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Pharmacotherapy: Pharmacokinetics and Pharmacodynamics (including: ADE, TDM, DUE)
Intraindividual variability in tacrolimus pharmacokinetics and its relationship with CYP3A5*3 polymorphism in renal transplant recipients: looking for new monitoring intervals
  1. M. Hernández Griso,
  2. J.E. Martínez de La Plata,
  3. M.A. López-Montenegro Soria,
  4. N.V. Jiménez Torres
  1. 1Hospital Universitario Dr. Peset, Pharmacy, Valencia, Spain
  2. 2Hospital de Poniente, Pharmacy, Almería, Spain

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.

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