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

INTRODUCTION: Somapacitan 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. METHODS: In 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/m(2), 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 (AUC(0–168 h)), while secondary endpoints included AUC(0–168 h) of insulin-like growth factor (IGF)-I. RESULTS: In the kidney impairment trial, somapacitan AUC(0–168 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). AUC(0–168 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 AUC(0–168 h) was significantly higher in the moderate impairment group compared with the normal hepatic function group (4.69 [2.92–7.52]). IGF-I AUC(0–168 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. CONCLUSIONS: In 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 REGISTRATION: NCT03186495 (kidney impairment trial, registered 12 June 2017); NCT03212131 (hepatic impairment trial, registered 30 June 2017).