Mads Kreilgaard

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 k_inand related to rhGH exposure through an E_maxrelationship. 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.

Gabapentin displays non-linear drug disposition, which complicates dosing for optimal therapeutic effect. Thus, the current study was performed to elucidate the pharmacokinetic/pharmacodynamic (PKPD) relationship of gabapentin’s effect on mechanical hypersensitivity in a rat model of CFA-induced inflammatory hyperalgesia. A semi-mechanistic population-based PKPD model was developed using nonlinear mixed-effects modelling, based on gabapentin plasma and brain extracellular fluid (ECF) time-concentration data and measurements of CFA-evoked mechanical hyperalgesia following administration of a range of gabapentin doses (oral and intravenous). The plasma/brain ECF concentration-time profiles of gabapentin were adequately described with a two-compartment plasma model with saturable intestinal absorption rate (K _m = 44.1 mg/kg, V _max = 41.9 mg/h∙kg) and dose-dependent oral bioavailability linked to brain ECF concentration through a transit compartment. Brain ECF concentration was directly linked to a sigmoid E _max function describing reversal of hyperalgesia (EC _{50, plasma} = 16.7 μg/mL, EC _{50, brain} = 3.3 μg/mL). The proposed semi-mechanistic population-based PKPD model provides further knowledge into the understanding of gabapentin’s non-linear pharmacokinetics and the link between plasma/brain disposition and anti-hyperalgesic effects. The model suggests that intestinal absorption is the primary source of non-linearity and that the investigated rat model provides reasonable predictions of clinically effective plasma concentrations for gabapentin.