T. Mizuno, C. Emoto, T. Fukuda, D. M. Adams, A. A. Vinks; Cincinnati Children's Hospital Medical Center, Cincinnati, OH

BACKGROUND: Sirolimus is an inhibitor of mammalian target of rapamycin increasingly being used in pediatrics. Sirolimus pharmacokinetics (PK) is known to change as a function of growth and maturation. In this study, sirolimus clearance (CL) was evaluated in neonates and infants based on serial PK evaluation over time to determine the developmental trajectory.
METHODS: PK data were obtained from a concentrations-controlled phase II clinical study of sirolimus in pediatric patients with vascular anomalies (NCT00975819). A total of 318 blood concentrations obtained from 24 younger children (5 weeks-3 year-old) over the course of treatment (1 month-1 year) were used for the analysis. Sirolimus CL was generated with respect to each concentration with Bayesian estimation using MW/Pharm ver. 3.82. CL was normalized by allometrically scaled body weight to standardize a body size effect.
RESULTS: Allometrically scaled sirolimus CL increased with age up to 2 years. In a population analysis, the relationship between CL and age could be described by the Emax model and compared with data from 28 older children and adolescents. Using a fully matured CL estimate (20.4 L/h/70 kg) as the fixed Emax value, the age at a half of matured CL (Age50) could be estimated in 11 neonates and infants. The median Age50 was 0.44 years (range 0.037-1.3 years).
CONCLUSION: This study provides the developmental trajectory of sirolimus CL which will be utilized for the model-based dosing optimization and clinical trial design in neonates and infants.