Using physiologically based pharmacokinetic (PBPK) modeling and simulations, this study estimated the exposure of sunitinib and its active metabolite SU012662 in pediatric patients. A PBPK simulator, SimCYP, was used to develop and validate the pharmacokinetic models. Model development employed a combined “bottom–up” and “top–down” approach to fully utilize the available in vitro or in silico experimental data and in vivo observed clinical data. First, the PBPK model for sunitinib was established, then the cytochrome P450 3A4–mediated metabolism of sunitinib was used as the input for SU012662. PBPK models were validated using pharmacokinetics of sunitinib and SU012662 from one study in adult patients with solid tumors and three clinical trials in pediatric patients with solid or gastrointestinal stromal tumors. The models were further used to predict the exposure of sunitinib and SU012662 by pediatric age groups. The PBPK models for sunitinib and SU012662 developed based on pharmacokinetic characteristics in adults successfully predicted the observed in vivo pharmacokinetics of sunitinib and SU012662 in both adults and pediatric patients. Based on the SimCYP model predictions, a daily dose of 20 mg/m2 will produce sunitinib and SU012662 total exposures in pediatric patients similar to those in adults with gastrointestinal stromal tumor treated with a clinical dose of 50 mg once daily.