Chandasana Hardik, Buchanan Ann M, McKenna Michael, Brothers Cindy, Hyatt Stephen, Adkison Kimberly, Goyal Navin, Tan Lionel K
GSK, Collegeville, PA, USA.
ViiV Healthcare, Durham, NC, USA.
J Clin Pharmacol. 2024 Sep 5;65(1):18-27. doi: 10.1002/jcph.6128.
In March 2022, the US Food and Drug Administration expanded indications of TRIUMEQ, a once-daily fixed-dose combination (FDC) containing abacavir (ABC), dolutegravir (DTG), and lamivudine (3TC) to include pediatric patients weighing at least 10 kg for the treatment of HIV-1. Prior to this extension, the ABC 600 mg/DTG 50 mg/3TC 300 mg FDC tablet was approved for use only in the adult/adolescent population, weighing ≥40 kg while each component of the FDC was approved for its use in pediatric patients at least 3 months and older. A new child-friendly formulation was developed as an FDC dispersible tablet (DT) of ABC 60 mg/DTG 5 mg/3TC 30 mg for pediatric patients with a body weight ≥ 6 kg. The present work demonstrates the utility of applying a model-informed drug development (MIDD) approach to expedite ABC/DTG/3TC FDC approval for pediatric patients (≥10 to <40 kg) based on data from the existing individual components and formulation bridging. Population pharmacokinetic models developed for pediatric participants across all three components of ABC/DTG/3TC FDC were employed for exposure prediction and incorporated relative bioavailability data. The predicted plasma exposures of ABC, DTG, and 3TC for FDC doses were consistent with those observed for the single entities in pediatric and adult studies. Thus, safety and efficacy observed in the individual component studies could be adequately extrapolated to the FDC that results in similar exposure. The current work demonstrates the significance of MIDD approaches in facilitating expedited access to child-friendly formulations in the HIV-1 therapeutic area.
2022年3月，美国食品药品监督管理局扩大了绥美凯（TRIUMEQ）的适应症，这是一种每日一次的固定剂量复方制剂（FDC），含有阿巴卡韦（ABC）、多替拉韦（DTG）和拉米夫定（3TC），可用于治疗体重至少10公斤的HIV-1感染儿科患者。在此扩展之前，ABC 600毫克/DTG 50毫克/3TC 300毫克FDC片剂仅被批准用于体重≥40公斤的成人/青少年人群，而FDC的每个成分都被批准用于至少3个月及以上的儿科患者。针对体重≥6公斤的儿科患者，开发了一种新的适合儿童使用的剂型，即ABC 60毫克/DTG 5毫克/3TC 30毫克的FDC分散片（DT）。本研究基于现有单一成分的数据和剂型桥接，展示了应用模型指导药物研发（MIDD）方法加快ABC/DTG/3TC FDC在儿科患者（≥10至<40公斤）中的批准的实用性。为ABC/DTG/3TC FDC的所有三个成分的儿科参与者开发的群体药代动力学模型用于暴露预测，并纳入了相对生物利用度数据。FDC剂量下ABC、DTG和3TC的预测血浆暴露量与儿科和成人研究中单一实体观察到的暴露量一致。因此，在单一成分研究中观察到的安全性和有效性可以充分外推至导致相似暴露的FDC。当前研究证明了MIDD方法在促进HIV-1治疗领域更快获得适合儿童使用的剂型方面的重要性。
