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, 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), while secondary endpoints included AUC of insulin-like growth factor (IGF)-I.

Results: In the kidney impairment trial, somapacitan AUC 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 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 was significantly higher in the moderate impairment group compared with the normal hepatic function group (4.69 [2.92-7.52]). IGF-I AUC 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).