RESUMO
Firsocostat is an oral, liver-targeted inhibitor of acetyl-coenzyme A carboxylase in development for the treatment of metabolic dysfunction-associated steatohepatitis. Hepatic organic anion transporting polypeptides play a significant role in the disposition of firsocostat with minimal contributions from uridine diphospho-glucuronosyltransferase and cytochrome P450 3A enzymes. This phase 1 study evaluated the pharmacokinetics and safety of firsocostat in participants with mild, moderate, or severe hepatic impairment. Participants with stable mild, moderate, or severe hepatic impairment (Child-Pugh A, B, or C, respectively [n = 10 per cohort]) and healthy matched controls with normal hepatic function (n = 10 per cohort) received a single oral dose of firsocostat (20 mg for mild and moderate hepatic impairment; 5 mg for severe hepatic impairment) with intensive pharmacokinetic sampling over 96 h. Safety was monitored throughout the study. Firsocostat plasma exposure (AUCinf) was 83%, 8.7-fold, and 30-fold higher in participants with mild, moderate, and severe hepatic impairment, respectively, relative to matched controls. Firsocostat was generally well tolerated, and all reported adverse events were mild in nature. Dose adjustment is not necessary for the administration of firsocostat in patients with mild hepatic impairment. However, based on the observed increases in firsocostat exposure, dose adjustment should be considered for patients with moderate or severe hepatic impairment, and additional safety and efficacy data from future clinical trials will further inform dose adjustment.
Assuntos
Acetil-CoA Carboxilase , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Acetil-CoA Carboxilase/antagonistas & inibidores , Adulto , Idoso , Furanos/farmacocinética , Furanos/efeitos adversos , Furanos/administração & dosagem , Hepatopatias , Área Sob a Curva , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/uso terapêutico , Índice de Gravidade de Doença , Isobutiratos/farmacocinética , Isobutiratos/efeitos adversos , Isobutiratos/administração & dosagem , Oxazóis , PirimidinasRESUMO
BACKGROUND: NAD(+) is an endogenous analyte and is unstable during blood sample collection, both of which present obstacles for quantitation. Moreover, current procedures for NAD(+) sample collection require onsite treatment with strong acid to stabilize the NAD(+) in mouse blood cells. RESULTS: NAD(+) can be stabilized by addition of acid before the frozen mouse blood sample was thawed. A simple sample collection procedure was proposed to facilitate the analysis of NAD(+) in mouse blood and tissue samples. A LC-MS/MS method was developed for quantifying NAD(+) in mouse blood and various tissue samples. The described method was used to measure endogenous NAD(+) levels in mouse blood following oral administration of the nicotinamide phosphoribosyltransferase inhibitor GNE-617. CONCLUSION: This study presents a suitable assay and sample collection procedure for high throughput screening of NAD(+) samples in preclinical discovery studies.