ORIGINAL ARTICLE Determination of initial i.v. CYA dosage to achieve target AUC values in pediatric hematopoietic stem cell transplant patients M Jin 1 , W Seto 1,2,3,4 , T Taylor 2,5 , EF Saunders 5 , J Doyle 4,5,6 and LL Dupuis 1,2,4,5 1 Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; 2 Department of Pharmacy, The Hospital for Sick Children, Toronto, Ontario, Canada; 3 Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada; 4 Division of Critical Care Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada; 5 Research Institute, University of Toronto, Toronto, Ontario, Canada and 6 Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada In solid organ transplantation, CYA dosing is based on the area under the concentration vs time curve (AUC inf ). This study aimed to develop a guideline for the initial i.v. CYA dose for pediatric hematopoietic SCT (HSCT) patients to achieve the target AUC inf recommended in solid organ transplantation. Whole-blood CYA concentrations were determined in 24 patients (0.5–16.9 years) after the first i.v. dose given over 2 h, 1 day before HSCT. The i.v. CYA dose predicted to achieve an AUC inf of 4200 lg  h/l was calculated for each patient and expressed as a function of each patient’s actual weight and body surface area (BSA). In patients p9 and 49 years of age, the mean i.v. CYA dose predicted to achieve the target AUC was 2.6 ± 0.94 and 2.1 ± 1.21 mg/kg, respectively. When these doses were expressed in terms of BSA, the mean dose was 65±23.1 and 68 ± 35.0mg/m 2 in children p9 and 49 years of age, respectively. In children 0.5–17 years of age undergoing HSCT, we recommend an initial i.v. CYA dose of 65mg/m 2 infused over 2 h to achieve an AUC inf of approximately 4200 lg  h/l. Bone Marrow Transplantation (2008) 42, 455–459; doi:10.1038/bmt.2008.189; published online 14 July 2008 Keywords: CYA; pharmacokinetics; hematopoietic stem cell transplant; pediatrics Introduction CYA continues to be a mainstay of regimens aimed at preventing acute GVHD (aGVHD) in patients undergoing hematopoietic SCT (HSCT). The most commonly pre- scribed initial i.v. CYA dose identified in a survey of European pediatric HSCT centers undertaken by the European Group for Blood and Marrow Transplantation was 3 mg/kg per day divided every 12 h. 1 Although the need to achieve target trough CYA whole-blood concentrations to effectively prevent aGVHD is generally acknowledged, no initial pediatric i.v. CYA dosing guideline for hemato- poietic stem cell transplant patients that incorporates known developmental differences in CYA pharmaco- kinetics exists. 2,3 A single initial CYA dose based on body weight alone is not likely to efficiently achieve pharmaco- kinetic targets in children. In pediatric and adult solid organ transplant patients receiving oral CYA, the area under the CYA concentration vs time curve (AUC) during the dosing interval at steady state is directly associated with the incidence of acute rejection. 4–6 AUC during the dosing interval at steady state is equivalent to the AUC from time 0 to infinity (AUC inf ) after the first dose. There is currently no published information regarding a potential relationship between AUC after i.v. CYA administration and the incidence of aGVHD though there recently has been interest in this concept. 7–11 The objective of this study was to develop a guideline for the initial i.v. CYA dose for pediatric HSCT patients that would achieve the target AUC values recommended for solid organ transplant patients. Methods This study was approved by the Research Ethics Com- mittee, The Hospital for Sick Children. Patients This study formed part of a larger prospective study of CYA pharmacokinetics after both i.v. and oral adminis- tration during HSCT. Methodology and results pertaining to the oral phase of this study have been published elsewhere. 12 In brief, patients who were undergoing allogeneic HSCT and were scheduled to receive CYA for aGVHD prophylaxis were eligible to participate. Patients with impaired liver function (defined as serum transaminase concentrations 43 times the upper limit of normal for their age and/or total bilirubin levels 42 mg per 100 ml (34 mmol/l) on the day of pharmacokinetic sampling were excluded. Patients receiving any drug known to substan- Received 9 November 2007; revised 7 May 2008; accepted 15 May 2008; published online 14 July 2008 Correspondence: LL Dupuis, Department of Pharmacy, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. E-mail: lee.dupuis@sickkids.ca Bone Marrow Transplantation (2008) 42, 455–459 & 2008 Macmillan Publishers Limited All rights reserved 0268-3369/08 $32.00 www.nature.com/bmt