Endocrine Abstracts

Somapacitan is a long-acting growth hormone (GH) derivative designed for once-weekly subcutaneous administration. Correct assessment of insulin-like growth factor-I (IGF-I) levels is essential during treatment of GH deficiency (GHD) and must account for fluctuations over a dosing interval. We evaluated whether reliable estimates of weekly mean and peak IGF-I could be obtained from a single IGF-I sample. A population pharmacokinetic/pharmacodynamic model was available from pharmacokinetic and IGF-I (ng/ml and standard deviation score [SDS]) profiles from phase 1 studies of healthy adults (NCT01514500), adults with GHD (NCT01706783) and children with GHD (NCT01973244). Simulation was performed to steady state at four dose levels for 26 adults (doses 0.02–0.12 mg/kg) and 23 children (0.02–0.16 mg/kg) with GHD. After 200 repetitions, 39.200 unique IGF-I profiles were simulated using a 4-hour grid from 0–168 hours after dose. Profiles with weekly average IGF-I SDS > 4 were removed. For each potential sample time, a linear model was used to estimate the correlation between IGF-I SDS value at a given time and the weekly mean/peak IGF-I value. The best fit to data included a dose (mg) covariate with body weight as an interaction in adults and a logarithmic dose level (mg/kg) covariate in children. The degree of linearisation was evaluated with correlation coefficient R², and precision of weekly mean/peak predictions were evaluated using residual standard deviation (RSD) and 90% prediction interval (PI; calculated as ± 1.645*RSD). Strong linear correlations were found between IGF-I SDS on any day and the weekly mean across the dose ranges, as well as between IGF-I SDS on days 1–5 and the weekly peak. In children and adults, the mean was predicted with good precision based on an IGF-I sample on any day (RSD < 0.4 for adults; < 0.3 for children); the most accurate prediction was on day 4 (RSD < 0.17 [90% PI ± 0.3 SDS]). The peak was best predicted with an IGF-I sample on days 1–4 (RSD <0.4); the most accurate prediction of IGF-I peak was on day 2 (RSD < 0.10 [90% PI ± 0.2 SDS]). A linear model provided a simple and reliable tool to predict weekly mean and peak IGF-I levels based on an accurate IGF-I sample following somapacitan dosing at steady state. Mean and peak IGF-I values could be predicted by IGF-I sampling on any day after somapacitan dose. The best predictive values were on day 4 (mean) and day 2 (peak) after dose.