title: Characterizing the Developmental Trajectory of Sirolimus Clearance in Neonates and Infants.
abstract: Sirolimus is increasingly being used in neonates and infants, but the mechanistic basis of age-dependent changes in sirolimus disposition has not been fully addressed yet. In order to characterize the age-dependent changes, serial sirolimus clearance (CL) estimates in individual young pediatric patients were collected and analyzed by population modeling analysis. In addition, sirolimus metabolite formation was also investigated to further substantiate the corresponding age-dependent change in CYP3A activity. The increasing pattern over time of allometrically size-normalized sirolimus CL estimates vs. age was well described by a sigmoidal Emax model. This age-dependent increase was also observed within each individual patient over a 4-year study period. CYP3A-dependent sirolimus metabolite formation changed in a similar fashion. This study clearly demonstrates the rapid increase of sirolimus CL over time in neonates and infants, indicating the developmental change. This developmental pattern can be explained by a parallel increase in CYP3A metabolic activity.
authors: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors: C
authors: C
authors: Emoto
authors: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors: T
authors: T
authors: Fukuda
authors: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors: T
authors: T
authors: Mizuno
authors: iC42 Integrated Solutions in Clinical Research and Development, University of Colorado, Anschutz Medical Center, Aurora, Colorado, USA.
authors: B
authors: B
authors: Schniedewind
authors: iC42 Integrated Solutions in Clinical Research and Development, University of Colorado, Anschutz Medical Center, Aurora, Colorado, USA.
authors: Uwe
authors: U
authors: Christians
authors: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.|Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors: D M
authors: DM
authors: Adams
authors: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors: A A
authors: AA
authors: Vinks
mesh_terms: D000293:Adolescent; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood* / Q000494:pharmacology / Q000627:therapeutic use; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000097:blood* / Q000494:pharmacology / Q000627:therapeutic use; D014652:Vascular Diseases / Q000097:blood / Q000188:drug therapy; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D020123:Sirolimus