Sirolimus is the first drug to show efficacy in the treatment of patients with complicated vascular anomalies. The current study expands on the evolution of a PK model-based strategy for the precision dosing of sirolimus as part of prospective concentration controlled clinical trials in pediatric patients with vascular anomalies. Twelve month follow up data collected from 52 pediatric patients participating in the Phase 2 clinical trial were analyzed. Target attainment across the age range of 3 weeks to 18 years after 2–3 months of therapy was 94% (49 out of 52 patients). The mean sirolimus dose to achieve the target of ~ 10 ng/mL for patients older than 2 years was 1.8 mg/m² twice daily (range 0.8–2.9), while it was 0.7 to 1.6 mg/m² twice daily for patients 3 weeks of age to 2 years. A total of 676 blood concentration data were used for the population PK analysis by nonlinear mixed effect modeling using NONMEM. The final model included a maturation function for sirolimus clearance and allometrically scaled body weight to account for size differences. The mean allometrically scaled sirolimus clearance estimates increased from 3.9 to 17.0 L/h per 70 kg with age from shortly after the birth to 2 years of age while the mean estimate for patients older than 2 years was 18.5 L/h per 70 kg. The developed model based dosing strategy provides a foundation for ongoing efforts to define the sirolimus exposure-response and clinical outcome relationships across the pediatric age spectrum from birth to adolescence.