title: Prediction of area under the cyclosporine concentration versus time curve in children undergoing hematopoietic stem cell transplantation.
abstract: This prospective study aimed to validate a previously developed first-dose limited sampling strategy (LSS) to predict the area under the cyclosporine concentration-versus-time curve (AUC) and to develop and then validate an LSS to predict cyclosporine AUC at steady state. This two-center Canadian study included children (ages .4 to 17.2 years) undergoing myeloablative allogeneic hematopoietic stem cell transplantation receiving cyclosporine for acute graft-versus-host disease prophylaxis. There were three cohorts, each incorporating 24 AUC determinations: first-dose LSS validation, steady-state LSS development, and steady-state LSS validation. Patients contributing data to either of the development cohorts were excluded from the corresponding validation group. Cyclosporine was given every 12 hours as a 2-hour infusion. Cyclosporine AUC was determined after administration of the first cyclosporine dose (8 samples) and then once weekly (9 samples) until engraftment. Steady-state LSSs were developed using stepwise multiple linear regression. An LSS was considered to provide an acceptable estimate of AUC if the lower limit of the 95% confidence limit (CL) of the intraclass coefficient was .8 or higher and both bias and precision were 15% or less. Fifty-three children age .4 to 18 years participated. Cyclosporine concentrations drawn up to 4 hours from the start of the infusion correlated most strongly with AUC. The previously developed first-dose LSSs and three steady-state LSSs met criteria for acceptability. The intraclass coefficients of the three-point first-dose LSS validation cohort, three-point steady-state LSS development cohort, and three-point steady-state LSS validation cohort were .974 (95% CL: .941 to .988), .984 (95% CL: .965 to .993), and .993 (95% CL: .984 to .997), respectively. The three-point first-dose (2, 6, and 8 hours) and steady-state (2, 2.5, and 8 hours) LSSs are valid measures of cyclosporine AUC after intravenous administration over 2 hours. Their use in a prospective evaluation of the relationship between cyclosporine AUC and hematopoietic stem cell transplantation clinical outcomes in children is suggested.
authors.affiliation: Department of Pharmacy, SickKids, 555 University Ave., Toronto, Ontario, Canada. lee.dupuis@sickkids.ca
authors.forename: L Lee
authors.initials: LL
authors.lastname: Dupuis
authors.forename: Winnie
authors.initials: W
authors.lastname: Seto
authors.forename: Oliver
authors.initials: O
authors.lastname: Teuffel
authors.forename: Paul
authors.initials: P
authors.lastname: Gibson
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Schultz
authors.forename: John D
authors.initials: JD
authors.lastname: Doyle
authors.forename: Adam
authors.initials: A
authors.lastname: Gassas
authors.forename: R Maarten
authors.initials: RM
authors.lastname: Egeler
authors.forename: Lillian
authors.initials: L
authors.lastname: Sung
authors.forename: Tal
authors.initials: T
authors.lastname: Schechter
mesh_terms: D000293:Adolescent; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000706:statistics & numerical data*; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007223:Infant; D007262:Infusions, Intravenous; D016014:Linear Models; D008297:Male; D019653:Myeloablative Agonists / Q000494:pharmacology / Q000627:therapeutic use; D011446:Prospective Studies; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D019653:Myeloablative Agonists; D016572:Cyclosporine