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
目的:探讨中剂量重组人生长激素(Recombinant human growth hormone,rhGH)对特发性矮小症(Idiopathic short stature,ISS)的疗效及安全性。方法:96例ISS患儿,均接受rhGH治疗,治疗剂量为0.35～0.42 mg/(kg.周),每晚睡前皮下注射,治疗1～3...目的:探讨中剂量重组人生长激素(Recombinant human growth hormone,rhGH)对特发性矮小症(Idiopathic short stature,ISS)的疗效及安全性。方法:96例ISS患儿,均接受rhGH治疗,治疗剂量为0.35～0.42 mg/(kg.周),每晚睡前皮下注射,治疗1～3年,评价治疗前后患儿身高、生长速度、身高标准差计数(Height standard deviation score,HtSDS)、骨龄(Bone age,BA)、预测成年身高(Predicted adult height,PAH)变化及副作用等。结果:(1)在中剂量rhGH治疗1、2、3年期间,96例患儿生长速率由治疗前4.46(4.07～4.68)cm/年分别提高到11.00(9.25～12.5)cm/年、8.10(7.00～9.50)cm/年和7.40(5.63～8.00)cm/年;身高SDS由治疗前-2.48(-2.83～-2.25)cm/年增至-1.58(-1.93～-1.17)、-1.00(-1.69～-0.58)cm/年及-0.52(-1.86～-0.13)cm/年;PAH由治疗前149.20(145.10～155.30)cm分别增加为155.90(150.30～162.70)cm、159.00(154.00～162.70)cm和160.05(153.18～166.80)cm(P<0.05)。(2)TannerⅠ、Ⅱ、Ⅲ期患儿治疗的促生长效果高于Ⅳ期。(3)BA增加值分别为1.10(0.80～1.30)岁、1.10(0.83～1.20)岁及1.10(0.98～1.30)岁(P>0.05)。治疗期间除少数有血糖暂时性升高,注射部位轻度反应外,无明显副作用。结论:中剂量rhGH可促进生长,增加PAH,在治疗期间未影响生长潜能,无严重副作用。展开更多
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.
文摘目的:探讨中剂量重组人生长激素(Recombinant human growth hormone,rhGH)对特发性矮小症(Idiopathic short stature,ISS)的疗效及安全性。方法:96例ISS患儿,均接受rhGH治疗,治疗剂量为0.35～0.42 mg/(kg.周),每晚睡前皮下注射,治疗1～3年,评价治疗前后患儿身高、生长速度、身高标准差计数(Height standard deviation score,HtSDS)、骨龄(Bone age,BA)、预测成年身高(Predicted adult height,PAH)变化及副作用等。结果:(1)在中剂量rhGH治疗1、2、3年期间,96例患儿生长速率由治疗前4.46(4.07～4.68)cm/年分别提高到11.00(9.25～12.5)cm/年、8.10(7.00～9.50)cm/年和7.40(5.63～8.00)cm/年;身高SDS由治疗前-2.48(-2.83～-2.25)cm/年增至-1.58(-1.93～-1.17)、-1.00(-1.69～-0.58)cm/年及-0.52(-1.86～-0.13)cm/年;PAH由治疗前149.20(145.10～155.30)cm分别增加为155.90(150.30～162.70)cm、159.00(154.00～162.70)cm和160.05(153.18～166.80)cm(P<0.05)。(2)TannerⅠ、Ⅱ、Ⅲ期患儿治疗的促生长效果高于Ⅳ期。(3)BA增加值分别为1.10(0.80～1.30)岁、1.10(0.83～1.20)岁及1.10(0.98～1.30)岁(P>0.05)。治疗期间除少数有血糖暂时性升高,注射部位轻度反应外,无明显副作用。结论:中剂量rhGH可促进生长,增加PAH,在治疗期间未影响生长潜能,无严重副作用。
