Pharmacokinetics and Pharmacodynamics of Once-Weekly Somapacitan in Children and Adults: Supporting Dosing Rationales with a Model-Based Analysis of Three Phase I Trials

Abstract

Background: Somapacitan, a long-acting growth hormone (GH) derivative, has been well-tolerated in children with GH deficiency (GHD) and adults (healthy and adult GHD), in phase I, single- and multiple-dose trials, respectively, and has pharmacokinetic and pharmacodynamic properties supporting a once-weekly dosing regimen.

Objective: In the absence of a multiple-dose phase I trial in children with GHD, the aim was to develop a pharmacokinetic/pharmacodynamic model to predict somapacitan exposure and insulin-like growth factor-I (IGF-I) response after once-weekly multiple doses in both children and adults with GHD.

Methods: Pharmacokinetic/pharmacodynamic models were developed from pharmacokinetic and IGF-I profiles in three phase I trials of somapacitan (doses: healthy adults, 0.01-0.32 mg/kg; adult with GHD, 0.02-0.12 mg/kg; children with GHD, 0.02-0.16 mg/kg) using non-linear mixed-effects modeling. Pharmacokinetics were described using a non-linear one-compartment model with dual first- and zero-order absorption through a transit compartment, with saturable elimination. IGF-I profiles were described using an indirect response pharmacokinetic/pharmacodynamic model, with sigmoidal-effect relationship.

Results: The non-linear pharmacokinetic and IGF-I data were well-described in order to confidently predict pharmacokinetic/pharmacodynamic profiles after multiple doses in adults and children with GHD. Body weight was found to be a significant covariate, predictive of the differences observed in the pharmacokinetics and pharmacodynamics between children and adults. Weekly dosing of somapacitan provided elevated IGF-I levels throughout the week, despite little or no accumulation of somapacitan, in both adults and children with GHD.

Conclusion: This analysis of somapacitan pharmacokinetic/pharmacodynamic data supports once-weekly dosing in adults and children with GHD.

Trial registration: ClinicalTrials.gov identifier numbers NCT01514500, NCT01706783, NCT01973244.

Conflict of interest statement

RVJ, MHR, HA, and RVO are employees/shareholders of Novo Nordisk A/S.

Figures

Fig. 1

Schematic diagram of the structural pharmacokinetic/pharmacodynamic model for somapacitan. The pharmacokinetic model included a dual pathway from absorption compartment [abs] to central compartment [central] through first-order absorption and zero-order absorption through a transit compartment [transit]. The pharmacokinetic/pharmacodynamic model included an indirect response relationship (dashed line) between the central compartment and the insulin-like growth factor-I compartment [IGF-I]. C somapacitan concentration in the central compartment, EC50 somapacitan concentration corresponding to half-maximum stimulation of IGF-I production rate, Emax maximum increase in IGF-I production rate, F bioavailability, IGF-I insulin-like growth factor-I, K0 zero-order rate constant, Ka linear absorption rate constant, Kin production rate of IGF-I, Km Michaelis-Menten constant for saturable elimination, Kout first-order turnover of IGF-I, Ktr linear transit rate constant, V volume of distribution, Vmax maximum elimination rate

Fig. 2

Pharmacokinetic profiles for somapacitan, with final model fit a for a single dose in healthy adults; b at steady state in healthy adults; c a single dose in subjects with AGHD; d at steady state in subjects with AGHD; and e for a single dose in children with GHD. Somapacitan concentration versus time profiles. Panels a, c, and e show single-dose and panels b and d show steady-state profiles for each dose group in trials of healthy adults (NCT01514500), subjects with AGHD (NCT01706783), and children with GHD (NCT01973244). Points are geometric mean with 95% confidence intervals. Lines are population predictions. AGHD adult growth hormone deficiency, GHD growth hormone deficiency

Fig. 3

Dose–exposure for a single dose and b multiple doses and exposure–response for c single dose and d multiple doses of somapacitan. Panels a and b show observed geometric mean for somapacitan Cavg with 95% confidence interval overlaid with individual simulations from all subjects on each dose level after a single dose and at steady state. Panels c and d show observed change from baseline (Δ) IGF-I levels (points) with mean (filled points) and 95% confidence intervals for each dose group overlaid with individual simulations (lines) based on all subjects on each dose level after a single dose and at steady state. Each dose group is plotted at the median average concentration. AGHD adulthood GHD, Cavg geometric mean, GHD growth hormone deficiency, IGF-I insulin-like growth factor-I, SDS standard deviation score

Fig. 4

Pharmacodynamic profiles with final model fit for somapacitan, with final model fit a for a single dose in healthy adults; b at steady state in healthy adults; c for a single dose in subjects with AGHD; d at steady state in subjects with AGHD; and e for a single dose in children with GHD. IGF-I change from baseline versus time profiles. Panels a, c, and e show the change from baseline profiles of IGF-I for single dose and steady state (panels b and d) for each somapacitan dose group in trials of healthy adults (NCT01514500), subjects with AGHD (NCT01706783), and children with GHD (NCT01973244). Points are geometric mean with 95% confidence intervals. Lines are population predictions. AGHD adult growth hormone deficiency, GHD growth hormone deficiency, IGF-I insulin-like growth factor-I

Fig. 5

Simulated a predicted pharmacokinetic and b IGF-I profiles for phase II trial doses in a mean population of children with growth hormone deficiency. Panel a shows mean population predicted pharmacokinetics and panel b shows IGF-I in children with growth hormone deficiency. The full horizontal line shows the mean observed pre-trial SDS (during hGH treatment) and the dotted horizontal line shows the mean observed baseline (after washout of hGH) for the observed population. Parameter confidence intervals and variabilities are available in Table 4 and are not shown here for clarity. hGH human growth hormone, IGF-I insulin-like growth factor-I, SDS standard deviation score