Pfizer Global R & D, Clinical Research, Department of Clinical Pharmacology, Tokyo, Japan.
J Clin Pharmacol. 2011 Dec;51(12):1628-43. doi: 10.1177/0091270010386954. Epub 2011 Jan 5.
Pegvisomant is a growth hormone (GH) receptor antagonist that normalizes insulin-like growth factor I (IGF-I) levels in patients with acromegaly. Although the dose of pegvisomant is determined by the IGF-I level, the pharmacokinetic and pharmacodynamic (PK/PD) model for pegvisomant concentration and IGF-I reduction has not been established. This study was conducted to characterize PK/PD of pegvisomant, and to determine the influence of covariates on the pegvisomant PK/PD. Based on the data from 5 phase III studies in 168 acromegaly patients, models were developed to characterize the PK/PD of pegvisomant. The PD variables were IGF-I serum concentrations. The modeling was performed with a nonlinear mixed-effects approach using NONMEM. After subcutaneous dosing, the PK of pegvisomant was described by a steady state PK model with dose- dependent clearance. Baseline GH and age were significant covariates for the clearance. A sigmoid E(max) model adequately described the relationship between IGF-I and pegvisomant concentrations. Baseline GH was found to be a significant covariate for the baseline effect (E(0)) and IC(50). The PK/PD properties of pegvisomant were not significantly different between Asian and Western patients.
培维索孟是一种生长激素（GH）受体拮抗剂，可使肢端肥大症患者的胰岛素样生长因子 I（IGF-I）水平恢复正常。虽然培维索孟的剂量取决于 IGF-I 水平，但尚未建立培维索孟浓度与 IGF-I 降低的药代动力学和药效学（PK/PD）模型。本研究旨在描述培维索孟的 PK/PD，并确定协变量对培维索孟 PK/PD 的影响。
基于来自 168 例肢端肥大症患者的 5 项 III 期研究的数据，采用非线性混合效应方法（NONMEM）建立了模型，以描述培维索孟的 PK/PD。PD 变量为 IGF-I 血清浓度。皮下给药后，培维索孟的 PK 采用具有剂量依赖性清除的稳态 PK 模型来描述。基线 GH 和年龄是清除率的重要协变量。
Sigmoid E(max) 模型能够很好地描述 IGF-I 与培维索孟浓度之间的关系。基线 GH 是基线效应（E(0)）和 IC(50)的重要协变量。培维索孟的 PK/PD 特性在亚洲和西方患者之间没有显著差异。
