From GlaxoSmithKline, Collegeville, PA.
ViiV Healthcare, Research Triangle Park, NC.
Pediatr Infect Dis J. 2022 Mar 1;41(3):230-237. doi: 10.1097/INF.0000000000003366.
The World Health Organization (WHO) 2019 antiretroviral treatment guidelines recommend use of optimal treatment regimens in all populations. Dolutegravir-based regimens are the preferred first-line and second-line treatment in infants and children with HIV 4 weeks of age and above. There is an urgent need for optimal pediatric formulations of dolutegravir as single-entity (SE) and fixed-dose combination (FDC) to ensure correct dosing and adherence for swallowing and palatability. This article outlines the chronology of dolutegravir pediatric formulation development as granules and conventional and dispersible tablets in a total of 5 pharmacokinetic studies evaluating the relative bioavailability of dolutegravir SE and FDC formulations in healthy adults.
The relative bioavailability studies were 2-part, Phase I, open-label, randomized studies in healthy adults. Dolutegravir SE study compared conventional dolutegravir 50 and 25 mg with equivalent conventional 10-mg and dispersible 5-mg tablets, respectively. Subsequently, dolutegravir FDC study compared adult FDC of abacavir/dolutegravir/lamivudine and adult FDC of dolutegravir/lamivudine with their respective pediatric FDC formulations, taken as dispersion immediately or swallowed whole.
As observed in previous studies, dolutegravir administered as dispersion (granules/dispersible tablets) showed relatively higher bioavailability compared with conventional tablets. The bioavailability of dolutegravir dispersible tablets (both SE and FDC) was approximately 1.6-fold higher when compared with conventional tablets. In addition, the bioavailability of abacavir/lamivudine was not impacted by dispersible formulation.
These studies demonstrate the successful development of pediatric dolutegravir-containing formulations as SE and FDC that permit pediatric dosing in line with WHO recommendations.
世界卫生组织（WHO）2019 年抗逆转录病毒治疗指南建议在所有人群中使用最佳治疗方案。在 4 周龄及以上的 HIV 感染婴儿和儿童中，基于多替拉韦的方案是首选的一线和二线治疗方案。迫切需要开发多替拉韦的最佳儿科制剂，包括单药制剂（SE）和固定剂量复方（FDC），以确保正确的剂量和吞咽及口感的依从性。本文概述了多替拉韦儿科制剂作为颗粒剂以及普通片剂和分散片的开发历程，总共进行了 5 项药代动力学研究，评估了健康成年人中单药制剂和 FDC 制剂多替拉韦的相对生物利用度。
这些相对生物利用度研究是 2 部分、I 期、开放标签、随机研究，在健康成年人中进行。多替拉韦 SE 研究比较了常规多替拉韦 50mg 和 25mg 与等效的常规 10mg 和分散片 5mg 片剂，随后，多替拉韦 FDC 研究比较了阿巴卡韦/多替拉韦/拉米夫定成人 FDC 和多替拉韦/拉米夫定成人 FDC 与各自的儿科 FDC 制剂，作为混悬液立即服用或整片吞服。
与之前的研究一样，多替拉韦作为混悬液（颗粒/分散片）给药时显示出相对较高的生物利用度，与普通片剂相比。多替拉韦分散片（SE 和 FDC）的生物利用度比普通片剂高约 1.6 倍。此外，拉米夫定的生物利用度不受分散片制剂的影响。
这些研究表明，成功开发了包含多替拉韦的儿科制剂，包括 SE 和 FDC，可按照世卫组织的建议进行儿科剂量。
