Amilon Carl, Boberg Mikael, Tarning Joel, Äbelö Angela, Ashton Michael, Jansson-Löfmark Rasmus
Unit for Pharmacokinetics and Drug Metabolism, Sahlgrenska Academy, University of Gothenburg, Box 431, S-405 30, Gothenburg, Sweden.
DMPK, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
AAPS J. 2022 Mar 25;24(3):48. doi: 10.1208/s12248-022-00693-2.
Eflornithine is a recommended treatment against late-stage gambiense human African trypanosomiasis, a neglected tropical disease. Standard dosing of eflornithine consists of repeated intravenous infusions of a racemic mixture of L- and D-eflornithine. Data from three clinical studies, (i) eflornithine intravenous monotherapy, (ii) nifurtimox-eflornithine combination therapy, and (iii) eflornithine oral monotherapy, were pooled and analyzed using a time-to-event pharmacodynamic modeling approach, supported by in vitro activity data of the individual enantiomers. Our aim was to assess (i) the efficacy of the eflornithine regimens in a time-to-event analysis and (ii) the feasibility of an L-eflornithine-based therapy integrating clinical and preclinical data. A pharmacodynamic time-to-event model was used to estimate the total dose of eflornithine, associated with 50% reduction in baseline hazard, when administered as monotherapy or in the nifurtimox-eflornithine combination therapy. The estimated total doses were 159, 60 and 291 g for intravenous eflornithine monotherapy, nifurtimox-eflornithine combination therapy and oral eflornithine monotherapy, respectively. Simulations suggested that L-eflornithine achieves a higher predicted median survival, compared to when racemate is administered, as treatment against late-stage gambiense human African trypanosomiasis. Our findings showed that oral L-eflornithine-based monotherapy would not result in adequate efficacy, even at high dose, and warrants further investigations to assess the potential of oral L-eflornithine-based treatment in combination with other treatments such as nifurtimox. An all-oral eflornithine-based regimen would provide easier access to treatment and reduce burden on patients and healthcare systems in gambiense human African trypanosomiasis endemic areas. Graphical abstract.
依氟鸟氨酸是治疗晚期冈比亚型人类非洲锥虫病（一种被忽视的热带疾病）的推荐药物。依氟鸟氨酸的标准给药方案是反复静脉输注L-和D-依氟鸟氨酸的外消旋混合物。来自三项临床研究的数据，即（i）依氟鸟氨酸静脉单药治疗、（ii）硝呋莫司-依氟鸟氨酸联合治疗和（iii）依氟鸟氨酸口服单药治疗，在单个对映体的体外活性数据支持下，采用事件发生时间药效学建模方法进行汇总和分析。我们的目的是评估（i）依氟鸟氨酸治疗方案在事件发生时间分析中的疗效，以及（ii）基于L-依氟鸟氨酸的治疗方案整合临床和临床前数据的可行性。使用药效学事件发生时间模型来估计依氟鸟氨酸作为单药治疗或与硝呋莫司联合治疗时，与基线风险降低50%相关的总剂量。静脉注射依氟鸟氨酸单药治疗、硝呋莫司-依氟鸟氨酸联合治疗和口服依氟鸟氨酸单药治疗的估计总剂量分别为159克、60克和291克。模拟结果表明，作为晚期冈比亚型人类非洲锥虫病的治疗药物，与使用外消旋体相比，L-依氟鸟氨酸的预测中位生存期更高。我们的研究结果表明，即使高剂量使用，基于口服L-依氟鸟氨酸的单药治疗也不会产生足够的疗效，需要进一步研究以评估基于口服L-依氟鸟氨酸的治疗与其他治疗方法（如硝呋莫司）联合使用的潜力。基于依氟鸟氨酸的全口服治疗方案将使治疗更容易获得，并减轻冈比亚型人类非洲锥虫病流行地区患者和医疗系统的负担。图形摘要。
