Clinical Pharmacokinetics of Tacrolimus after the First Oral Administration in Renal Transplant Recipients on Triple Immunosuppressive Therapy Radmila M. Velickovic-Radovanovic, Goran Paunovic, Momir Mikov, Vidojko Djordjevic, Mariola Stojanovic, Aleksandra Catic-Djordjevic and Tatjana Cvetkovic Department of Pharmacy, Faculty of medicine, University of Nis, Nis, Serbia and Montenegro (Received 8 September 2009; Accepted 29 October 2009) Abstract: Monitoring of tacrolimus blood concentration is of utmost importance in the management of renal transplant recipients because of Narrow Therapeutic Index and highly variable pharmacokinetics. The aim of this study was to detect inter-patient pharmacokinetic variability of tacrolimus and to assess the predictability of individual tacrolimus concentrations at various times of the area under the curve (AUC) seeking to find the best sampling time to predict the exposure of tacroli- mus in renal transplant recipients with triple therapy. This oral dose tacrolimus pharmacokinetics study was conducted in 18 Serbian renal transplant recipients on triple immunosuppressive therapy, including basiliximab. The first oral dose of tacroli- mus (0.05 mg ⁄ kg) was given on day 5 post-transplant; blood concentration was measured by microparticle enzyme immuno- assay method. Associations between each sampling time-point of concentrations and AUC 12 were evaluated by Pearson correlation coefficients. Abbreviated sampling equations were derived by multiple, stepwise regression analyses. The variance in the strength of association between predicted AUC (AUC p ) and AUC 12 was reflected by linear regression coefficients. AUC 12 showed remarkable inter-individual variations after the first oral dose of tacrolimus. The area of the maximum AUC was four times higher than that of the minimum AUC. C 4 seems to be an indicator of total body exposure to tacrolimus. Alternatively, the concentrations at 1.5, 4 and 8 hr as an abbreviated AUC were as good a predictor as a full pharmacokinetic study. Our results show a significant difference between men and women. A three-point sampling method seemed to be the best abbreviated AUC for a cost-effective tacrolimus monitoring strategy. Rejection prophylaxis using calcineurin inhibitors (cyclospor- ine or tacrolimus) remains the best practice pending publica- tion of long-term results using newer agents [1–3]. The choice of cyclosporine or tacrolimus depends on immunolog- ical risk, recipient characteristics, concomitant immunosup- pression and socio-economic factors. Tacrolimus (FK 506) is superior to cyclosporine in improving graft survival and preventing acute rejection after kidney transplantation, but increases post-transplant diabetes, neurological and gastroin- testinal side effects [3,4]. Monitoring of tacrolimus blood concentrations is of utmost importance in the management of renal transplant recipients because of the narrow thera- peutic range and highly variable pharmacokinetics of the drug [1–4]. If the concentration is lower than the range, the transplanted kidney will be rejected because of insufficient immunosuppression by tacrolimus. If the concentration is higher than the range, adverse effects will be observed because of the excess concentration of tacrolimus. High sys- temic exposure to tacrolimus might induce many side effects including nephrotoxicity, neurotoxicity and post-transplant diabetes mellitus [3,4]. Therapeutic monitoring of tacrolimus plays a crucial role not only in the evaluation of the drug efficacy but also in the control of potential adverse effects. Before and after organ transplantation, patients are co-medi- cated with multiple drugs to prevent rejection of the trans- planted organ and to maintain them in a good condition. Although the area under the concentration–time curve moni- toring is the ideal method for the optimal immunosuppres- sion, the current status of this technology does not permit a routine use of this procedure in clinical practice because of its complexity and costliness [4,5]. As accurate tacrolimus blood concentration monitoring is necessary in the early post-transplant days, there is a need to find a new predict- able method for routine clinical use. About 80 uraemic patients per year undergo renal trans- plantation in Serbia. Although previous studies have shown significant pharmacokinetic interactions among tacrolimus, mycophenolate mofetil (MMF) and corticosteroids [5–11], tacrolimus pharmacokinetic data in combination with MMF, methylprednisolone (MP) and basiliximab (Bas) are scarce in renal transplant recipients [12–14]. The main objective of this study was to detect inter-indi- vidual pharmacokinetic variability of tacrolimus after the first oral dose in renal transplant recipients on triple immu- nosuppressive therapy, including Bas. The secondary objec- tive was to assess the predictability of individual tacrolimus concentrations at various times to estimate the area under the curve (AUC) and derive an abbreviated AUC that predicts total body exposure to tacrolimus for routine clinical use. Author for correspondence: Radmila M. Velickovic-Radovanovic, Department of Pharmacy, Faculty of Medicine, University of Nis, Z. Djindjica 81, Nis 18000, Serbia and Montenegro (fax 38118550721, e-mail radavel@medfak.ni.ac.rs). Ó 2010 The Authors Doi: 10.1111/j.1742-7843.2009.00535.x Journal compilation Ó 2010 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology , 106, 505–510