title: Population pharmacokinetic and pharmacodynamic modeling of pegvisomant in asian and Western acromegaly patients.
abstract: 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.
authors.affiliation: Pfizer Global R & D, Clinical Research, Department of Clinical Pharmacology, Tokyo, Japan. chieko.muto@pfizer.com
authors.forename: Chieko
authors.initials: C
authors.lastname: Muto
authors.forename: Koji
authors.initials: K
authors.lastname: Chiba
authors.forename: Toshio
authors.initials: T
authors.lastname: Suwa
mesh_terms: D000172:Acromegaly / Q000188:drug therapy / Q000378:metabolism*; D000328:Adult; D000367:Age Factors; D000368:Aged; D044466:Asian People; D005260:Female; D013006:Growth Hormone / Q000097:blood; D019382:Human Growth Hormone / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011986:Receptors, Somatotropin / Q000037:antagonists & inhibitors; D044465:White People; D055815:Young Adult
chemical_list: D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C406545:pegvisomant