PII-108

C. Emoto,1 T. Fukuda,1 T. Mizuno,1 B. Schniedewind,2 U. Christians,2 D. M. Adams,3 B. C. Widemann,4 M. J. Fisher,5 J. Perentesis,3 B. Weiss,3 A. A. Vinks1; 1Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 2iC42 Integrated Solutions in Clinical Research and Development, University of Colorado, Aurora, CO, 3Cancer & Blood Disease Institute, Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 4Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, 5Division of Oncology, The Children’s Hospital of Philadelphia, Philadelphia, PA

BACKGROUND: Sirolimus (Sir) is an inhibitor of mammalian target of rapamycin (mTOR) and exhibits large between patient variability in its pharmacokinetics. CYP3As contribute to the major metabolic pathway involved in Sir elimination. This study was conducted to explore in vivo age-dependent Sir metabolite formation with in vitro data and the effect of growth on Sir clearance (CL) in pediatric patients with neurofibromatosis type 1 (NF1) or vascular anomalies (VA).
METHODS: Sir trough samples obtained at steady-state as part of a clinical study in 63 patients with NF1 (median age 9 years, range 3-45 years) and 45 patients with VA (5 years, 1 month-18 years) were available for estimation of CL. Metabolite profiles were assayed in samples from 25 patients (18 NF1, 7 VA; 10 years, 3-45 years). Sir and concentrations of 5 metabolites (24-, 25-, 46-hydroxysirolimus, 16-O- and 39-O-demethysirolimus) were determined by LC-MS/MS. Recombinant CYPs (BD Bioscience) were used to confirm in vivo metabolite patterns. Individual CL estimates were generated with Bayesian estimation by using MW/Pharm ver. 3.82. Metabolic ratios defined as the metabolite concentration divided by Sir concentration in blood were analyzed as a function of age.
RESULTS: Sir CL (L/h) was significantly associated with age in both patients with NF1 and VA and could be described by the Emax model. Metabolic ratios of main metabolites, 16-O-demethylsirolimus and 24-hydroxysirolimus, showed an age-dependent increase. In vitro incubation studies revealed the CYP3A pathway as the major contributor to Sir metabolite formation as identified in blood samples.
CONCLUSION: These findings suggest that the age-dependent changes in sirolimus CL observed in vivo can be explained by parallel age-related increases in CYP3A metabolic capacity.