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

Abstract

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/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.

Results: In 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.

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).

Conflict of interest statement

BBD, MDB, CB, and MHR are employed by and have shares in Novo Nordisk. SLD is employed by Novo Nordisk.

© 2021. The Author(s).

Figures

Fig. 1

Trial design (applicable to both trials). Visits 2, 3, and 4 were in-house. PK pharmacokinetic, V visit

Fig. 2

Patient flow in the a kidney and b hepatic impairment trials. FAS full analysis set, n number of subjects, SAS safety analysis set

Fig. 3

Geometric mean curve of somapacitan full profile on the logarithmic scale in a four kidney impairment groups and the normal function group, and b mild and moderate hepatic impairment groups and the normal hepatic function group

Fig. 4

Somapacitan AUC0–168 h (ng·h/mL) after the last dose on day 15 for a four kidney impairment groups and the normal function group, and b mild and moderate hepatic impairment groups and the normal hepatic function group. Filled symbols represents the mean, center line represents the median, box represents the 25th and 75th percentiles, and whiskers represent the range. AUC0–168 h area under the plasma drug concentration-time curve, n number of subjects

Fig. 5

Association of AUC0–168 h with a eGFR and b CLCr in patients with kidney impairment and normal kidney function. AUC area under the plasma drug concentration–time curve, CLCr creatinine clearance, eGFR estimated glomerular filtration rate

Fig. 6

Somapacitan Cmax in a four kidney impairment groups and the normal function group, and b mild and moderate hepatic impairment groups and the normal hepatic function group. Filled symbol represents the mean, center line represents the median, box represents the 25th and 75th percentiles, and whiskers represent the range. Cmax maximum serum concentration, n number of subjects

Fig. 7

Mean IGF-I full profiles for a four kidney impairment groups and the normal function group, and b mild and moderate hepatic impairment groups and the normal hepatic function group. IGF-I, insulin-like growth factor-I