Population Pharmacokinetics and Pharmacodynamics of Once-Daily Growth Hormone Norditropin® in Children and Adults

Abstract

Background and objective: Once-daily injectable recombinant human growth hormone (GH) formulations (e.g. Norditropin®; Novo Nordisk A/S) are used to treat GH deficiency in children and adults, with much of the therapeutic effect mediated via the insulin-like growth factor-I (IGF-I) response. Despite a long history of use, there are few data on the pharmacokinetics and pharmacodynamics (serum IGF-I response) of this therapy, or of potential differences in the relationship of GH pharmacokinetic/pharmacodynamic (PK/PD) effects between children and adults. This study aimed to characterise the GH pharmacokinetics and IGF-I profile following daily subcutaneous GH in adults and children with GH deficiency.

Methods: A model was developed based on a population PK/PD modelling meta-analysis of data from three phase I clinical trials (two using Norditropin® as a comparator with somapacitan, and one as a comparator with a pegylated GH product). Sequential model building was performed, first developing a model that could describe GH pharmacokinetics. A PD model of IGF-I data was then developed using PK and PD data, and where all PK parameters were kept fixed to those estimated in the PK model.

Results: The model developed accurately describes and predicts GH pharmacokinetics and IGF-I response. Body weight was shown to have an important inversely correlated influence on GH exposure (and IGF-I standard deviation score), and this largely explained differences between adults and children.

Conclusions: The pharmacokinetics/pharmacodynamics developed here can inform expectations about the PD effects of different doses of GH in patients with GH deficiency of different body weights, regardless of their age.

Clinical trial registration: Pooled modelling analysis of data from ClinicalTrials.gov identifiers NCT01973244, NCT00936403 and NCT01706783.

Dates of registration: NCT01973244: 22 October, 2013; NCT00936403: 9 July, 2009; NCT01706783: 11 October, 2012.

Conflict of interest statement

Theodoros Papathanasiou and Birgitte Bentz Damholt were employees/shareholders of Novo Nordisk A/S at the time of writing. Henrik Agersø, Michael Højby Rasmussen and Rasmus Juul Kildemoes are employees/shareholders of Novo Nordisk A/S.

© 2021. The Author(s).

Figures

Fig. 1

Schematic of the structural pharmacokinetic/pharmacodynamic (PK/PD) model for growth hormone (GH). The PK model included a single pathway from the absorption compartment (abs) to the central compartment (central) through first-order absorption. The baseline GH levels observed prior to initial dosing were described via a zero-GH production rate. The PK/PD model included an indirect response relationship (dashed line) between the central compartment and the insulin-like growth factor-I (IGF-I) compartment. c growth hormone concentration in the central compartment, CL growth hormone systemic clearance, Emax maximum increase in IGF-I production rate, EC50 GH concentration corresponding to half-maximum stimulation of IGF-I production rate, F bioavailability, Ka linear absorption rate constant, Kendo zero-order process for endogenous growth hormone production, Kin zero order production rate of IGF-I, Kout first-order elimination rate of IGF-I, V volume of distribution

Fig. 2

Growth hormone (GH) pharmacokinetic (PK) profile (a) and pharmacodynamic (PD) profile (b) with final model fit for multiple doses in children (dark blue) and adults (light blue) with GH deficiency (GHD). Data are presented as geometric mean, with 95% confidence intervals. Lines represent the geometric mean of the population model predictions. Only full PK profiles up to 4 days after the first dose are presented for clarity. The observed and model-predicted GH concentration–time profiles for the fourth week of GH treatment in adults with GHD are presented in Fig. S1 of the ESM. IGF-I insulin-like growth factor-I

Fig. 3

Relationship between steady-state dose-normalized growth hormone (GH) concentration in children (light blue) and adults (dark blue) with GH deficiency (GHD) and body weight. Body weight is adequate for explaining the difference in GH pharmacokinetics between children and adults with GHD. Cavg average concentration at steady state, PK pharmacokinetic

Fig. 4

Simulated steady-state dose-exposure (a) and steady-state exposure–response (b) between growth hormone (GH) pharmacokinetics and insulin-like growth factor-I (IGF-I) standard deviation score (SDS) for once-daily subcutaneous administration of GH, and GH concentration (c) and IGF-I SDS profiles (d) at dose concentrations giving a matching response in children (dark blue) and adults (light blue) with GH deficiency (GHD). In (a) and (b), lines are means of individual predictions across the dose and exposure range. Vertical dotted lines denote the dose and exposure giving an average IGF-I response of approximately 1.1 SDS. In (c) and (d), lines are means of individual prediction at dose levels of 3 µg/kg/day for adults and 30 µg/kg/day for children, both providing an IGF-I average SDS of approximately 1.1. PK pharmacokinetic