Toward personalized medicine in renal transplantation.
BACKGROUND
The pharmacokinetics of tacrolimus (TRL) are clearly affected by genetic polymorphisms in drug-metabolizing enzymes, which lead to large interindividual differences in dose-response relations. In addition, TRL has a narrow therapeutic index requiring monitoring of blood levels. The objective of the present observational, retrospective 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 χ2 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 requirements: 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.


CONCLUSIONS
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.
Nephrology Department, Hospital Cruces, Bilbao, Spain. ildefonso.lampreabegaztelu@osakidetza.net
I
I
Lampreabe
F J
FJ
Gainza de los Rios
A
A
Arrieta Gutiérrez
L
L
Jofre-Monseny
M
M
Rodriguez
J J
JJ
Amenabar Iribar
S
S
Zárraga Larrondo
D
D
Tejedor
A
A
Martinez
E
E
Olano-Martin
D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004247:DNA / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005819:Genetic Markers; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D057285:Precision Medicine; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use
D005819:Genetic Markers; D007166:Immunosuppressive Agents; D004247:DNA; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus