Translational mixed-effects PKPD modelling of recombinant human growth hormone - from hypophysectomized rat to patients.

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  • Anders Thorsted, Novo Nordisk, Denmark
  • Peter Thygesen, Exploratory ADME, Biopharmaceuticals, Novo Nordisk, Denmark
  • Henrik Agersø, Novo Nordisk, Denmark
  • Torben Laursen
  • Martin Kreilgaard, Novo Nordisk
BACKGROUND AND PURPOSE:

We aimed to develop a mechanistic mixed-effects pharmacokinetic (PK)-pharmacodynamic (PD) (PKPD) model for recombinant human growth hormone (rhGH) in hypophysectomized rats and to predict the human PKPD relationship.

EXPERIMENTAL APPROACH:

A non-linear mixed-effects model was developed from experimental PKPD studies of rhGH and effects of long-term treatment as measured by insulin-like growth factor 1 (IGF-1) and bodyweight gain in rats. Modelled parameter values were scaled to human values using the allometric approach with fixed exponents for PKs and unscaled for PDs and validated through simulations relative to patient data.

KEY RESULTS:

The final model described rhGH PK as a two compartmental model with parallel linear and non-linear elimination terms, parallel first-order absorption with a total s.c. bioavailability of 87% in rats. Induction of IGF-1 was described by an indirect response model with stimulation of kin and related to rhGH exposure through an Emax relationship. Increase in bodyweight was directly linked to individual concentrations of IGF-1 by a linear relation. The scaled model provided robust predictions of human systemic PK of rhGH, but exposure following s.c. administration was over predicted. After correction of the human s.c. absorption model, the induction model for IGF-1 well described the human PKPD data.

CONCLUSIONS:

A translational mechanistic PKPD model for rhGH was successfully developed from experimental rat data. The model links a clinically relevant biomarker, IGF-1, to a primary clinical end-point, growth/bodyweight gain. Scaling of the model parameters provided robust predictions of the human PKPD in growth hormone-deficient patients including variability.
Original languageEnglish
JournalBritish Journal of Pharmacology
Volume173
Issue11
Pages (from-to)1742-1755
Number of pages14
ISSN0007-1188
Publication statusPublished - 2016

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