A Pharmacokinetic and Tolerability Study of Fexinidazole in a Single Oral Dose in Adult Participants With Mild and Moderate Hepatic Impairment

In human, metabolic hepatic clearance represents a significant part of the total clearance of fexinidazole and could be decreased in patients with liver impairment, leading to some overexposure, and conversely, the formation of the 2 active metabolites could be decreased, leading to decreased exposure in hepatic impairment (HI).As there is no experience of use in patients with hepatic impairment, in fexinidazole summary of product characteristics (SmPC) approved by the European Medicines Agency (EMA), fexinidazole is contra-indicated in patients with clinical signs of cirrhosis or jaundice, and in the proposed USA product information, fexinidazole is contra-indicated in patients with liver impairment.Therefore, FDA requested a study with the objective to evaluate the effect of mild and moderate hepatic impairment (HI) on the pharmacokinetics (PK) of fexinidazole and its 2 metabolites, as a post-marketing requirement.

Inclusion Criteria:Male or female participants, between 18 and 75 years of age, inclusive12-lead ECG without clinically significant abnormality, in the judgment of the Investigator; normal QT interval confirmedContraception (with double contraception methods) for male and female (unless postmenopausal) participants; not pregnant or breastfeeding for female participants; no sperm donation for male participants.Having given written informed consent prior to any procedure related to the studyCovered by a health insurance system where applicable, and/or in compliance with the recommendations of the national laws in force relating to biomedical researchNot under any administrative or legal supervisionParticipants with HIBody weight between 50.0 and 125.0 kg, inclusive if male, and between 40.0 and 110.0 kg, inclusive if female, body mass index (BMI) between 18.00 and 34.99 kg/m2, inclusiveStable chronic liver disease assessed by medical history, physical examination, laboratory valuesVital signs after 10 minutes resting in supine position within the following range [or if out of range, considered not clinically significant (NCS) by the Investigator]:95 mmHg < systolic blood pressure (SBP) < 180 mmHg45 mmHg < diastolic blood pressure (DBP) < 100 mmHg40 bpm < HR < 100 bpmLaboratory parameters within the acceptable range for participants with HI; however, serum creatinine should be strictly below the upper laboratory normFor moderate HI cohort: Child-Pugh total score ranging from 7 to 9, inclusiveFor mild HI cohort: Child-Pugh total score ranging from 5 to 6, inclusiveMatched participants with normal hepatic functionBody weight within 15% of the mean body weight of the participants with HI to be matched, and BMI between 18.00 and 34.99 kg/m2, inclusiveCertified as healthy by a comprehensive clinical assessmentVital signs after 10 minutes resting in the supine position within the following range:95 mmHg < SBP < 160 mmHg45 mmHg < DBP < 90 mmHg40 bpm < HR < 100 bpmLaboratory parameters within the normal range, excluding specific exceptions allowed per protocol.Exclusion Criteria:Participant has clinical signs and symptoms consistent with COVID-19, e.g., fever, dry cough, dyspnea, loss of taste and smell, sore throat, fatigue or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening. Participant who had severe course of COVID-19Positive test for SARS-CoV-2Blood donation within 2 months before inclusionPostural hypotension - symptomatic or asymptomatic (decrease in SBP ≥ 30 mmHg within 3 minutes).Excessive consumption of beverages with xanthine basesCOVID-19 vaccination: last administration of a vaccine within 1 week (symptom free) to 2 weeks before inclusionAny participant who, in the judgment of the Investigator, is likely to be noncompliant during the study, or unable to cooperate because of a language problem or poor mental developmentAny participant in the exclusion period of a previous study according to applicable regulationsAny participant who cannot be contacted in case of emergencyPositive alcohol breath testAny consumption of citrus fruits or their juices within 5 days before inclusionUnable or not agreeing to self-complete the hospital anxiety and depression scale (HADS)Hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.Positive result on anti-human immunodeficiency virus 1 and/or 2 antibodiesParticipants with HIUncontrolled clinically relevant cardiovascular, pulmonary, gastrointestinal, metabolic, hematological, neurological, psychiatric, systemic, ocular, gynecological (if female), or infectious disease, or signs of acute illnessHepatocarcinomaAcute hepatitisHepatic encephalopathy grade 2, 3, and 4Presence or history of drug hypersensitivity, or allergic disease, including active seasonal rhinitis, diagnosed and treated by a physicianHistory or presence of regular use of recreational drugs or alcohol abuse within 2 years before inclusionSmoking more than 15 cigarettes or equivalent per day, unable to refrain from smoking over 5 cigarettes per day from D-1 and throughout the entire institutionalizationAny significant change in chronic treatment medication within 14 days before inclusionConsumption of CYP450 potent inducers or inhibitors that could impact the pharmacokinetics of the investigational productPositive results on urine drug screen outside documented medical prescriptionPre-existing cardiac disease, long QT syndrome, or use of drugs known to block potassium channels, prolong the QT interval and/or induce bradycardiaMatched participants with normal hepatic functionAny history or presence of clinically relevant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, metabolic, hematological, neurological, osteomuscular, articular, psychiatric, systemic, ocular, gynecological (if female), or infectious disease, or signs of acute illnessFrequent headaches and/or migraine, recurrent nausea and/or vomitingPresence or history of drug hypersensitivity, or allergic disease diagnosed and treated by a physician, except seasonal rhinitisHistory or presence of regular use of recreational drugs or alcohol abuseSmoking more than 5 cigarettes or equivalent per day, unable to stop smoking from D-1 and throughout the entire institutionalizationAny medication (including CYP450 inducers or inhibitors, or omeprazole) within 14 days before inclusion or within 5 times the elimination half-life or pharmacodynamic (PD) half-life of the medication (except HRT and contraception when applicable), any vaccination within the last 28 days (except COVID-19 vaccination) and any biologics (antibody or its derivatives) given within 4 months before inclusionPositive result on any of the following tests: hepatitis B surface antigen, antihepatitis B core antibodies, anti-hepatitis C virus antibodiesPositive result on urine drug screenThe above information is not intended to contain all considerations relevant to a potential participation in a clinical trial.