Dataset Information

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.

SUBMITTER: Papathanasiou T

PROVIDER: S-EPMC8416863 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

Dataset Information

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

Background and objective

Methods

Results

Conclusions

Clinical trial registration

Dates of registration

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Background and objective

Methods

Results

Conclusions

Clinical trial registration

Dates of registration

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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