Ribavarin for treating Lassa fever: A systematic review of pre-clinical studies and implications for human dosing

Alex P. Salam*, Alexandre Duvignaud, Marie Jaspard, Denis Malvy, Miles Carroll, Joel Tarning, Piero L. Olliaro, Peter W. Horby

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Ribavirin is currently the standard of care for treating Lassa fever. However, the human clinical trial data supporting its use suffer from several serious flaws that render the results and conclusions unreliable. We performed a systematic review of available pre-clinical data and human pharmacokinetic data on ribavirin in Lassa. In in-vitro studies, the EC50 of ribavirin ranged from 0.6 μg/ml to 21.72 μg/ml and the EC90 ranged from 1.5 μg/ml to 29 μg/ml. The mean EC50 was 7 μg/ml and the mean EC90 was 15 μg/ml. Human PK data in patients with Lassa fever was sparse and did not allow for estimation of concentration profiles or pharma-cokinetic parameters. Pharmacokinetic modelling based on healthy human data suggests that the concentration profiles of current ribavirin regimes only exceed the mean EC50 for less than 20% of the time and the mean EC90 for less than 10% of the time, raising the pos-sibility that the current ribavirin regimens in clinical use are unlikely to reliably achieve serum concentrations required to inhibit Lassa virus replication. The results of this review highlight serious issues with the evidence, which, by today standards, would be unlikely to support the transition of ribavirin from pre-clinical studies to human clinical trials. Additional pre-clini-cal studies are needed before embarking on expensive and challenging clinical trials of riba-virin in Lassa fever.

Original languageEnglish
Article numbere0010289
JournalPLoS Neglected Tropical Diseases
Volume16
Issue number3
DOIs
Publication statusPublished - Mar 2022
Externally publishedYes

Bibliographical note

Funding Information:
APS is funded by UK aid from the Department of Health and Social Care via the UK Public Health Rapid Support Team Research Programme. The funder had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

Publisher Copyright:
© 2022 Salam et al.

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