title: Effect of hepatic impairment on the pharmacokinetics of pasireotide (SOM230): results from a multicenter phase I study.
abstract: Pasireotide is a novel, multireceptor-targeted somatostatin analogue with high affinity for sst(1,2,3) and sst(5) under clinical evaluation in tumors of neuroendocrine origin, including Cushing's disease, acromegaly, and neuroendocrine tumors. In this phase I, open-label, multicenter study, the pharmacokinetics and safety of a single subcutaneous (SC) injection of pasireotide 600 µg were evaluated in adults with normal hepatic function (n = 15) and mild (n = 6), moderate (n = 7), or severe hepatic impairment (n = 6). Following a single dose of pasireotide SC 600 µg, there were no significant differences in the plasma exposure of pasireotide between participants with normal hepatic function or mild hepatic impairment. Subjects with moderate and severe hepatic impairment showed an increase in AUC(∞) by 56% and 42%, respectively; this increase was 60% and 79% respectively, after adjusting for differences in age, BMI, and baseline serum albumin level between treatment groups. The incidence and severity of adverse events were similar across cohorts, with no clinically relevant differences in type or frequency of adverse events between cohorts. In conclusion, a single dose of pasireotide SC 600 µg was well tolerated in subjects with hepatic impairment. Drug exposure in subjects with mild hepatic impairment was similar to that seen in healthy volunteers, whereas subjects with moderate and severe hepatic impairment experienced higher exposure to pasireotide. Adjustment of the pasireotide dose may be required for patients with moderate and severe hepatic impairment.
authors.affiliation: Clinical Pharmacology Unit, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Louvain-la-Neuve, Belgium. Yves.Horsmans@uclouvain.be
authors.forename: Yves
authors.initials: Y
authors.lastname: Horsmans
authors.forename: Ke
authors.initials: K
authors.lastname: Hu
authors.forename: Matthieu
authors.initials: M
authors.lastname: Ruffin
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Dongweon
authors.initials: D
authors.lastname: Song
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bouillaud
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Dago
authors.initials: D
authors.lastname: Mazur
authors.forename: Frans-Peter
authors.initials: FP
authors.lastname: Botha
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Heuman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D013004:Somatostatin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D013004:Somatostatin; C517782:pasireotide