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:观察聚乙二醇化重组人改构白介素11(PEGylated IL-11 mutein,PEG-m IL 11)不同给药次数和给药剂量对骨髓抑制的小鼠血小板减少症的治疗作用,并与m IL-11进行比较,为临床应用提供参考。方法:BALB/c小鼠经2.5 Gy全身^(60)Coγ射线照...目的:观察聚乙二醇化重组人改构白介素11(PEGylated IL-11 mutein,PEG-m IL 11)不同给药次数和给药剂量对骨髓抑制的小鼠血小板减少症的治疗作用,并与m IL-11进行比较,为临床应用提供参考。方法:BALB/c小鼠经2.5 Gy全身^(60)Coγ射线照射后,腹腔注射50 mg/kg卡铂制备血小板减少症模型。在给药次数研究中,将30只造模成功的BALB/c小鼠随机分为5组:溶剂对照组:d 1,4,7每日1次,共3次;m IL-11组:m IL-11200μg/(kg·d)×9 d;PEG-m IL 11 A组:PEG-m IL 111800μg/(kg·d)×1 d(d 1);PEG-m IL 11 B组:900μg/(kg·d)×2 d(d 1,5)和PEG-m IL 11 C组:600μg/(kg·d)×3 d(d 1,4,7),各组小鼠均为皮下注射给药。监测5周内血小板的变化情况;在给药剂量研究中将100只造模成功的BALB/c小鼠随机分为5组:溶剂对照组:d 1,5每日1次,共2次;m IL-11组:m IL-11200μg/(kg·d)×9 d、PEG-m IL 11低、中、高剂量组(200、420、900μg/(kg·d)×2 d,d 1,5),对各组小鼠均皮下注射给药,在5周内每隔2-3 d检测外周血细胞,并于给药后d 8选取部分动物安乐死后进行骨髓细胞培养。结果:与造模前相比,溶剂对照组Plt在最低点时降低幅度达到80%以上。给药次数研究中,PEG-m IL 11各给药组在最低点时的Plt值均明显高于溶剂对照组和m IL-11组(P<0.05),但不同给药次数的3组间差异不显著;在给药剂量研究中,PEG-m IL 11各治疗组在Plt最低点的降低幅度明显低于溶剂对照组和m IL-11治疗组(P<0.05),在最低点后Plt的恢复速度明显快于溶剂对照组,在d 10呈剂量依赖性的升高(r=0.92);PEG-m IL 11各治疗组的RBC在最低点的降低幅度明显减小并且恢复明显加快;各组WBC的变化趋势基本一致。CFU-M eg测定结果显示,PEG-m IL 11和m IL-11组同溶剂对照比相比CFU-M eg有增多的趋势,且PEG-m IL 11治疗组动物的集落数更高。结论:PEG-m IL 11对骨髓抑制小鼠血小板减少症有明显的治疗作用,而且同m IL-11相比,可以减少给药次数,提高治疗的顺应性,为开发重组白介素11的长效制剂提供了一定的依据。展开更多
目的探讨初级与次级预防性使用聚乙二醇化重组人粒细胞集落刺激因子(pegylated recombinant human granulocyte colony-stimulating factor,PEG-rhG-CSF)在卵巢癌初始肿瘤细胞减灭术后化疗的价值。方法2019年1月~2020年6月我院76例卵巢...目的探讨初级与次级预防性使用聚乙二醇化重组人粒细胞集落刺激因子(pegylated recombinant human granulocyte colony-stimulating factor,PEG-rhG-CSF)在卵巢癌初始肿瘤细胞减灭术后化疗的价值。方法2019年1月~2020年6月我院76例卵巢癌初始肿瘤细胞减灭术后行紫杉醇和卡铂联合化疗,根据初次预防性使用PEG-rhG-CSF分为初级预防组(n=49)和次级预防组(n=27),比较2组中性粒细胞减少发生率、需要补充重组人粒细胞集落刺激因子(recombinant human granulocyte colony-stimulating factor,rhG-CSF)率、中性粒细胞减少相关重复住院率、中性粒细胞减少相关化疗周期延迟发生率等。结果第一、二疗程中,初级预防组3、4度中性粒细胞减少发生率分别为8.2%(4/49)、6.1%(3/49),明显低于次级预防组发生率66.7%(18/27)、37.0%(10/27)(Z=-6.569,P=0.000;Z=-4.338,P=0.000)。在第三~六疗程中,2组中性粒细胞减少发生率无明显统计学差异(Z=-0.938,P=0.348;Z=-0.145,P=0.884;Z=-1.069,P=0.285;Z=-0.027,P=0.978)。化疗结束后初级预防组9例因中性粒细胞减少需补充rhG-CSF,发生率18.4%(9/49),次级预防组22例,发生率81.5%(22/27),2组比较差异有统计学意义(χ^(2)=28.711,P=0.000)。初级预防组2例因中性粒细胞减少需重复住院,发生率4.1%(2/49),次级预防组7例,发生率25.9%(7/27),2组比较差异有统计学意义(χ^(2)=6.002,P=0.014)。初级预防组1例因中性粒细胞减少导致化疗延迟,发生率2.0%(1/49),次级预防组5例,发生率18.5%(5/27),2组比较差异有统计学意义(χ^(2)=4.431,P=0.035)。结论卵巢癌初始肿瘤细胞减灭术后化疗过程中初级预防性应用PEG-rhG-CSF可显著降低第一、二疗程中性粒细胞减少发生率,从而降低中性粒细胞减少相关重复住院率,保证化疗周期如期顺利进行。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:观察聚乙二醇化重组人改构白介素11(PEGylated IL-11 mutein,PEG-m IL 11)不同给药次数和给药剂量对骨髓抑制的小鼠血小板减少症的治疗作用,并与m IL-11进行比较,为临床应用提供参考。方法:BALB/c小鼠经2.5 Gy全身^(60)Coγ射线照射后,腹腔注射50 mg/kg卡铂制备血小板减少症模型。在给药次数研究中,将30只造模成功的BALB/c小鼠随机分为5组:溶剂对照组:d 1,4,7每日1次,共3次;m IL-11组:m IL-11200μg/(kg·d)×9 d;PEG-m IL 11 A组:PEG-m IL 111800μg/(kg·d)×1 d(d 1);PEG-m IL 11 B组:900μg/(kg·d)×2 d(d 1,5)和PEG-m IL 11 C组:600μg/(kg·d)×3 d(d 1,4,7),各组小鼠均为皮下注射给药。监测5周内血小板的变化情况;在给药剂量研究中将100只造模成功的BALB/c小鼠随机分为5组:溶剂对照组:d 1,5每日1次,共2次;m IL-11组:m IL-11200μg/(kg·d)×9 d、PEG-m IL 11低、中、高剂量组(200、420、900μg/(kg·d)×2 d,d 1,5),对各组小鼠均皮下注射给药,在5周内每隔2-3 d检测外周血细胞,并于给药后d 8选取部分动物安乐死后进行骨髓细胞培养。结果:与造模前相比,溶剂对照组Plt在最低点时降低幅度达到80%以上。给药次数研究中,PEG-m IL 11各给药组在最低点时的Plt值均明显高于溶剂对照组和m IL-11组(P<0.05),但不同给药次数的3组间差异不显著;在给药剂量研究中,PEG-m IL 11各治疗组在Plt最低点的降低幅度明显低于溶剂对照组和m IL-11治疗组(P<0.05),在最低点后Plt的恢复速度明显快于溶剂对照组,在d 10呈剂量依赖性的升高(r=0.92);PEG-m IL 11各治疗组的RBC在最低点的降低幅度明显减小并且恢复明显加快;各组WBC的变化趋势基本一致。CFU-M eg测定结果显示,PEG-m IL 11和m IL-11组同溶剂对照比相比CFU-M eg有增多的趋势,且PEG-m IL 11治疗组动物的集落数更高。结论:PEG-m IL 11对骨髓抑制小鼠血小板减少症有明显的治疗作用,而且同m IL-11相比,可以减少给药次数,提高治疗的顺应性,为开发重组白介素11的长效制剂提供了一定的依据。
文摘目的探讨初级与次级预防性使用聚乙二醇化重组人粒细胞集落刺激因子(pegylated recombinant human granulocyte colony-stimulating factor,PEG-rhG-CSF)在卵巢癌初始肿瘤细胞减灭术后化疗的价值。方法2019年1月~2020年6月我院76例卵巢癌初始肿瘤细胞减灭术后行紫杉醇和卡铂联合化疗,根据初次预防性使用PEG-rhG-CSF分为初级预防组(n=49)和次级预防组(n=27),比较2组中性粒细胞减少发生率、需要补充重组人粒细胞集落刺激因子(recombinant human granulocyte colony-stimulating factor,rhG-CSF)率、中性粒细胞减少相关重复住院率、中性粒细胞减少相关化疗周期延迟发生率等。结果第一、二疗程中,初级预防组3、4度中性粒细胞减少发生率分别为8.2%(4/49)、6.1%(3/49),明显低于次级预防组发生率66.7%(18/27)、37.0%(10/27)(Z=-6.569,P=0.000;Z=-4.338,P=0.000)。在第三~六疗程中,2组中性粒细胞减少发生率无明显统计学差异(Z=-0.938,P=0.348;Z=-0.145,P=0.884;Z=-1.069,P=0.285;Z=-0.027,P=0.978)。化疗结束后初级预防组9例因中性粒细胞减少需补充rhG-CSF,发生率18.4%(9/49),次级预防组22例,发生率81.5%(22/27),2组比较差异有统计学意义(χ^(2)=28.711,P=0.000)。初级预防组2例因中性粒细胞减少需重复住院,发生率4.1%(2/49),次级预防组7例,发生率25.9%(7/27),2组比较差异有统计学意义(χ^(2)=6.002,P=0.014)。初级预防组1例因中性粒细胞减少导致化疗延迟,发生率2.0%(1/49),次级预防组5例,发生率18.5%(5/27),2组比较差异有统计学意义(χ^(2)=4.431,P=0.035)。结论卵巢癌初始肿瘤细胞减灭术后化疗过程中初级预防性应用PEG-rhG-CSF可显著降低第一、二疗程中性粒细胞减少发生率,从而降低中性粒细胞减少相关重复住院率,保证化疗周期如期顺利进行。
