Intraindividual variability in tacrolimus pharmacokinetics and its relationship with CYP3A5*3 polymorphism in renal transplant recipients: looking for new monitoring intervals

Abstract

Background Tacrolimus, the basic component of immunosuppressive therapy to prevent allograft rejection after kidney transplantation, is characterised by great inter/intraindividual variability in its pharmacokinetics, partly explained by polymorphisms in metabolising enzymes. Purpose To determine the relationship between CYP3A5*3 polymorphism and intraindividual variability in tacrolimus pharmacokinetics to assess monitoring trends. Materials and methods Retrospective study in renal transplant recipients treated with tacrolimus, mycophenolate and methylprednisolone (May/2003-May/2011). Daily dose (DD), blood concentration (Cb, IMx and Architect immunoassay methods), monitoring date and CYP3A5*3 polymorphism (Real-Time PCR method) were recorded. To assess intraindividual variability, coefficient of variation of Cb/DD ratio (CVCp/DD) and % variation per day between consecutive Cb/DD (VCp/DD) were calculated. Stability was defined as the period in which the same DD was maintained for at least 3 months with Cb on target (5-10 ng/mL) and a VCp/DD<1%/day. Three post-transplant periods were studied (immediate (day 0-42), prestability and stability). Mean differences between groups were analysed by SPSS 18.0 (statistical significance if pt-Student<0.05). Results 38 patients were included, 95% (31 homozygous (HM), 5 heterozygous (HT)) achieved stability at follow-up (839±141 days). Times to stability were 40% higher in homozygous (HM: 367±65 vs HT: 258±117 days; p=0.067) and their variability was 25% greater in prestability time (CVCp/DD (%): HM: 33.40±4.88 vs HT: 26.73±3.47; p<0.05). No differences were observed in CVCp/DD in the immediate post-transplant period (HM: 30.28±3.51 vs HT: 32.52±8.92) or stability (HM: 19.88±3.42 vs HT: 19.28±10.3) or VCp/DD in any period (global values (%/day): 19.28±10.3, 1.04±0.16, 0.36±0.09). Once stability was achieved, time with the same DD and Cb on target was similar in both groups (HM: 160±33 vs HT: 136±83 days) and 200-300% higher than between consecutive determinations (57±6 vs 64±17 days). Conclusions CYP3A5*3 polymorphism increases, but does not fully explain, intraindividual variability in tacrolimus pharmacokinetics. Our data suggest that monitoring of patients can be extended to every 4-5 months from the 8th month (heterozygous) or the year post-transplant (homozygous) without compromising safety.