Abstract
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.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1007/s40261-026-01588-2.
Key Points
| Patients with mild and moderate HI treated with fexinidazole showed slight PK changes in fexinidazole, and its active components M1 and M2, compared with healthy participants. | |
| Findings suggested that the PK changes should not modify the efficacy and safety of fexinidazole in patients with HAT with mild or moderate HI. |
Introduction
Human African trypanosomiasis (HAT), commonly referred to sleeping sickness, is a parasitic disease transmitted by Trypanosoma brucei-infected tsetse flies. It represents a major neglected tropical disease in Africa and remains particularly prevalent in sub‑Saharan areas. In 2000, an estimated 25,000 cases of HAT were reported worldwide. This disease burden declined markedly to fewer than 10,000 cases by 2009 and have continued to decrease, with fewer than 1000 cases reported each year since 2018 [1, 2]. The predominant form of HAT, attributable to T. brucei gambiense, mainly occurs in young adults whose routine activities often increase exposure to infected tsetse flies, thereby enhancing human-to-vector transmission [3, 4]. Prior to 2018, treatments options for HAT consisted of stage-specific injectables targeting either stage 1 (haemolymphatic) or stage 2 (meningoencephalitic) disease, with no single regimen demonstrating efficacy across both stages. Furthermore, these treatments required intravenous administration by skilled personnel, further contributing to the financial burden on patients. Fexinidazole was developed through a collaboration between the Drugs for Neglected Diseases initiative and Sanofi [5–7]. Fexinidazole, recognised as the first all-oral therapy effective against both stages 1 and 2 of the disease, was approved by the European Medicines Agency (EMA) in 2018, the Democratic Republic of Congo in 2019, and the US Food and Drug Administration (FDA) in 2021. The approval of fexinidazole represented a major advance in the management of HAT [5, 6, 8]. Its inclusion in the World Health Organization (WHO) Essential Medicines List in 2019 improved accessibility and positioned it as a comprehensive treatment option for HAT [9]. In 2024, fexinidazole was used to treat 75% of patients diagnosed with gambiense-HAT (g-HAT; caused by T. brucei gambiense) and 56% of patients diagnosed with rhodesiense-HAT (caused by T. brucei rhodesiense), establishing it as the mostly used treatment for sleeping sickness [10]. In 2026, acoziborole, the first single-dose oral treatment obtained a positive opinion from the EMA in patients from 12 years old with body weight ≥ 40 kg diagnosed with g-HAT. However, the use of acoziborole in patients with hepatic impairment (HI) has not been studied, and caution is recommended when treating patients with mild to moderate HI [11]. Its use in patients with severe HI is not recommended. In this context, optimising fexinidazole use in special populations such as patients with HI is clinically relevant.
Fexinidazole (2-substituted 5-nitroimidazole) and its primary metabolites a sulfoxide (M1) and a sulfone (M2) are all pharmacologically active and exhibit broad-spectrum antiprotozoal activity. In vitro studies demonstrated that M1 and M2 possess a slightly more potent trypanocidal activity but within the same order of magnitude as the parent compound (minimum inhibitory concentrations [MIC], 4.7, 2.2 and 5.0 µg/mL, respectively). However, due to their substantially higher systemic exposures in humans (M1 and M2 exposure are 11-fold and 34-fold higher than that of fexinidazole, respectively), M1 and M2 are considered the primary contributors to the therapeutic effect [12]. The chemical structures of fexinidazole and its two primary metabolites, M1 and M2, are presented in Fig. S1. After oral intake, fexinidazole undergoes rapid absorption and substantial metabolism to form its pharmacologically active metabolites, M1 and M2, through several cytochrome P450 (CYP) enzymes, including CYP1A2, 2B6, 2C19, 2D6, 3A4 and 3A5, and flavin-containing monooxygenases (FMOs), without major involvement of a single CYP or FMO [13]. Food intake considerably increases the bioavailability of fexinidazole and its metabolites, resulting in increase of exposure by four-fold to five-fold. Following administration of the recommended therapeutic regimen (1800 mg once daily [OD] for 4 days, followed by 1200 mg OD for 6 days), the median peak plasma concentration (Cmax) occurred at 4 h for fexinidazole and M1 and at 6 h for M2 after the first dose, and the mean terminal half-life (t½z) for fexinidazole, M1 and M2 was 14, 15 and 23 h, respectively, in healthy volunteers under fed conditions [12]. These distinct but overlapping pharmacokinetics (PK) profiles of these three active compounds contribute to the anti-trypanosomal activity of fexinidazole, ensuring effective systemic exposure and therapeutic efficacy. Finally, the single-dose and repeated-dose PK data on fexinidazole and its two metabolites demonstrate that their PK do not deviate from linearity within the range of doses of the therapeutic loading and maintenance doses (1800 and 1200 mg) and over time upon repeated dosing, allowing the use of 1200 mg single-dose findings in the repeated-dosing scenario within the therapeutic range [13].
Studies have indicated that 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 [7]. Consequently, in patients with HI, total clearance may be decreased, potentially resulting in overexposure of fexinidazole and could lead to modification of the exposures of its two metabolites.
Considering the potential PK modification due to HI and the lack of clinical evidence, fexinidazole is contraindicated in patients with severe HI in the USA [14] or in those presenting with clinical signs of cirrhosis or jaundice according to the EMA-approved product information [12]. The present study aims to assess the effect of mild and moderate HI on the PK of fexinidazole, and its active metabolites compared with that in matched participants with normal hepatic function, following a single oral dose of 1200 mg of fexinidazole, to support clinical recommendations for its use in patients with mild and moderate HI. Severe HI was not evaluated in this study due to safety considerations and the contraindication of fexinidazole in this subpopulation [12].
Methods
Study Design
This Phase I, multicentre, open-label, non-randomised study was conducted at two centres, one in Bulgaria and the other in France, from 18 January 2023 to 3 May 2023. The study was performed in accordance with the standards of ethics outlined in the Declaration of Helsinki. All participants received a single oral dose of 1200 mg of fexinidazole. HI was assessed according to the Child–Pugh classification. The participants were divided into three groups: Group 1, with mild HI (n = 7; Child–Pugh score of 5–6); Group 2, with moderate HI (n = 7; Child–Pugh score of 7–9); and Group 3, with normal hepatic function (n = 7). Group 3 participants were matched to those with HI on the basis of body weight, as this was the only significant covariate among the different covariates tested in the population PK (POP PK) model developed for fexinidazole and its two active metabolites in patients with HAT (data not shown). The maximum duration of the study for a participant was 38 days, spanning from the screening visit to the end-of-study visit. Following completion of the study, participants were required to observe a 3-month exclusion period before participating in another clinical study. The study design is illustrated in Fig. S2.
PK Study Objectives
The primary objective of this study was to evaluate the impact of mild and moderate HI on the PK of fexinidazole and its active metabolites, M1 and M2, compared with that in matched participants with normal hepatic function, following a single oral dose of 1200 mg of fexinidazole, as assessed by Cmax and AUCinf of fexinidazole, M1 and M2. The secondary objectives were to assess the effect of mild and moderate HI on additional PK parameters, including the time to reach the maximal concentration and t½z, free fraction of fexinidazole and tolerability of fexinidazole in participants with mild and moderate HI as well as in the matched participants with normal hepatic function.
Study Population
Eligible participants with HI were male or female, were aged 18–75 years, had a body weight ranging from 50.0 to 125.0 kg (for male participants) and 40.0 to 110.0 kg (for female participants) and had a body mass index (BMI) between 18.0 and 34.99 kg/m2. Participants were required to have stable chronic liver disease, normal vital signs and a 12-lead electrocardiogram (ECG) without clinically significant abnormalities. HI was assessed according to the Child–Pugh classification (grading system for liver cirrhosis), with scores of 5–6 and 7–9 indicating mild and moderate HI, respectively. For the matched participants with normal hepatic function, body weight was required to be within 15% of the mean body weight of participants with HI. Seven participants with mild HI, seven participants with moderate HI and seven control participants matched for body weight were included; this sample size is consistent with that recommended in the FDA guidance on PK in patients with impaired hepatic function for study designs including more than one group of participants with HI [15].
Participants with HI were excluded if they had uncontrolled, clinically relevant diseases; signs of acute illness; or significant changes in chronic treatment medication within 14 days before inclusion. Participants using CYP450 potent inducers or inhibitors were also excluded. Matched participants with normal hepatic function were excluded if they had used any medication (including CYP450 inducers/inhibitors or omeprazole) within 14 days before inclusion or had received any vaccination within the previous 28 days (except for that for coronavirus disease 2019 [COVID-19]) or any biologics within 4 months before inclusion. The eligibility criteria are provided in the Supplementary Materials S1.
Study Drugs and Dosage
After an overnight fast, participants consumed a standard breakfast and were subsequently administered fexinidazole (under fed conditions). Each participant was orally administered two tablets (600 mg each) of fexinidazole with 240 mL of water, corresponding to the approved daily maintenance dose of 1200 mg OD for patients with HAT, administered for 6 days following a loading dose regimen of 1800 mg OD for 4 days. The single dose of 1200 mg of fexinidazole under fed conditions was selected for several reasons. Food intake leads to four-fold to five-fold increase in the bioavailability of fexinidazole and its two active metabolites. PK data from single and repeated doses of fexinidazole and its metabolites demonstrate linearity within the therapeutic range, predicting similar effects with repeated dosing. Safety data indicated that fexinidazole was well-tolerated up to 3600 mg, providing an acceptable safety margin for increased exposure in participants with HI. In participants with HI, the formation of M1 could be slightly modified or remain unchanged, and the formation of M2 from M1 could be decreased (as M2 is not further metabolised), rendering a significant increase in their exposures unlikely and eliminating the need to extrapolate safety margins for these metabolites.
PK Assessment
Blood samples were collected for PK analysis of fexinidazole and its metabolites at the pre-dose (within 30 min before dosing) time point on Day 1 and up to 120 h, with specific sampling times at 0.5, 1, 2, 3, 4, 6, 9, 12, 16, 24, 48, 72, 96 and 120 h post-dose, to account for the possible extension of the respective t½z values of fexinidazole, M1 and M2. Additionally, blood samples for the unbound fraction (fu) of fexinidazole were collected at 4 and 24 h post-dose. FDA guidance recommends assessing fu for drugs with extensively plasma protein binding and an fu < 10% [15]. Considering that fexinidazole has a human plasma protein binding of 98%, only its free fraction was assessed. The free fractions of metabolites M1 and M2 were not assessed, as they exhibit low protein binding (14% and 57%, respectively). All plasma samples for the determination of fexinidazole, M1 and M2 plasma concentrations as well as ultrafiltered fexinidazole plasma concentrations were collected in accordance with the protocol-specified sampling schedule. The plasma concentrations of fexinidazole, M1 and M2 were measured using a validated liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) method with a lower limit of quantification (LLOQ) of 5 ng/mL for fexinidazole and M1 and 10 ng/mL for M2. Ultrafiltered plasma concentrations of fexinidazole were measured using a validated LC–MS/MS method with an LLOQ of 0.5 ng/mL. Further methodological details are available in the Supplementary Information provided by Gassiot et al. [13].
The primary endpoints included the observed Cmax and AUCinf of fexinidazole, M1 and M2, while the secondary endpoints for fexinidazole and its metabolites included time to reach Cmax (tmax) and t½z. The fu, unbound maximum plasma concentration observed (Cmaxu) and unbound area under the plasma concentration versus time curve (AUCu) of fexinidazole were also assessed. Considering that fu was similar at both time points (4 and 24 h post-dose) for each participant, the average value was used for the individual calculation of unbound Cmax (Cmax × fu) and unbound AUC (AUC × fu). PK parameters were evaluated using a non-compartmental analysis of plasma concentrations of fexinidazole, M1 and M2 and ultrafiltered plasma concentrations of fexinidazole via validated software (DatAssist NCA 1.0 and Phoenix 8.2.2 [Certara™]). Descriptive analyses, including summary statistics (arithmetic and geometric means, standard deviation [SD], percentage of coefficient of variation [CV], median, minimum and maximum) of PK parameters were carried out. To quantify the effect of mild and moderate HI on PK of fexinidazole and its metabolites compared with that in participants with normal hepatic function, point estimates with 90% confidence interval (CI) of geometric mean ratio were calculated (mild- and moderate-HI groups versus normal-hepatic-function group).
Furthermore, laboratory, ECG, vital signs and physical examination parameters; adverse events (AEs); and Hospital Anxiety and Depression Scale (HADS) scores were assessed to evaluate the tolerability of fexinidazole.
Results
Demographics and Baseline Characteristics
A total of 21 participants—7 with mild HI, 7 with moderate HI and 7 matched controls with normal hepatic function—were enrolled. The baseline characteristics of the study participants are summarised in Table S1. The mean (SD) age of the study population was 50.8 (13.6) years, with the majority being male (81.0%), White (95.2%) and not Hispanic or Latino (95.2%). Overall, participants had a mean ± SD baseline weight and BMI of 82.85 ± 16.68 kg and 26.68 ± 5.12 kg/m2, respectively. The mean ± SD baseline weight and BMI of participants were 79.4 ± 20.68 kg and 25.97 ± 5.96 kg/m2 in the mild-HI group, 90.16 ± 19.31 kg and 29.44 ± 5.96 kg/m2 in the moderate-HI group and 79.26 ± 5.75 kg and 24.64 ± 1.41 kg/m2 in matched participants with normal hepatic function. While the moderate-HI group showed a numerically higher mean weight compared with the controls, the matching criterion (within 15% of the mean body weight of participants with HI) was met. Therefore, the mean weight of participants in the mild- and moderate-HI groups was considered similar to those of the matched participants with normal hepatic function. Of the 14 participants with HI, 7 participants (50.0%) had mild HI with a Child–Pugh score of 5. The remaining seven participants had moderate HI, with four (28.6%) having a Child–Pugh score of 7, two (14.3%) having a score of 8 and one (7.1%) having a score of 9.
PK Profiles and Parameters of Fexinidazole, M1 and M2 by Population
A detailed overview of the PK profiles and descriptive statistics of PK parameters for fexinidazole and its metabolites in participants with mild or moderate HI or those with normal hepatic functions are presented in supplementary material (Figs. S3–5; Tables S2–4).
The mean plasma concentration–time profiles and descriptive statistics of PK parameters for fexinidazole, M1 and M2 after a single 1200 mg oral dose in participants with mild or moderate HI and those with normal hepatic function under fed conditions are illustrated in Fig. 1 and Table 1, respectively.
Fig. 1.
Mean plasma concentrations versus time profile for (a) fexinidazole (n = 7), (b) M1 (n = 7) and (c) M2 (n = 7) after a single oral dose of 1200 mg of fexinidazole administered to participants with mild and moderate hepatic impairment (HI) and the matched healthy participants—semi-log scale until 120 h. HI, hepatic impairment; M1, sulfoxide metabolite; M2 sulfone metabolite
Table 1.
Summary of the descriptive statistics of PK parameters for fexinidazole, M1 and M2 by population
| PK parameters, mean ± SD (geometric mean) [CV%] | Fexinidazole | M1 | M2 |
|---|---|---|---|
| Participants with mild HI (n = 7) | |||
| Cmax (µg/mL) | 0.613 ± 0.182 (0.589) [30.0] | 4.58 ± 1.19 (4.47) [26.0] | 3.95 ± 2.11 (3.61) [54.0] |
| tmaxa (h) | 3.00 (2.00–4.00) | 4.00 (3.00–6.00) | 12.00 (12.00–24.00) |
| AUCinf (μg × h/mL) | 7.97 ± 1.58 (7.82) [20.0] | 60.0 ± 18.0 (57.9) [30.0] | 209 ± 74.5 (200) [36.0] |
| t½z (h) | 19.7 ± 9.76 (17.7) [50.0] | 20.6 ± 8.00 (19.1) [39.0] | 22.1 ± 5.97 (21.4) [27.0] |
| fu | 0.022 ± 0.002 (0.022) [10.0] | – | – |
| Participants with moderate HI (n= 7) | |||
| Cmax (µg/mL) | 0.682 ± 0.357 (0.601) [52.0] | 3.62 ± 1.66 (3.32) [46.0] | 1.78 ± 0.880 (1.49) [50.0] |
| tmaxa (h) | 3.00 (2.00–4.00) | 6.00 (3.00–12.00) | 24.00 (12.00–120.00) |
| AUCinf (μg × h/mL) | 8.81 ± 4.12 (7.60) [47.0] | 104 ± 84.0 (77.3) [81.0] | 134 ± 54.8b (124) [41.0] |
| t½z (h) | 22.4 ± 10.10 (20.2) [45.0] | 20.4 ± 7.67 (19.0) [38.0] | 28.8 ± 7.60b (27.9) [26.0] |
| fu | 0.029 ± 0.005 (0.029) [16.0] | – | – |
| Healthy participants (n = 7) | |||
| Cmax (µg/mL) | 0.636 ± 0.344 (0.571) [54.0] | 4.67 ± 1.27 (4.53) [27.0] | 3.93 ± 0.994 (3.83) [25.0] |
| tmaxa (h) | 4.00 (3.00–4.00) | 4.00 (3.00–4.00) | 12.00 (12.00–24.00) |
| AUCinf (μg × h/mL) | 6.45 ± 2.99 (5.62) [46.0] | 55.2 ± 13.5 (53.6) [25.0] | 197 ± 50.5 (191) [26.0] |
| t½z (h) | 12.9 ± 6.45 (10.8) [50.0] | 15.9 ± 5.79 (14.7) [36.0] | 21.0 ± 2.53 (20.8) [12.0] |
| fu | 0.028 ± 0.003 (0.028) [12.0] | – | – |
AUCinf area under the plasma concentration versus time curve extrapolated to infinity, Cmax maximum plasma concentration observed, CV coefficient of variation, fu unbound fraction, M1 sulfoxide metabolite, M2 sulfone metabolite, PK pharmacokinetics, SD standard deviation, t½z terminal half-life, tmax time to reach Cmax
aMedian (min–max)
bn = 6 because, for one participant in the moderate-HI group, the terminal elimination phase of M2 could not be adequately estimated and was excluded from the calculation of these parameters
The effect of mild or moderate HI on PK parameters (the point estimate with a 90% CI) of fexinidazole, M1 and M2 is summarised in Table 2.
Table 2.
Summary of the population effect on fexinidazole, M1 and M2: Cmax, AUCinf and t½z
| Parameters | Ratio between participants with HI and healthy participants (point estimates and 90% CI) | |||||
|---|---|---|---|---|---|---|
| Ratio between participants with mild HI and healthy participants | Ratio between participants with moderate HI and healthy participants | |||||
| Fexinidazole | M1 | M2 | Fexinidazole | M1 | M2 | |
| Cmax (µg/mL) | 1.13 (0.69–1.86) | 1.12 (0.81–1.55) | 1.35 (0.86–2.10) | 1.09 (0.70–1.70) | 0.76 (0.57–1.03) | 0.44 (0.29–0.65) |
| AUCinf (μg × h/mL) | 1.40 (0.78–2.53) | 1.13 (0.63–2.02) | 1.20 (0.82–1.74) | 1.36 (0.79–2.31) | 1.46 (0.86–2.48) | 0.65 (0.46–0.90) |
| t½z (h) | 1.38 (0.74–2.58) | 1.18 (0.74–1.89) | 0.93 (0.72–1.20) | 1.77 (1.00–3.13) | 1.25 (0.82–1.92) | 1.34 (1.07–1.69) |
AUCinf area under the plasma concentration versus time curve extrapolated to infinity, CI confidence interval, Cmax maximum plasma concentration observed, HI hepatic impairment, M1 sulfoxide metabolite, M2 sulfone metabolite, t½z terminal half-life
Following a single oral dose of 1200 mg of fexinidazole under fed conditions, in participants with mild HI compared with the matched healthy participants:
The mean Cmax and AUCinf of fexinidazole, M1 and M2 were similar or slightly higher by a maximum of 1.40-fold.
The mean fu of fexinidazole was similar.
The mean t½z of fexinidazole, M1 and M2 was similar or slightly longer, by a maximum of 1.38-fold.
Following a single oral dose of 1200 mg of fexinidazole under fed conditions, in participants with moderate HI compared with the matched healthy participants:
For fexinidazole, the mean Cmax and fu were unchanged, and the mean AUCinf and t½z increased by 1.36-fold and 1.77-fold, respectively.
For M1, the mean Cmax decreased by 24%, and the mean AUCinf and t½z increased by 1.46-fold and 1.25-fold, respectively.
For M2, the mean Cmax and AUCinf decreased by 56% and 35%, respectively, and the mean t½z increased by 1.34-fold.
Safety
A total of six mild treatment-emergent adverse events (TEAEs), not related to fexinidazole as per the investigator, were reported in six participants: one with mild HI, one with moderate HI, and four with normal hepatic function. Each of these participants experienced one TEAE following administration of a single oral dose of 1200 mg of fexinidazole (Table S5). No treatment-emergent serious adverse events or TEAEs led to permanent study discontinuation. An adverse event of special interest (decreased neutrophil count) was observed in three participants with normal hepatic function, but none in participants with HI. Corrective therapy was provided to two participants: one with mild HI and one with moderate HI. Each participant received paracetamol for ‘headache’ following administration of a single oral dose of 1200 mg of fexinidazole. No clinically significant anomalies were observed in clinical laboratory parameters, vital signs or ECG in participants with mild and moderate HI and in participants with normal hepatic function, and the HADS score remained stable and normal for all participants during the study.
Discussion
In this multicentre, open-label study, the effect of mild and moderate HI on the PK of fexinidazole and its two active metabolites was assessed after a single oral dose of 1200 mg of fexinidazole. Healthy participants were matched by body weight, as this was the only significant covariate affecting the PK of fexinidazole and its two active metabolites in patients with HAT.
As observed in previous clinical studies in healthy participants and patients, metabolites M1 and M2 are the major active circulating entities [12]. Based on AUCinf values of our study, M1 and M2 exposures were 7.4-fold to 10-fold and 16-fold to 34-fold higher, respectively, than fexinidazole exposure across all three groups (mild HI, moderate HI and normal hepatic function), confirming that M1 and M2 remain the predominant circulating moieties regardless of hepatic function status.
The PK results demonstrated that mild HI has only a limited or no effect on the exposures and PK of fexinidazole (exposure increased by 1.40-fold, and fu remained similar) and its two active metabolites (exposures remained similar, and t½z remained similar or slightly increased by a maximum of 1.38-fold) (Table 2). For moderate HI, the PK results demonstrated mild modifications in the exposure and PK of fexinidazole (exposure and t½z increased by 1.36-fold and 1.77-fold, respectively, with no change in unbound fraction) and its two metabolites (M1 exposure increased by 1.46-fold, whereas M2 exposure decreased by 35%). The mild decrease in M2 exposure is likely due to a decrease in its formation clearance from M1.
Considering the linearity of the PK of fexinidazole, M1 and M2 over time, from single to repeated administration, these findings in participants with mild and moderate HI after a single dose can be directly extrapolated to repeated dosing in patients with mild and moderate HI. With repeated fexinidazole dosing, mild HI is expected to result in a 1.40-fold increase in fexinidazole exposure with no change in M1 and M2 exposures, while moderate HI is expected to lead to 1.36-fold and 1.46-fold increases in fexinidazole and M1 exposures, respectively, with a 35% decrease in M2 exposure. Despite these changes, following the loading or maintenance dose regimen, all resulting exposures should remain within the variability and ranges observed in patients with HAT from the efficacy/safety studies (internal data) and are not expected to raise safety concerns (Fig. S6; Table S6).
M1 and M2 exhibited a similar magnitude of trypanocidal activity against Trypanosoma parasites compared with fexinidazole (MIC values of 4.7 μg/mL and 2.2 μg/mL compared with 5.0 µg/mL) but presented much higher exposures in humans. The recommended therapeutic dosing regimen (1800 mg OD for 4 days, followed by 1200 mg OD for 6 days) allowed for reaching and maintaining systemic M1 and M2 exposures above or close to trypanocidal concentrations throughout the treatment period. Such exposures achieved in patients with HAT in the pivotal efficacy study. Furthermore, exposure–response analyses from the pivotal efficacy study showed no clear relationship between individual M1 or M2 exposures and treatment outcomes (relapse versus cure); specifically, a few patients with relapses had exposures within the range of those without relapses. Overall, the totality of the PK/pharmacodynamic (PD) data shows that trypanocidal activity and efficacy are linked to the total exposure and daily AUC of the two active metabolites rather than their Cmax (data not shown).
It is predicted that, in patients with HAT who have moderate HI, the AUCinf of the main active metabolite M2 would be lower by 35% under the approved therapeutic dosing regimen. In terms of the main pharmacologically active entities, M1 and M2, this decrease in M2 exposure is partly compensated by the 1.46-fold increase in the active metabolite M1 exposure. The sum of the active metabolite’s AUCinf M1 + M2 (M1 is the sulfoxide and M2 is the sulfone of fexinidazole; their molecular weights differ by only 5%) remains in the same range (a ratio of 0.82) in participants with moderate HI versus healthy participants and is predicted to remain similar in patients with HAT who have moderate HI (Table 3).
Table 3.
Geometric mean exposure of M1, M2 and the sum of M1+M2 in participants with moderate HI and healthy participants and corresponding ratio
| M1 | M2 | M1+M2 | |
|---|---|---|---|
| Participants with moderate HI | |||
| AUCinf (μg × h/mL) | 77.3 | 124 | 201 |
| Healthy participants | |||
| AUCinf (μg × h/mL) | 53.6 | 191 | 245 |
| Ratio of participants with moderate HI versus healthy participants | |||
| AUCinf ratio | 1.46 | 0.65 | 0.82 |
AUCinf area under the plasma concentration versus time curve extrapolated to infinity, HI hepatic impairment, M1 sulfoxide metabolite, M2 sulfone metabolite
Overall, these arguments support that the trypanocidal activity and efficacy, as well as the safety, of the approved therapeutic dosing regimen of fexinidazole in patients with HAT who have moderate HI would remain similar to that in those without HI.
Strengths and Limitations
The study was well-designed, with an appropriate fexinidazole dosing regimen and a sample size that enabled a suitable balance between scientific rigour and ethical considerations in this special population.
While the sample size may be considered relatively small and larger studies could potentially yield narrower CIs, the current study design and sample size follow regulatory guidance to provide adequate conclusions to support clinical recommendations. Additionally, this study included participants with mild and moderate HI only; patients with severe HI were not evaluated due to safety considerations and existing contraindications. However, these limitations do not impact the clinical interpretation and recommendation, as the PK evaluation was comprehensive, generating robust in vivo data that consistently demonstrated the mild impact of mild to moderate HI on the PK of fexinidazole following a single dose, which can be directly extrapolated to repeated dosing conditions.
Conclusions
This study, conducted in participants with mild and moderate HI versus the matched healthy participants, showed that mild or moderate HI only slightly modifies the PK of fexinidazole and its two major active metabolites. According to PK results, it is predicted that exposure to fexinidazole and its two major active metabolites will only be slightly modified in patients with HAT who have mild or moderate HI following administration of the approved therapeutic regimen. According to the PK/PD relationships and the efficacy/safety versus PK exposure relationships in patients with HAT from the original submission dossier for the USA and European Union (EU) (data not shown), the efficacy and safety of fexinidazole, M1 and M2 in patients with HAT who have mild or moderate HI should remain similar to that in patients with HAT without HI.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors acknowledge medical writing and editorial assistance provided by Dr. Rini Dhawan and Dr. Pritha Choudhury from Sanofi.
Funding
The study was funded by Sanofi. Sanofi was responsible for the study design and contributed to the conduct of the study, data collection, data analysis, data interpretation and writing of this manuscript.
Declarations
Conflict of interest
Matthieu Gassiot, Jean Pierre Beaucire and Céline Beauchard are employees of Sanofi and may hold stocks and/or stock options in the company. Eric Sultan was an employee of Sanofi when this study was conducted and may hold stock and/or stock options. Sophie Hays and Sarah Lezzar have no conflicts of interest directly relevant to the content of this article.
Data Availability Statement
The data that support the findings of this study are derived from the submitted clinical study report (CSR) and regulatory dossier (2.7.2). These data are not openly available to maintain the confidentiality and privacy of the study participants. For more information, please contact the corresponding author.
Ethics Approval
The study was conducted in accordance with the principles laid down by the Declaration of Helsinki and Good Clinical Practice guidelines (EudraCT No: 2021-004580-27). The study was approved by the Ethics Committee of the Comité de Protection des Personnes (CPP) Sud-Ouest et Outre-Mer II, ARS Occitanie, Toulouse, France (Protocol No. POP17145 V3.0 of 10 March, 2023) and the Ethics Committee for Clinical Trials (ECCT), Sofia, Bulgaria (Notification No. POP17145 V3.0 of 24 April, 2023).
Consent to Participate
Written informed consent was obtained from all participants before their inclusion in the study. Participants were informed of the nature of the trial, its aim, its possible risks, its duration and the compensation they would receive before their selection for the study. All the participants freely gave their written informed consent before any study-related procedures were conducted. A copy of the informed consent forms (ICFs) was given to the participant.
Consent for Publication
Not applicable.
Code Availability
Not applicable.
Authors’ Contributions
G.M. performed formal analyses and interpretation of results. J.P.B. conducted safety assessments. H.S. served as the principal investigator of the study. S.L. performed formal analyses. C.B. led the project. E.S. conceptualised the study and interpreted the results. G.M., J.P.B. and C.B. contributed to writing—review and editing of the manuscript. All authors reviewed the manuscript critically and approved the final version. All authors agreed to be accountable for all aspects of the work.
Footnotes
Eric Sultan: At the time of the study in the Sanofi R&D.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are derived from the submitted clinical study report (CSR) and regulatory dossier (2.7.2). These data are not openly available to maintain the confidentiality and privacy of the study participants. For more information, please contact the corresponding author.