Dose–exposure–IGF-I response of once-weekly somapacitan in adults with GH deficiency

Abstract

Objective: Growth hormone (GH) replacement therapy in patients with adult growth hormone deficiency (AGHD) is individually titrated due to variable dose–responses among patients. Our objective was to provide clinical guidance on dosing and titration of the novel long-acting GH derivative somapacitan based on analyses of somapacitan dose–insulin-like growth factor I (IGF-I) responses in AGHD patients. Design: Analyses of dosing information, 4364 somapacitan concentration samples and 4880 IGF-I samples from 330 AGHD patients treated with somapacitan in three phase 3 trials. Methods: Pharmacokinetic/pharmacodynamic modelling was used to evaluate starting dose groups by age and oral oestrogen therapy, characterise the dose–IGF-I response in the overall AGHD population and patient subgroups, predict the IGF-I response to dose changes and simulate missed dosing. Results: The analyses supported the clinical recommendations of higher starting doses for younger patients and women on oral oestrogen replacement therapy. For patients switching from daily GH treatment, the mean maintenance dose ratio between somapacitan (mg/week) and somatropin (mg/day) was predicted to be 8.2 (observed interquartile range of 6.7-9.1). Simulations of IGF-I SDS profiles confirmed the appropriate time for IGF-I sampling to be 3-4 days after somapacitan dosing, and supported somapacitan administration with up to 3 days delay in case of missed dosing. Subgroup analyses characterised the dose-exposure-IGF I response in patient subgroups and indicated that dose requirements are mainly influenced by sex and oral oestrogen treatment. Conclusions: This study extends knowledge of the somapacitan dose–IGF-I response and provides information on clinical dosing of once-weekly somapacitan in patients with AGHD.

Guidance for the treatment of adult growth hormone deficiency with somapacitan, a long-acting growth hormone preparation

“…• Published modelling data have indicated that there is a ratio of approximately 8.2 (observed interquartile range of 6.7-9.1) between somapacitan (mg/week) and somatropin (mg/day) maintenance doses that resulted in equivalent weekly IGF-I levels within the upper normal range (16). This conversion ratio therefore may be useful when estimating the required somapacitan maintenance dose for patients who have previously required very high or very low doses of daily GH.…”

“…Oral estrogen replacement therapy can promote this effect by suppressing GH-dependent hepatic IGF-I production (21)(22)(23). In phase III trials, patients on oral estrogen received an average somapacitan maintenance dose of 3.8 mg/week, which is higher than the starting dose of 2.0 mg/week (16). This indicates that clinicians can anticipate that women on oral estrogen will need higher maintenance doses than women on no estrogen, or on transdermal estrogen (which does not have this effect).…”

“…IGF-I sampling should take place after the second or third weekly dose to ensure that steady state levels have been reached (15,31). It is then recommended that IGF-I measurements be taken 3-4 days after administration of somapacitan (Table 3A) for the best estimate of weekly mean IGF-I levels as shown in two recently published modelling studies (15,16). In the first study, a PK-PD model was used to simulate IGF-I levels following somapacitan dosing in children and adults using data derived from three phase I trials (NCT01514500; NCT01706783; NCT01973244) (15).…”

“…In both adults and children, peak IGF-I levels were found to be best predicted from measurements taken on day two after administration and mean weekly IGF-I levels were best predicted from samples taken four days after dosing. In the second more recent study, somapacitan PK-PD models were based on data from phase III clinical trials in patients with AGHD (REAL1, REAL2, REAL Japan) (16). IGF-I profiles were simulated using the average maintenance doses for somapacitan and daily GH (somatropin).…”

“…Modelling analysis conducted using data from 330 patients with AGHD who received somapacitan in three phase III clinical trials indicated that there is an average ratio of 8.2 (interquartile range: 6.7-9.1) between somapacitan (mg/week) and somatropin (mg/day) maintenance doses that result in equivalent weekly IGF-I levels within the upper normal range (16). For example, a patient >60 years of age taking daily GH at a maintenance dose of 0.17 mg/day would be expected to receive 1.4 mg/week of somapacitan after dose titration.…”