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中国药理学会临床药理学专业委员会会议暨第十次全国临床药理学学术会议

作者： Didier Eric Harris Philip Milligan Peter A Karlsson Mats O pgrd sandwich UK Clinical Pharmacometrics Pfizer Global Research & Development(pgrd) SandwichUK Department of Pharmaceutical Biosciences Uppsala University Sweden

AIM:The purpose of this analysis was to construct approp- riate 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 en- rolled into a clinical *** received in a random- ised 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 500μg/kg, and iii)PHA-794428 0,10,or 30μg/*** PK and IGF-1 data were collected up to 336 h *** 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 da- ta were analysed simultaneously. RESULTS:PHA-794428 exhibited non-linearity with re- spect to dose.A one-compartment disposition model with parallel linear and non-linear elimination most appropriate- ly described the PHA-794428 serum concentrations versus time *** absorption of PHA-794428 was character- ised as a first-order process involving two absorption rate *** nonlinear elimination,characterised in terms of the maximal elimination capacity(V=91.5 μg/h for 70 kg)and Michaelis-Menten constant(K= 73.9μg/L)describing the concentration at which elimina- tion is at half *** 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 *** IGF-1 concentrations versus time data were best described by an indirect response model with PEG-hGH stimulating IGF-1 production *** effect was appropriately char- acterised by a maximum effect(E)*** maxi- mal IGF-1 production rate could increase up to 8-fold across the dose range *** PHA-794428 concen- tration at half Emax(EC)is 56.5 ng/mL.A negative feedback loop was incorporated into the PK/IGF-1 model. The maximal inhibition(I)

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乙二醇重组人生长激素(PHA-794428)的群体药代动力学/群体药效动力学在健康男性志愿者中的研究

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中国临床药理学与治疗学 2007年第10期12卷 1192-1193页

作者： XIE Ru-jia Didier Eric Harris Philip Milligan Peter A Karlsson Mats O Clinical Pharmacometrics Pfizer Global Research＆Development （PGRD） Sandwich UK pgrd Sandwich UK Department of Pharmaceutical Biosciences Uppsala University Sweden

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

关键词：乙二醇重组人生长激素群体药代动力学群体药效动力学男性健康受试者

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