目的研究聚乙二醇化新型集成干扰素(pegylated consensus interferon,PEG-cIFN)注射液在大鼠体内的药代动力学特征,并与非聚乙二醇化的集成干扰素(consensus interferon,cIFN)进行比较。方法大鼠分别单次皮下注射不同剂量PEG-cIFN(7、14...目的研究聚乙二醇化新型集成干扰素(pegylated consensus interferon,PEG-cIFN)注射液在大鼠体内的药代动力学特征,并与非聚乙二醇化的集成干扰素(consensus interferon,cIFN)进行比较。方法大鼠分别单次皮下注射不同剂量PEG-cIFN(7、14和28μg/kg)和cIFN(7μg/kg),采用酶联免疫分析法测定不同时间血清药物浓度,实验数据以DAS 3.0药动程序拟合并计算药动参数。结果大鼠分别单次皮下注射PEG-cIFN低、中和高3个剂量组后,峰浓度(the peak concentration,Cmax)和药时曲线下面积(the area under the serum concentration-time curve,AUC)随剂量增加呈更大比例增大,清除率(clearance,CL)随剂量增大而降低;达峰时间(the time to reach peak concentration,Tmax)和消除半衰期(elimination half life,t1/2β)与剂量呈非相关,且较为恒定(10～20 h);相同剂量下的PEG-cIFN较cIFN t1/2β延长15倍;CL降低10倍;Tmax滞后约10倍;AUC增加8倍,而Cmax降低近1倍。结论上述研究结果表明,PEG化后的IFN确实能改善和提高药代动力学/药效动力学特性,延长半衰期,降低清除率,增加暴露量,减小血清峰-谷浓度比率,延缓药物体内作用时间,具有长效作用。展开更多
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-...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.展开更多
文摘目的研究聚乙二醇化新型集成干扰素(pegylated consensus interferon,PEG-cIFN)注射液在大鼠体内的药代动力学特征,并与非聚乙二醇化的集成干扰素(consensus interferon,cIFN)进行比较。方法大鼠分别单次皮下注射不同剂量PEG-cIFN(7、14和28μg/kg)和cIFN(7μg/kg),采用酶联免疫分析法测定不同时间血清药物浓度,实验数据以DAS 3.0药动程序拟合并计算药动参数。结果大鼠分别单次皮下注射PEG-cIFN低、中和高3个剂量组后,峰浓度(the peak concentration,Cmax)和药时曲线下面积(the area under the serum concentration-time curve,AUC)随剂量增加呈更大比例增大,清除率(clearance,CL)随剂量增大而降低;达峰时间(the time to reach peak concentration,Tmax)和消除半衰期(elimination half life,t1/2β)与剂量呈非相关,且较为恒定(10～20 h);相同剂量下的PEG-cIFN较cIFN t1/2β延长15倍;CL降低10倍;Tmax滞后约10倍;AUC增加8倍,而Cmax降低近1倍。结论上述研究结果表明,PEG化后的IFN确实能改善和提高药代动力学/药效动力学特性,延长半衰期,降低清除率,增加暴露量,减小血清峰-谷浓度比率,延缓药物体内作用时间,具有长效作用。
文摘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.
