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The ileal bile acid transporter inhibitor A4250 decreases serum bile acids by interrupting the enterohepatic circulation . BACKGROUND Reabsorption of bile acids from the intestine by ileal bile acid transporter is pivotal for the enterohepatic circulation of BAs and sterol homoeostasis . AIM To assess tolerability and study , bile acid metabolism in a phase 1 trial with the selective ileal bile acid transporter inhibitor A4250 . METHODS A randomised double-blind , single-ascending dose ( SAD ) and multiple-ascending-dose study consisting of five cohorts comprising 40 individuals with a single administration of A4250 ( 0.1 , 0.3 , 1 , 3 , or 10 mg ) or placebo and three cohorts comprising 24 individuals with a 1-week administration of A4250 ( 1 or 3 mg once daily or 1.5 mg twice daily ) or placebo . For the multiple-ascending-dose study , bile acids were measured by HPLC-MS in plasma and faeces , and fibroblast growth factor 19 ( FGF19 ) and 7α-hydroxy-4-cholesten-3-one ( C4 ) were measured in plasma . RESULTS No serious adverse events occurred and all participants finished the trial per protocol . At the end of the multiple-ascending-dose study , plasma total bile acids and FGF19 decreased by 47 % and 76 % , respectively , at 3 mg/day ( P < 0.01 ) , and by 15 % and 16 % , respectively , at 1.5 mg twice daily ( P < 0.05 ) . Plasma C4 and faecal bile acids increased at all dose regimens , by 555 % , 664 % , 292 % and 338 % , 421 % , 420 % , respectively ( P < 0.01-0.05 ) . The primary bile acids cholic and chenodeoxycholic acids constituted the majority of faecal bile acids in the A4250-treated groups . CONCLUSIONS A4250 is well tolerated . By blocking ileal bile acid transporter in the terminal ileum , it highly efficiently interrupts the enterohepatic circulation of BAs , and should be of benefit to patients with cholestatic liver diseases . Clinical Trial registration EudraCT 2013-001175-21 .
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Intervention_Pharmacological
ileal bile acid transporter inhibitor A4250
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Intervention_Pharmacological
A4250
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Outcome_Physical
serum bile acids
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Outcome_Other
tolerability
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Outcome_Physical
bile acid metabolism
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Participant_Sample-size
40
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Participant_Sample-size
24
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Participant_Condition
cholestatic liver