Effect of Kidney or Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Somapacitan: Two Open-Label, Parallel-Group Trials

Abstract

IntroductionSomapacitan is a long-acting growth hormone (GH) derivative being developed for once-weekly dosing in patients with GH deficiency (GHD). Our objective was to evaluate the impact of kidney or hepatic impairment on somapacitan exposure in adults.MethodsIn two open-label, parallel-group, single-center, 6-week trials, eligible subjects (18–75 years of age, body mass index 18.5–34.9 kg/m2, GH-naïve, without GHD) were divided into five kidney (total n = 44) or three hepatic (n = 34) function groups. Subjects with normal kidney/hepatic function were matched to those with kidney/hepatic impairment by age, sex, and body weight. Subjects received three subcutaneous somapacitan administrations (0.08 mg/kg) on days 1, 8, and 15. Blood samples were collected before each dose, at 28 time points throughout 2 weeks after the last dose, and at follow-up (3–4 weeks after the last dose). The primary endpoint was area under the somapacitan serum concentration–time curve up to 1 week after the last dose (AUC0–168 h), while secondary endpoints included AUC0–168 h of insulin-like growth factor (IGF)-I.ResultsIn the kidney impairment trial, somapacitan AUC0–168 h was higher in groups with severe kidney impairment and requiring hemodialysis versus the normal kidney function group (estimated ratio and 90% confidence interval 1.75 [1.00–3.06] and 1.63 [1.01–2.61], respectively). AUC0–168 h of IGF-I was increased in the moderate impairment group (1.35 [1.09–1.66]), severe impairment group (1.40 [1.10–1.78]), and requiring hemodialysis group (1.24 [1.01–1.52]), compared with the normal function group. In the hepatic impairment trial, somapacitan AUC0–168 h was significantly higher in the moderate impairment group compared with the normal hepatic function group (4.69 [2.92–7.52]). IGF-I AUC0–168 h was lower in both hepatic impairment groups (0.85 [0.67–1.08] for the mild impairment group and 0.75 [0.60–0.95] for the moderate impairment group) compared with the normal function group. No new safety or tolerability issues were observed.ConclusionsIn summary, somapacitan exposure increased with level of kidney/hepatic impairment. Clinically, this will be taken into account when treating adults with GHD with somapacitan, as doses should be individually titrated.Clinical Trial RegistrationNCT03186495 (kidney impairment trial, registered 12 June 2017); NCT03212131 (hepatic impairment trial, registered 30 June 2017).