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

Plain Language Summary Somapacitan is a long-acting growth hormone molecule for patients with growth hormone deficiency. After its administration as a subcutaneous injection, the action of somapacitan can be affected by kidney or liver disease. Thus, we conducted two trials in which the pharmacokinetic and pharmacodynamic properties of somapacitan were compared between adult subjects with different degrees of worsened kidney or liver function and their healthy counterparts. We found that subjects with severely impaired kidney function and those requiring hemodialysis had a higher somapacitan exposure in blood serum compared with subjects with normal kidney function. The concentration of insulin-like growth factor (IGF)-I, an effector molecule of growth hormone, was also increased with decreased kidney function. In subjects with moderate hepatic function impairment, somapacitan exposure was also higher than those with normal hepatic function; however, the IGF-I concentrations were lower, both at baseline and after dosing with somapacitan. Our results indicate that patients with growth hormone deficiency and kidney or liver disease may need different doses of somapacitan than people with healthy kidneys and/or liver. However, this will be taken into account because somapacitan doses will be individually titrated for each patient with growth hormone deficiency. 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-naive, 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.

Automated summary

Two trials showed that exposure of somapacitan increased in patients with impaired kidney or liver function, leading to changes in IGF-I concentrations. This indicates that individualized dosage adjustments based on the kidney or liver conditions of patients are necessary when using somapacitan for those with growth hormone deficiency.