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

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.