Zhou H, Chen T L, Marino M, Lau H, Miller T, Kalafsky G, McLeod J F
Department of Clinical Pharmacology, Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
Br J Clin Pharmacol. 2000 Dec;50(6):543-52. doi: 10.1046/j.1365-2125.2000.00297.x.
To develop a population model that can describe the pharmacokinetic profile of microencapsulated octreotide acetate in healthy cholecystectomized subjects. To investigate the correlation between serum IGF-1 and octreotide concentration.
A population pharmacokinetic analysis was performed on octreotide data obtained following a single dose of 30 mg microencapsulated octreotide acetate intramuscularly. The relationship between serum IGF-1 concentration and octreotide concentration was effectively described by a population pharmacokinetic/pharmacodynamic model.
The pharmacokinetic profile of octreotide was characterized by an initial peak of octreotide followed by a sustained-release of drug. Plateau concentration were sustained up to day 70, and gradually declined to below the detection limit by day 112. A one-compartment linear model was constructed which consisted of two absorption processes, characterized by KIR and KSR, rate constants for immediate-release and sustained-release, respectively, with first-order elimination (Ke; 1.05 h-1). The surface, unencapsulated drug was immediately absorbed into the central compartment with first-order absorption (KIR; 0.0312 h-1), while the microencapsulated drug was first released in a zero-order fashion into a depot before being absorbed into the central compartment with first-order absorption (KSR; 0.00469 h-1) during a period of tau (1680 h). Body weight and gender were important covariates for the apparent volume of distribution. The type of formulation was an important covariate for KIR but had no effect on KSR. An inhibitory Emax population pharmacokinetic/pharmacodynamic model could adequately describe the relationship between IGF-1 (expressed as percent baseline) and octreotide concentration. Baseline IGF-1 concentration was found to be a significant covariate for the baseline effect (E0). A relationship between GH concentration and octreotide concentration was not established.
The pharmacokinetic profile of microencapsulated octreotide acetate was effectively described by the derived population model. The relationship between IGF-1 and drug concentration could be used to guide optimization of therapeutic octreotide dosage regimens.
建立一个能描述微囊化醋酸奥曲肽在健康胆囊切除受试者体内药代动力学特征的群体模型。研究血清胰岛素样生长因子-1（IGF-1）与奥曲肽浓度之间的相关性。
对单次肌内注射30mg微囊化醋酸奥曲肽后获得的奥曲肽数据进行群体药代动力学分析。通过群体药代动力学/药效学模型有效描述血清IGF-1浓度与奥曲肽浓度之间的关系。
奥曲肽的药代动力学特征为奥曲肽初始峰值后药物持续释放。平台浓度维持至第70天，到第112天逐渐降至检测限以下。构建了一个一室线性模型，该模型由两个吸收过程组成，分别以KIR和KSR为特征，KIR和KSR分别为速释和缓释的速率常数，具有一级消除（Ke；1.05 h-1）。表面未包封的药物以一级吸收（KIR；0.0312 h-1）立即吸收进入中央室，而微囊化药物首先以零级方式释放到贮库中，然后在tau（1680 h）期间以一级吸收（KSR；0.00469 h-1）吸收进入中央室。体重和性别是分布容积的重要协变量。制剂类型是KIR的重要协变量，但对KSR无影响。抑制性Emax群体药代动力学/药效学模型可以充分描述IGF-1（以基线百分比表示）与奥曲肽浓度之间的关系。发现基线IGF-1浓度是基线效应（E0）的显著协变量。未建立生长激素（GH）浓度与奥曲肽浓度之间的关系。
推导得到的群体模型有效描述了微囊化醋酸奥曲肽的药代动力学特征。IGF-1与药物浓度之间的关系可用于指导奥曲肽治疗剂量方案的优化。
