ORIGINAL ARTICLE Development and Validation of Limited Sampling Strategies for Estimation of Cyclosporine Area Under the Concentration–Time Curve in Hematopoietic Stem Cell Transplant Patients Molouk Hadjibabaie, BCPS,* Iman Vazirian, PharmD,† Masoud Iravani, MD,‡ Seyed Asadollah Moosavi, MD,‡ Kamran Alimoghaddam, MD,‡ Ardeshir Ghavamzadeh, MD,‡ and Saeed Rezaee, PhD§ Abstract: The aim of this study was to develop and validate limited sampling strategies for accurately predicting 12-hour area under the concentration–time curve (AUC 0–12 h ) to provide a practical method for more precise therapeutic drug monitoring of cyclosporine A in stem cell transplant patients. Steady-state cyclosporine blood con- centrations were measured within a dosing interval (12 hours post administration) in 35 allogeneic bone marrow transplant patients receiving 238 mg (6117 mg) twice-daily dose of cyclosporine. Limited sampling strategies were developed by multiple linear regression analysis of relationship between cyclosporine A full AUC 0–12 h values and different combinations of preselected blood concentrations. Validation of the estimating equations was done by a bootstrap-like cross-validation method. Cross-validation results showed that cyclosporine AUC 0–12 h could be estimated using either 2 or 3 samples within the first 4 hours after drug administration with good accuracy and precision (absolute prediction error of less than 6.2%). The number of estimated area under the drug concentration– time curves within 15% of observed values was greater than 26 (74%) for models used predose concentration with either c 2h and c 4h or both. Most of the previously reported single-sample models showed a systematic error in predicting AUC 0–12 h . Although a statistically significant difference in precision of prediction was seen between 3-sample model using c 0 ,c 2h , and c 4h and 2-sample models (c 0 ,c 2h or c 0 , and c 4h ), such a difference (2%) could not be of clinical impor- tance. Other 2-sample estimating equations (models using c 2h with either c 6h or c 10h ) with the same degree of precision appear to be less feasible clinically. Cyclosporine AUC 0–12 h in bone marrow transplant patients could be estimated using 2 or 3 samples within the first 4 hours after drug administration with good accuracy and precision. Key Words: cyclosporine, bone marrow transplantation, AUC, limited sampling methods (Ther Drug Monit 2011;33:673–680) INTRODUCTION Since its introduction, cyclosporine A (CsA) has significantly improved the success rates of transplantation procedures. 1 It is still the most commonly used immunosup- pressive drug for prevention of transplant rejection and graft versus host disease (GVHD), 1,2 which is a major cause of toxicity after stem cell transplantation (SCT). 1,3 CsA is a highly lipophilic polypeptide with limited solubility; slow, incomplete, and variable absorption, un- predictable pharmacokinetics; and a narrow therapeutic window. 4,5 Although the newer formulation of CsA, Neoral, shows some improvements in the pharmacokinetic features compared with the original one, Sandimmune, it is still mandatory to individualize the CsA dosage using therapeutic drug monitoring (TDM). 6 The TDM of CsA has been discussed and evolved through the last 25 years. It has been shown that the 12-hour area under the concentration–time curve (AUC 0–12 h ) is the best estimate of systemic drug exposure for each individual patient. 7 Measuring AUC 0–12 h therefore could be realized as an ideal way for optimizing the dose of CsA. 2,7 However, the need for drawing and analyzing multiple blood samples, which in turn is more time, cost, and effort consuming, makes it less than a practical approach. 2,7,8 In an attempt to address these problems, limited sampling strategy (LSS) was described in 1990, 9 by which area under the drug concentration–time curve (AUC) monitoring could be simplified for use in routine clinical setting. 4,10 Many articles have been published on sparse sampling methods for estimating cyclosporine AUC in different types of transplantations and reviewed elsewhere. 7,11 However, a few investigations are available dealing with sparse sampling methods of estimating AUC in bone marrow transplant patients. 5,12 The aim of this study was to develop and validate LSSs for accurately predicting AUC 0–12 h to provide a practical method for more precise TDM of CsA in Iranian SCT patients. Received for publication April 11, 2011; accepted September 1, 2011. From the Departments of *Clinical Pharmacy; †Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences; ‡Hematology- Oncology and SCT Research Center, Department of Hematology- Oncology, Shariati Hospital, Tehran University of Medical Sciences, Tehran; and §Department of Pharmaceutics, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. Supported by a grant from Tehran University of Medical Sciences. The authors declare no conflict of interest. Correspondence: Saeed Rezaee, PharmD, PhD, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, 6135733184, Ahvaz, Iran (e-mail: s.rezaee@ajums.ac.ir). Copyright Ó 2011 by Lippincott Williams & Wilkins Ther Drug Monit  Volume 33, Number 6, December 2011 673