Chemical formula: C₄₀H₅₆ClN₃O₄S Molecular mass: 674.96 g/mol
Maralixibat is a minimally absorbed, reversible, potent, selective inhibitor of the ileal bile acid transporter (IBAT).
Maralixibat acts locally in the distal ileum to decrease the reuptake of bile acids and increase the clearance of bile acids through the colon, reducing the concentration of bile acids in the serum.
The target of maralixibat is in the lumen of the small intestine, such that plasma levels of maralixibat are not required and not relevant to its efficacy. Maralixibat is minimally absorbed, and plasma concentrations are often below the limit of detection (0.25 ng/mL) after single or multiple doses at therapeutic dose levels. The absolute bioavailability is estimated to be <1%.
Maralixibat absorption is relatively higher when administered in the fasted state, but no dose adjustment for food effects is necessary. Maralixibat can be taken before (up to 30 minutes) or with a meal, in the morning.
Maralixibat shows high binding (91%) to human plasma in vitro. In a clinical ADME trial dosing [14C] maralixibat, circulating radioactivity was below the limit of detection at all time points. There is no apparent accumulation of maralixibat.
No metabolites have been detected in plasma, and maralixibat also undergoes minimal metabolism in the gastrointestinal tract.
Maralixibat is primarily eliminated in the faeces as unmetabolised parent compound, with 0.066% of the administered dose excreted in the urine.
No clinically significant differences in the pharmacokinetics of maralixibat were observed based on age, sex, or race.
Clinical studies of maralixibat included ALGS patients with some level of liver impairment. The majority of ALGS patients presented with some degree of hepatic impairment according to the NCI-ODWG classification due to the disease. Whether this classification is, however, appropriate in cholestatic disease, and in ALGS to predict the influence on PK of the compound is currently unclear. Maralixibat is minimally absorbed, and animal data indicate that the very low plasma levels are due to low absorption and not a first pass effect in the liver, and plasma levels of maralixibat were not increased in ALGS patients with liver impairment according to the NCI-ODWG. However, the PK of maralixibat have not been systematically investigated in patients classified according to the Child-Pugh classification (patients with cirrhosis and signs of decompensation).
The pharmacokinetics of maralixibat were not studied in patients with impaired renal function, including those with ESRD or those on haemodialysis. However, renal impairment is not expected to impact maralixibat PK due to the low systemic exposure and lack of urinary excretion.
Non-clinical data reveal no specific hazard for humans based on studies of safety pharmacology, secondary pharmacology, repeated-dose toxicity, genotoxicity, fertility, toxicity to reproduction and development, and juvenile animal toxicity.
There were higher incidences of bronchiolo-alveolar adenoma and carcinoma following oral administration of maralixibat to male TgRasH2 mice at doses of 25 mg/kg/day for 26 weeks, but the incidence of these lung findings remained within the documented range of historical control data for the mouse strain, and human relevance of these findings is unknown. A 2-year rat carcinogenicity study is still ongoing.
No effects on fertility were observed in female rats treated orally with up to 2 000 mg/kg/day or in male rats treated orally with up to 750 mg/kg/day.
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