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 firstand 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.

Optimal Monitoring of Weekly IGF-I Levels During Growth Hormone Therapy With Once-Weekly Somapacitan

“…This is also the case if the somapacitan dose is changed. For precise prediction of mean and/or peak IGF-I SDS following a dose change, at least one dosing interval at the new dose must be allowed to pass before sampling, to ensure that steady state has been achieved ( 34 ).…”

“…A PK/PD model was available for simulation of full PK and IGF-I profiles following somapacitan dosing. The model has previously been qualified and published ( 34 ). Data for the PK/PD model were derived from 3 phase 1 trials of somapacitan, including data from healthy adults (ClinicalTrials.gov identifier NCT01514500; first human dose trial) ( 35 ) and from 2 randomized studies of patients with GHD.…”

“…The demographic characteristics of subjects were retained as in the data that were used to develop the PK/PD model and all subjects were simulated at all dose levels investigated in the trials. Thus, all adults with GHD (n = 26) and children with GHD (n = 23) were simulated at 4 dose levels (0.02-0.12 mg/kg for adults and 0.02-0.16 mg/kg for children), and simulations were repeated 200 times to obtain a population of 39 200 new simulated IGF-I profiles ( 34 ). Steady-state IGF-I profiles were constructed from individual predictions using a 4-hour grid from 0 to 168 hours after dose.…”

“…As a consequence, monitoring of IGF-I levels following long-acting GH products must take into account the time after dose that the IGF-I sample has been collected. For somapacitan, IGF-I fluctuation over a dosing interval is well characterized in clinical trials in adults and children with GHD and is quantified using population pharmacokinetic (PK)/pharmacodynamic (PD) modeling ( 34 ).…”

Usefulness and Potential Pitfalls of Long-Acting Growth Hormone Analogs

“…In August 2020, once-weekly Somapacitan (Sogroya ® , Novo Nordisk A/S, Denmark) was approved by the FDA for treatment of adult GHD ( ). Somapacitan is a long-acting human GH derivative to which a small noncovalent albumin-binding moiety is attached to facilitate reversible binding to endogenous albumin, delaying its elimination, and thereby extending its duration of action with little to no accumulation of the drug when administered once-weekly ( 52 ). In previous short-term clinical trials, Somapacitan was well-tolerated in healthy adults ( 81 ) and in adults and children with GHD ( 53 , 54 , 82 ), and provided similar safety and efficacy to daily rhGH in previously rhGH-treated adults with GHD ( 54 , 55 ).…”