Pharmacokinetics and Tolerability of Fexinidazole in Subjects with Hepatic Impairment.

BACKGROUND: Human African trypanosomiasis (HAT), also known as sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei species. Fexinidazole, an oral treatment for HAT, has shown efficacy in both hemo-lymphatic and meningo-encephalitic stages of the disease. After oral administration, only a small fraction of fexinidazole is eliminated unchanged via the renal route; therefore, hepatic metabolic clearance represents a significant portion of the total clearance of fexinidazole. Consequently, in patients with hepatic impairment (HI), total clearance may be decreased, potentially resulting in overexposure of fexinidazole and could lead to modification of the exposures of its two metabolites. This study aims to evaluate the effect of mild and moderate HI on the pharmacokinetics (PK) of fexinidazole and its active metabolites compared with that in participants with normal hepatic function. METHODS: This Phase I, multicentric, open-label, non-randomised study included 21 participants divided into three groups: mild HI (n = 7), moderate HI (n = 7) and normal hepatic function (n = 7). Each participant received a single oral dose of 1200 mg fexinidazole under fed conditions. PK parameters, including the maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUCinf) and terminal half-life (t½z), of fexinidazole and its metabolites M1 (sulfoxide metabolite) and M2 (sulfone metabolite) were assessed. Safety and tolerability were evaluated through adverse events, laboratory tests and vital signs. RESULTS: In participants with mild HI, the mean Cmax and AUCinf of fexinidazole, M1 and M2 were similar to or slightly higher (up to 1.40-fold; 90% confidence interval [CI]: 0.78-2.53) than those of healthy controls. In participants with moderate HI, the mean Cmax and AUCinf of fexinidazole and M1 were similar or slightly higher (up to 1.46-fold; 90% CI 0.86-2.48), whereas the mean Cmax and AUCinf of M2 were lower (0.44-fold for Cmax [90% CI 0.29-0.65] and 0.65-fold for AUCinf [90% CI 0.46-0.90]). The t½z of fexinidazole, M1 and M2 was longer in subjects with moderate HI (up to 1.77-fold). The unbound fraction of fexinidazole remained unchanged in both the mild- and moderate-HI groups. Six mild treatment-emergent adverse events (TEAEs) (one each in the mild- and moderate-HI groups and four in participants with normal hepatic function), not related to the study drug as per the investigator, were reported. All TEAEs had resolved by the end of the study. No serious adverse events or deaths occurred. CONCLUSIONS: A single oral dose of 1200 mg of fexinidazole showed a good safety profile and was well-tolerated in participants with mild and moderate HI and matched healthy controls. These slight PK modifications suggest they should not modify the efficacy and safety of fexinidazole in patients with HAT who have mild or moderate HI, compared with those without HI, supporting its use in this population with appropriate clinical recommendations. TRIAL REGISTRATION: EudraCT No.: 2021-004580-27.