Toward Personalized Medicine in Renal Transplantation I. Lampreabe, F.J. Gainza de los Rios, A. Arrieta Gutiérrez, L. Jofre-Monseny, M. Rodriguez, J.J. Amenabar Iribar, S. Zárraga Larrondo, D. Tejedor, A. Martinez, and E. Olano-Martin ABSTRACT Background. The pharmacokinetics of tacrolimus (TRL) are clearly affected by genetic polymorphisms in drug-metabolizing enzymes, which lead to large interindividual differ- ences in dose–response relations. In addition, TRL has a narrow therapeutic index requiring monitoring of blood levels. The objective of the present observational, retro- spective study was to associate maintenance TRL doses with various genetic markers seeking to guide optimization of the initial dose. Methods. Results of DNA samples from 15 kidney transplant patients were correlated retrospectively with clinical information from medical records. Samples were genotyped using PHARMAchip. Association studies were performed with  2 and Pearson tests and by analysis of variance. The study was carried out in accordance with international ethical standards of the Helsinki Declaration and approved by our ethics committee. Results. Two patient groups were identified to show a difference in TRL dose require- ments: a control (0.014 – 0.10 mg/kg/per day) and an high-dose group (0.14 – 0.15 mg/kg/per day). The presence of CYP3A5*1 and the null allele in GSTM1 were significantly associated (P = .01 and P = .04) with the need for higher immunosuppressive doses (0.10 mg/kg/per day). There were no differences in plasma levels of TRL or other clinical variables between the patient groups. Conclusion. Determination of the CYP3A5 genotype might be used to predict initial TRL requirements, although other genetic variants also provide important information to adjust the drug dose. A BOUT 120 –130 kidney transplants are performed an- nually in the Basque Country (Spain). 1 These are patients require chronic immunosuppressive medication, adjusted to dose optimization to avoid adverse effects. Immunosuppressive therapy with tacrolimus (TRL) is an effective alternative to cyclosporine, but it is difficult to adjust the dose because it shows a narrow therapeutic index. The rate of adverse effects and their severity are associated with overall drug exposure, defined in terms of concentra- tions and treatment duration. The incidence of acute rejec- tion episodes increases with blood concentrations 10 g/L at 12 hours post-dose with greater toxicity at levels 20 g/L. 2 In addition, there is a significant interindividual variation in the drug dose required to achieve therapeutic concentrations. 3,4 Therefore, monitoring of TRL blood levels is used to adjust individual doses. The patient’s drug requirements are influenced by differ- ences in absorption, distribution, and metabolism. Pharmaco- kinetics are clearly mediated by phase I, phase II, and trans- porter enzymes. The bioavailability and metabolism of TRL are primarily controlled by the protein ATP-binding cassette trans- porter B1 (ABCB1 also known as MDR1) and isoenzymes of the cytochrome P450 family (mainly CYP3A4 and CYP3A5). 5 Various studies have shown that carriers of the allelic variant CYP3A5*1 show a 25%– 45% higher clearance than From the Nephrology Department (I.L., F.J.G.d.l.R., J.J.A.I., S.Z.L.), Hospital Cruces; the Immunology Department (A.A.G.), Hospital Cruces, Bilbao; the Progenika Biopharma S.A. (L.J.M., D.T., A.M., E.O.M.), Derio; and the Nursing Division (M.R.), Hospital Cruces, Bilbao, Spain. Supported by a national research grant from MEC - Ministerio de Educaion y Ciencia withing the OSAGEN project (PSE- 010000-2006-1). Address reprint requests to I. Lampreabe, Nephrology Depart- ment, Hospital cruces, Bilbao, Spain. E-mail: ildefonso. lampreabegaztelu@osakidetza.net 0041-1345/10/$–see front matter © 2010 Published by Elsevier Inc. doi:10.1016/j.transproceed.2010.08.009 360 Park Avenue South, New York, NY 10010-1710 2864 Transplantation Proceedings, 42, 2864 –2867 (2010)