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.
Keywords: cancer; cilengitide; integrins; pharmacokinetics; population PK model.
© 2014, The American College of Clinical Pharmacology.