Cyclosporin twice or three times daily dosing in pediatric transplant patients – It is not the same! CyA remains a mainstay in antirejection therapy after solid organ and bone marrow transplanta- tion. One of the major limitations of CyA-ME is its nephrotoxicity (1). While it is unclear whether toxicity is more closely related to the exposure or the peak concentration, physicians may be inclined to convert patients from b.i.d. dosing to t.i.d. dosing in order to reduce the peak concentration. In a recent publication, Fanta et al. (2) taught us how to account for t.i.d. dosing of CyA-ME. The authors focused mostly on the evaluation of different abbreviated approaches to estimate the drug exposure or AUC. They concluded that the pre-dose trough blood con- centrations (C 0 ) and two-hour concentrations (C 2 ) are both useful for monitoring t.i.d. dosing of CyA-ME. They also suggested that the target C 2 should be approximately 30% lower after t.i.d. than after b.i.d. dosing while the target trough blood concentrations should be similar. This group and other authors have proposed to accommodate the faster elimination of CyA-ME in young pediatric renal transplant recipients (3) by adding a third dose to achieve a drug exposure similar to that of patients with slower elimin- ation. It is important to note that neither target C 0 nor C 2 concentrations nor target eight-hour AUC have been established for t.i.d. dosing. In fact, the targets for the C 2 concentrations on b.i.d. dosing also remain vague (4). C 0 and C 2 concentrations are only surrogate markers of Filler G, Rocha de Barros V, Jagger JE, Christians U. Cyclosporin twice or three times daily dosing in pediatric transplant patients – It is not the same! Pediatr Transplantation 2006: 10: 953–956. Ó 2006 Blackwell Munksgaard Abstract: Not infrequently, physicians elect to divide CyA-ME from b.i.d. to t.i.d. dosing in an effort to minimize toxicity. Equivalent exposure is assumed. Few studies have compared 24-h PK profiles on both dosing regimes in the same patient. We retrospectively studied a heterogeneous population of seven pediatric patients (one heart trans- plant, five renal transplants and one FSGS patient) on both dosing regimes who had complete 24-h PK profiles on CyA-ME. Four patients were converted from b.i.d. to t.i.d. and three patients from t.i.d. to b.i.d. dosing. There was no difference in the dose/kg (5.66 ± 2.52 mg/kg on b.i.d. dosing and 5.75 ± 1.81 mg/kg on t.i.d. dosing, p ¼ 0.8578, two- sided t-test). When comparing the dose-normalized AUCs over 24 h, every single patient demonstrated lower CyA-ME exposure on t.i.d. than on b.i.d. dosing with an average relative bioavailability that was 37.9% lower on t.i.d. than on b.i.d. dosing. The median dose-normal- ized AUC 0 fi24h dropped from 1620 ng · h · kg/mL · mg (range: 1253–4319) on b.i.d. to 1016 ng · h · kg/mL · mg (range: 712–1485, p ¼ 0.02, Wilcoxon’s matched pairs test) on t.i.d. dosing. Our results indicate t.i.d. dosing of CyA-ME results in significantly lower exposure when the same total dose is administered in two divided doses. This reduced exposure may potentially increase the risk for rejection. Guido Filler 1 , Viviane Rocha de Barros 2 , Justin E. Jagger 1 and Uwe Christians 3 1 Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada, 2 Pediatric Nephrology Unit, Hospital da CrianÅa Santo Antônio, Complexo Hospitalar Santa Casa, Fundażo Faculdade Federal de CiÞncias MØdicas de Porto Alegre, FFFCMPA, Porto Alegre, Brasil, 3 Clinical Research and Development, Department of Anesthesiology, University of Colorado Health Science Center, Denver, CO, USA Key words: cyclosporin – renal transplantation – therapeutic drug monitoring – AUC monitoring- pediatric patients – immunosuppressive dose regimens Guido Filler, Professor and Head, Division of Nephrology, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON K1H 8L1, Canada Tel.: +1 613 737 7600/3957 Fax: +1 613 738 3254 E-mail: filler@cheo.on.ca Accepted for publication 11 May 2006 Abbreviations: AUC, area under the time–concentration curve; b.i.d., twice daily; CyA-ME, microemulsified cy- closporin; PK, pharmacokinetic; PK, pharmacokinetic; t.i.d., three times daily. Pediatr Transplantation 2006: 10: 953–956. Copyright Ó 2006 Blackwell Munksgaard Pediatric Transplantation DOI: 10.1111/j.1399-3046.2006.00592.x 953