The objective of this paper is to present a population PK model which adequately describes the time-concentration profiles of different doses of ctanercept (Enbrel) administered subcutaneously to subjects with moderate-to-severe psoriasis and to simulate the time courses of concentrations following 50 mg once weekly (QW) dosing. Pharmacokinetic (PK) data from three clinical studies with doses 25 mg QW 25 mg twice weekly (BIW) and 50 mg BIW, were used. A one-compartment model with gender, weight and time covariates on the apparent clearance and weight covariate on the apparent volume of distribution was developed. The population mean of the apparent steady state clearance in males was 0.129 l/h. compared to 0.148 l/h in females. The clearance varied with time being lower in the first 2 weeks of the therapy, increasing sharply during weeks 3-4. and converging gradually after that to its steady state level. The population mean of the apparent volume of distribution also varied with time and was 16.11 during week 1, 20.01 during weeks 2-4 and 22.51 after week 4. The population PK model adequately described the observed concentration-time profiles in subjects with psoriasis. Despite a somewhat different covariate set, the parameter estimates of the population PK model for etanercept are very similar between the psoriasis and rheumatoid arthritis populations. The population PK model was used to simulate the pharmacokinetic profiles after a novel 50 mg QW dosing regimen. The simulations show good agreement with the observed data from 84 subjects participating in a fourth study (50 mg QW dose) used as an external validation set. The simulations of the 50 mg QW and the 25 mg BIW dosing regimens show that there is a significant overlap between the profiles yielding similar steady state exposures with both dosing regimens. The latter is an indication that the respective efficacy and safety profiles after those two dosing regimens are likely to be similar.

中文翻译：

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牛皮癣患者皮下注射依那西普的群体药代动力学模型。

本文的目的是提供一个人口PK模型，该模型充分描述了皮下注射给中度至重度牛皮癣患者的不同剂量ctanercept（Enbrel）的时间-浓度曲线，并模拟了50 mg以下浓度的时间过程每周一次（QW）剂量。使用了三项临床研究的药代动力学（PK）数据，剂量分别为25 mg QW，每周两次（BIW）25 mg和50 mg BIW。建立了具有性别，体重和时间在表观清除率上协变量，体重在表观分布量上协变量的一室模型。男性表观稳态清除率的总体平均值为0.129 l / h。相比之下，女性为0.148 l / h。在治疗的前2周内，清除率随时间而变化，在3-4周内急剧增加。然后逐渐收敛到稳态水平。表观分布体积的人口平均数也随时间变化，在第1周时为16.11，在第2-4周时为20.01，在第4周后为22.51。人口PK模型充分描述了在牛皮癣患者中观察到的浓度-时间曲线。尽管协变量集有所不同，但牛皮癣和类风湿性关节炎人群之间的依那西普PK模型参数估计非常相似。在新的50 mg QW给药方案后，群体PK模型用于模拟药代动力学特征。模拟显示与参与第四项研究（50 mg QW剂量）的84名受试者的观察数据高度吻合，该研究用作外部验证集。50 mg QW和25 mg BIW给药方案的模拟显示，两种给药方案在产生相似稳态暴露的曲线之间存在显着重叠。后者表明这两种给药方案后各自的功效和安全性概况可能相似。