Population Pharmacokinetic and Pharmacodynamic Modeling of Pegvisomant in Asian and Western Acromegaly Patients

• Published in: Journal of clinical pharmacology 2011-12, Vol.51 (12), p.1628-1643
• Main Authors: Muto, Chieko, Chiba, Koji, Suwa, Toshio
• Format: Article
• Language: English
• Subjects: acromegaly; Acromegaly - drug therapy; Acromegaly - metabolism; Adult; Age Factors; Aged; Asian Continental Ancestry Group; European Continental Ancestry Group; Female; Growth Hormone - blood; growth hormone receptor antagonist; Growth hormones; Human Growth Hormone - analogs & derivatives; Human Growth Hormone - blood; Human Growth Hormone - pharmacokinetics; Human Growth Hormone - pharmacology; Humans; IGF-I; Insulin; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factors; Male; Middle Aged; Models, Biological; Pegvisomant; population PK/PD; Receptors, Somatotropin - antagonists & inhibitors; Young Adult
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1177/0091270010386954

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 Emax model adequately described the relationship between IGF‐I and pegvisomant concentrations. Baseline GH was found to be a significant covariate for the baseline effect (E0) and IC50. The PK/PD properties of pegvisomant were not significantly different between Asian and Western patients.