Population pharmacokinetics of cilengitide in adult and pediatric cancer patients from a nonlinear mixed-effects analysis.

Abstract

Cilengitide is an αvβ3/αvβ5-integrin inhibitor investigated as an anticancer agent. This study aimed to develop a cilengitide population pharmacokinetic model using nonlinear mixed-effects modeling of 136 adult patients with advanced solid tumors and to scale the pharmacokinetic parameters to the pediatric population. A stepwise approach was used, beginning with exploratory analyses checking database/target covariate relationships. A two-compartment structural model was developed to describe cilengitide's concentration-time profile and assess covariates' impact on pharmacokinetic parameters. A bootstrap procedure validated the base/final model stability. A two-compartment model best described concentration-time data. Estimated structural model parameters were: 2.79 L h(-) (1)  m(-) (2) central compartment mean systemic clearance, 6.75 L m(-) (2) central compartment volume of distribution, 1.3 L h(-) (1)  m(-) (2) intercompartmental clearance, and 3.85 L m(-) (2) peripheral compartment volume of distribution. Mean half-life was 0.9 and 3.8 h (α/β-phase). Co-medications and study populations had no impact, as the different studies were not significant model covariates. Weight and body surface area correlated with the pharmacokinetic parameters (r = 0.95, P < 0.01). Pharmacokinetic parameters were consistent with individual study-derived parameters; their allometric scaling enabled pediatric pharmacokinetic profile predictions as corroborated by independent data. This model provides the basis for pharmacokinetic profile simulations of different dosages/regimens in different populations.

• Authors: Michael Zühlsdorf, Venkatesh Atul Bhattaram, Marco Campioni, Sonja Krösser, Hartmut Derendorf, Andreas Kovar
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 54 Issue 12 Pg. 1391-9 (Dec 2014) ISSN: 1552-4604 [Electronic] England
• PMID: 24911832 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2014, The American College of Clinical Pharmacology.

Chemical References

• Snake Venoms
• Cilengitide

Topics

• Adult
• Aged
• Aged, 80 and over
• Area Under Curve
• Body Surface Area
• Body Weight
• Child
• Computer Simulation
• Humans
• Middle Aged
• Models, Biological
• Neoplasms (metabolism)
• Snake Venoms (pharmacokinetics)