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Endocrine Abstracts (2019) 63 OC13.4 | DOI: 10.1530/endoabs.63.OC13.4

ECE2019 Oral Communications Anterior and Posterior pituitary 2 (5 abstracts)

Pharmacokinetics of somapacitan in individuals with hepatic impairment: an open-label, parallel group, phase 1 study

Birgitte Bentz Damholt , Mette Dahl Bendtsen , Christian Hollensen & Michael Højby Rasmussen

Novo Nordisk A/S, Søborg, Denmark.

Background: Somapacitan is a reversible albumin-binding growth hormone (GH) derivative developed for once-weekly administration. Non-covalent binding to endogenous albumin delays somapacitan elimination, prolonging its half-life and duration of action. Somapacitan is not cleared by a specific organ, but impaired hepatic function may affect its pharmacokinetics. We report data from an open-label, parallel group, phase I trial (NCT03212131) investigating the pharmacokinetic and pharmacodynamic properties, and safety of somapacitan in individuals with mild and moderate hepatic impairment, and normal hepatic function.

Methods: Participants were enrolled in a 16:9:9 ratio to normal hepatic function, mild hepatic impairment, and moderate hepatic impairment, respectively. Participants received a total of three somapacitan administrations (0.08 mg/kg), one per week for 3 weeks.

Results: Thirty-four participants were included: normal function, n=16; mild impairment, n=9; moderate impairment, n=9. Somapacitan AUC0–168h was higher in the moderate impairment group (estimated ratio [ER]=4.69; 90% confidence interval [CI]: 2.92–7.52) and similar in the mild impairment group (ER=1.08; 90% CI: 0.66–1.75), versus the normal function group. Cmax had a similar pattern to AUC0-168h. Median tmax was longer for the moderate impairment group (15.8 hours), versus the mild impairment (11.8 hours) and normal function groups (11.9 hours). AUC0-168h of IGF-I and IGFBP-3 were similar in the mild and moderate impairment groups, but lower than the normal function group (AUCIGF-I,0-168h ER=0.85 [90% CI: 0.67–1.08] and 0.75 [90% CI: 0.60–0.95], respectively). Lower levels of IGF-I and IGFBP-3 were noted at baseline in both impairment groups compared with the normal function group. Albumin values were within normal range for all but two moderate impairment group participants. No unexpected safety signals were reported.

Conclusions: Despite greater exposure to somapacitan, individuals with hepatic impairment exhibited a decreased IGF-I and IGFBP-3 response. GH resistance associated with hepatic impairment may potentially explain the lower response. The increased exposure may indicate that liver GH receptors are either reduced in number, creating a saturation effect for elimination, or not fully functioning after GH binding, slowing elimination. Since albumin concentrations were mostly within normal range, and somapacitan occupancy of albumin is very low (<0.0005%), it is highly unlikely that decreased albumin concentrations caused increased exposure. Despite the higher exposure in individuals with moderate hepatic impairment, adequate treatment response may require higher somapacitan doses owing to the reduced IGF-I response. However, as somapacitan is planned to be individually dose-titrated, no specific adjustments to the dosing recommendations are relevant.

Volume 63

21st European Congress of Endocrinology

Lyon, France
18 May 2019 - 21 May 2019

European Society of Endocrinology 

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