AIM: The purpose of this analysis was to construct appropriate models to characterise population pharmacokinetics (PK) for PHA-794428 and PK/pharmacodynamics (PD) for the efficacy biomarker Insulin-like Growth factor-1 (IGF-1). METHODS: Fifty-six male healthy volunteers were enrolled into a clinical study. Subjects received in a randomised manner 3 subcutaneous injections over 3 periods: i) 3.6 mg recombinant human growth hormone (rhGH), ii) PHA-794428 0, 3, 10, 30, 60, 100, 300 or 500 μg/kg, and iii) PHA-794428 0, 10, or 30 μg/kg. Both PK and IGF-1 data were collected up to 336 h post-dose. The PK and PK/PD models were constructed in 3 stages: i) the PK model was developed, ii) the PK parameters were fixed during IGF-1 model building, iii) PK and IGF-1 data were analysed simultaneously. RESULTS: PHA-794428 exhibited non-linearity with respect to dose. A one-compartment disposition model with parallel linear and non-linear elimination most appropriately described the PHA-794428 serum concentrations versus time data. The absorption of PHA-794428 was characterised as a first-order process involving two absorption rate constants. The nonlinear elimination, characterised in terms of the maximal elimination capacity (Vmax=91.5 μg/h for 70 kg) and Michaelis-Menten constant (Km=73.9 μg/L) describing the concentration at which elimination is at half Vmax. The non-linear elimination pathway is approximately 10 times higher than the linear route (0.129 L/h). PHA-794428 has a limited distribution in the blood (V=4.4 L), due to its large molecular weight. Serum IGF-1 concentrations versus time data were best described by an indirect response model with PEG-hGH stimulating IGF-1 production rate. Drug effect was appropriately characterised by a maximum effect (Emax) model. The maximal IGF-1 production rate could increase up to 8-fold across the dose range studied. The PHA-794428 concentration at half Emax (EC50) is 56.5 ng/mL. A negative feedback loop was incorporated into the PK/IGF-1 model. The maximal inhibition (Imax) of IGF-1 on endogenous GH secretion was set to 100% and IC50, the IGF-1 concentration decreasing GH secretion by 50%, was 382 ng/mL. Placebo effect was negligible. CONCLUSION: Serum data of PHA-794428 and IGF-1 could be adequately described by PK and PK/IGF-1 models, which were successfully used to predict the doses and time course of PK and IGF-1 and study design for the subsequent clinical trials in adult patients with growth hormone deficiency (AGHD). PK/PD modelling and simulation demonstrated that PHA-794428 has a potential to return low IGF-1 levels to within the normal range by weekly dosing. AIM: The purpose of this analysis was to construct appropriate models to characterise population pharmacokinetics (PK) for PHA-794428 and PK / pharmacodynamics (PD) for the efficacy biomarker Insulin-like Growth factor-1 (METHODS: Fifty Subjects received in a randomized manner 3 subcutaneous injections over 3 periods: i) 3.6 mg recombinant human growth hormone (rhGH), ii) PHA-794428 0, 3, 10, 30, PK, and PK / PD) were also collected. Both PK and IGF-1 data were collected up to 336 h post-dose. The PK and PK / PD models were constructed in 3 stages: i) the PK model was developed, ii) the PK parameters were fixed during IGF-1 model building, iii) PK and IGF-1 data were analyzed simultaneously. with respect to dose. A one-compartment disposition model with parallel linear and non-linearization elimination the most aptly described the PHA-794428 serum concentrations versus time data. The absorption of PHA-794428 was characterized as a first-order process involving two absorption rate constants. The nonlinear elimination, characterized in terms of the maximal elimination capacity (Vmax = 91.5 μg / h for 70 kg) and Michaelis The non-linear elimination pathway is approximately 10 times higher than the linear route (0.129 L / h). PHA-794428 has a limited Distribution in the blood (V = 4.4 L), due to its large molecular weight. Serum IGF-1 concentrations versus time data were best described by an indirect response model with PEG-hGH stimulating IGF-1 production rate. The maximal IGF-1 production rate could increase up to 8-fold across the dose range studied. The PHA-794428 concentration at half Emax (EC50) was 56.5 ng / mL. A negative feedback loop was incorporated into th e PKThe maximal inhibition (Imax) of IGF-1 on endogenous GH secretion was set to 100% and IC50, the IGF-1 concentration decreased GH secretion by 50%, was 382 ng / mL. Placebo effect was negligible . CONCLUSION: Serum data of PHA-794428 and IGF-1 could be stably described by PK and PK / IGF-1 models, which were successfully used to predict the doses and time course of PK and IGF-1 and study design for the subsequent clinical trials in adult patients with growth hormone deficiency (AGHD). PK / PD modeling and simulation of that PHA-794428 has a potential to return low IGF-1 levels to within the normal range by weekly dosing.