부산대학교 도서관

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 pharmacokinetic 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 possibility 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-clinical studies are needed before embarking on expensive and challenging clinical trials of ribavirin in Lassa fever. Author summary: Lassa fever is a disease endemic to West Africa that has been highlighted by the World Health Organisation as one of the top ten threats to global health. Ribavirin has been used to treat Lassa fever for more than 30 years. However, the clinical evidence for ribavirin is poor. We conducted a systematic review of the pre-clinical and human pharmacokinetic data in Lassa. We found that the minimum concentrations of ribavirin that inhibited Lassa virus replication varied hugely according to the experimental design and the type of cell and Lassa virus strain used. There was no comprehensive data on the concentrations of ribavirin in the blood of Lassa fever patients. Modelling of ribavirin concentration data from healthy humans suggest that the doses of ribavirin currently used to treat Lassa fever patients do not reliably achieve the concentrations required to inhibit viral replication. [ABSTRACT FROM AUTHOR]