title: Evidence of a drug-drug interaction linked to inhibition of ester hydrolysis by orlistat.
abstract: : Orlistat, a lipase inhibitor taken with meals at doses of 60 mg (available over-the-counter) or 120 mg (prescription only) for treatment of obesity, is known to impair the absorption of fat-soluble molecules. Dalcetrapib, a modulator of cholesteryl ester transfer protein activity, is a lipophilic thioester prodrug. Lipase-induced and pancreatin-induced hydrolysis of dalcetrapib in biorelevant media in vitro was very efficiently inhibited by orlistat. Thus, the potential for orlistat to affect the bioavailability of concomitantly administered dalcetrapib was studied in an open-label 2-cohort study in 24 healthy volunteers as follows: single 600-mg doses of dalcetrapib were administered with increasing doses of orlistat (cohort A: 10, 40, 120 mg; cohort B: 20, 60, 120 mg). Exposure to the active form of dalcetrapib was more than 50% lower when taken with orlistat 60 mg or 120 mg than when taken alone. Similar trends were observed with lower orlistat doses (20 mg and 40 mg). Concomitant administration of orlistat also reduced the pharmacodynamic effects of dalcetrapib treatment on cholesteryl ester transfer protein activity. The interaction exceeds that predicted on the basis of dalcetrapib lipophilicity. These findings demonstrate the potential for large interactions between orlistat and esters that undergo de-esterification in the gastrointestinal tract, independent of lipophilicity.
authors: Pharma Research and early Development, Roche Products Ltd, Welwyn Garden City, United Kingdom. darren.bently@roche.com
authors: Darren
authors: D
authors: Bentley
authors: Anne-Marie
authors: AM
authors: Young
authors: Lucy
authors: L
authors: Rowell
authors: Günter
authors: G
authors: Gross
authors: Joseph
authors: J
authors: Tardio
authors: David
authors: D
authors: Carlile
mesh_terms: D000328:Adult; D000577:Amides; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000924:Anticholesteremic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D053480:Cholesterol Ester Transfer Proteins / Q000187:drug effects / Q000378:metabolism; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004952:Esters; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006868:Hydrolysis; D007783:Lactones / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D000077403:Orlistat; D011355:Prodrugs; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000577:Amides; D019440:Anti-Obesity Agents; D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D004952:Esters; D007783:Lactones; D011355:Prodrugs; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; D000077403:Orlistat