ESPE Abstracts

Growth hormone (GH) stimulates insulin like growth factor I (IGF I) release. IGF-I is the standard biomarker for monitoring GH effects during treatment and to achieve optimal long-term safety, and to a limited extent, monitor efficacy in children with GH deficiency (GHD). The IGF I profile during treatment with a long acting GH (LAGH), such as once weekly somapacitan (Novo Nordisk), differs from the daily GH profile by exhibiting larger peaks and troughs over the dosing interval. Pragmatic guidance on the interpretation of IGF-I concentrations during LAGH therapy is required by prescribing physicians. We used pharmacokinetic/pharmacodynamic modelling based on data from 186 paediatric patients with GHD treated with 0.16 mg/kg/week somapacitan for 52 weeks in two randomized controlled trials: phase 2 REAL3 (NCT02616562) and phase 3 REAL4 (NCT03811535). IGF-I sampling was performed before first dose, 1-4 days and 4-6 days after dosing and before next dose to determine baseline, estimated maximum, weekly average and minimum IGF-I concentrations, respectively. A linear relationship was found between somapacitan dose and IGF I response: a somapacitan dose change of 0.02 mg/kg is expected to result in a change in weekly IGF I average of 0.32 SDS [0.28;0.37]_95%CI. We established linear models between individual estimated steady state IGF I concentrations (SDS and ng/ml) at various times after dosing and weekly IGF I average concentrations (SDS and ng/ml) at steady state (achieved after 1-2 doses). We derived formulas to approximate IGF I average SDS and absolute concentration (ng/ml) based on IGF-I measurements on different days within the weekly somapacitan dosing interval. The IGF I measurement closest to the weekly IGF I average occurs approximately 4 days (97 120h) after dosing. Where practical, measuring IGF-I on day 4 after somapacitan dosing may be optimal to estimate average weekly IGF-I (since no correction needed). We developed a simple calculation table for estimating weekly IGF I average SDS and absolute concentration (ng/mL) from IGF I samples taken on any other day after somapacitan dosing to offer flexibility. We approximated the results into a correction parameter for each daily interval (24 hours) for ease of use. In summary, we characterized the dose-IGF I response of somapacitan in children with GHD. We present a practical guide to support physicians to estimate expected weekly IGF I average concentrations in patients during IGF I monitoring in the clinic.