Population pharmacodynamic modeling of eflornithine-based treatments against late-stage gambiense human African trypanosomiasis and efficacy predictions of l-eflornithine-based therapy

Journal article

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.

Authors: Amilon, C; Boberg, M; Tarning, J; Äbelö, A; Ashton, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Spinger Nature
• Journal: The AAPS journal
• Volume: 24
• Issue: 3
• Article number: 48
• Publication date: 2022-03-25
• Acceptance date: 2022-02-21
• DOI: 10.1208/s12248-022-00693-2
• EISSN: 1550-7416
• Pmid: 35338410
• Language: English
• Keywords: enantiomers; time-to-event analysis; nonlinear mixed-effects modeling; sleeping sickness; neglected tropical diseases; FFR