for some SC injections. Pharmacokinetics, adverse events (AEs), and participant-reported outcomes were assessed. Overall, 138 participants were enrolled. Absorption was faster with CAB400-D versus CAB200. Within 4 weeks, CAB400-D plasma exposures were similar across administration routes and higher than those of CAB200. Co-administration with rHuPH20 increased the spontaneous absorption rate of CAB400-D but not CAB200. No deaths or drug-related serious AEs were observed. Five (4%) participants discontinued treatment due to AEs (injection-site reactions [ISRs], n = 3 discontinuations). Most (99%) participants experienced ≥ 1 ISR. Participants reported good acceptability of injections. Although CAB400-D injections demonstrated acceptable safety/tolerability, faster absorption than CAB200 limited potential dosing intervals to monthly dosing. Alternative cabotegravir formulations with longer dosing intervals are under clinical evaluation.

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一项评估高浓度长效卡博特韦制剂在无HIV成人中的药代动力学、安全性和耐受性的随机i期研究。
长效(LA) cabotegravir 200mg /mL (CAB200)注射剂被批准用于HIV-1预防,并与利匹韦林(rilpivirine)一起作为完整的LA HIV-1治疗方案。开发了一种高浓度悬浮液制剂,cabotegravir 400mg /mL (CAB400-D),以减少给药频率和自我给药。这项1期双盲随机研究(NCT04484337)评估了未感染艾滋病毒的成年人臀肌注射(IM)、腹部皮下注射(SC)和大腿皮下注射CAB400-D (200-800 mg [0.5-2.0 mL]),以CAB200注射作为主动对照。与重组人透明质酸酶(rHuPH20)、外用非甾体抗炎药或外用类固醇共同给药对一些SC注射进行了评估。评估药代动力学、不良事件(ae)和参与者报告的结果。总共有138名参与者被招募。CAB400-D比CAB200吸收更快。在4周内,CAB400-D的血浆暴露量在给药途径中相似,且高于CAB200。与rHuPH20共给药可提高CAB400-D的自发吸收率,但对CAB200无明显影响。未观察到死亡或与药物相关的严重不良反应。5名(4%)参与者因ae(注射部位反应[ISRs], n = 3例停药)而停止治疗。大多数(99%)参与者的ISR≥1。参与者报告了注射的良好可接受性。虽然CAB400-D注射剂显示出可接受的安全性/耐受性,但比CAB200更快的吸收将潜在给药间隔限制在每月给药。较长给药间隔的替代性卡布特韦制剂正在临床评估中。
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来源期刊
CiteScore
3.70
自引率
10.00%
发文量
154
期刊介绍: Clinical Pharmacology in Drug Development is an international, peer-reviewed, online publication focused on publishing high-quality clinical pharmacology studies in drug development which are primarily (but not exclusively) performed in early development phases in healthy subjects.
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