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

Cilengitideisan avb3/avb5-integrininhibitorinvestigatedasananticanceragent.Thisstudyaimedtodevelopacilengitidepopulationpharmacokinetic 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 twocompartment 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. Estimatedstructuralmodelparameterswere:2.79Lh 1 m 2 centralcompartmentmeansystemicclearance,6.75Lm 2 centralcompartmentvolume ofdistribution,1.3Lh 1 m 2 intercompartmentalclearance,and3.85Lm 2 peripheralcompartmentvolumeofdistribution.Meanhalf-lifewas0.9and 3.8h (a/b-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 (ra0.95, 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.