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The interactions of age, sex, body mass index, genetics, and steroid weight-based doses on tacrolimus dosing requirement after adult kidney transplantation

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The aim of this study was to evaluate the effect of different clinical covariates on tacrolimus dose requirements in adult kidney transplant patients with a specific focus on drug interactions.

Patients

Tacrolimus dosing requirement, normalized by drug levels and expressed as the concentration/dose (C/D) ratio as a surrogate index of tacrolimus bioavailability, was employed to identify four categories of tacrolimus dosing requirement, namely, very high, high, small, and very-small, in very fast, fast, slow, and very slow metabolizers, respectively. Steroid weight-based doses were analyzed instead of fixed doses, and genetic analysis of cytochrome P450 (CYP) 3A5*1/*3 and multi-drug resistance 1 (MDR1) C3435T and C1236T polymorphisms were performed

Results

Multivariate analysis on 450 adult transplant patients identified six risk factors for being slow metabolizers and therefore requiring small tacrolimus doses: male sex (OR  1.615, p = 0.020); age >60 years (OR 2.456, p = 0.0005); body mass index ≥25 (OR 1.546, p = 0.046), hepatitis C virus positivity (OR 2.800, p = 0.0004); low steroid dose <0.06 mg/kg (OR 3.101, p < 0.0001). Patients with a small tacrolimus requirement were at increased risk for multiple infections (OR  1.533, p = 0.0008) and higher systolic blood pressure (OR  1.385, p = 0.022) and showed a significant association with the CYP3A5*3/*3 genotype adjusted by MDR1 polymorphisms C3435T and C1236T (OR 8.104, p = 0.0001).

Conclusions

Our results demonstrate the importance of the interaction among genetic and clinical factors in conditioning tacrolimus disposition, with corticosteroid weight-based dose being the only modifiable risk factor for tacrolimus requirement. As the tacrolimus dosing requirement increases with increasing tacrolimus clearance through concomitant steroid use, undesirable changes in tacrolimus levels may occur when steroid doses are tapered, predominantly in slow metabolizers. This often neglected drug interaction has to be monitored to optimize tacrolimus exposure in kidney transplant patients.

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Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, Nephrology and Transplantation, and Interdisciplinary Research Center Autoimmune Disease (IRCAD), Amedeo Avogadro University–Maggiore Hospital of Novara, Novara, Italy

    P. Stratta, M. Quaglia, R. Antoniotti, R. Fenoglio & A. Menegotto

  2. Medical Statistics and Cancer Epidemiology Unit, Amedeo Avogadro University–Maggiore Hospital of Novara, Novara, Italy

    T. Cena, D. Ferrante & C. Magnani

  3. Department of Chemical Science, Pharmaceutics and Pharmacology, Amedeo Avogadro University, Maggiore Hospital of Novara, Novara, Italy

    A. Genazzani & S. Terrazzino

  4. Nephrology and Transplantation, Department of Nephro-Urology, and Interdisciplinary Research Center Autoimmune Disease (IRCAD), Amedeo Avogadro University–Ospedale “Maggiore Della Carità”, Corso Mazzini 18, 28100, Novara, Italy

    P. Stratta

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  1. P. Stratta
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Stratta, P., Quaglia, M., Cena, T. et al. The interactions of age, sex, body mass index, genetics, and steroid weight-based doses on tacrolimus dosing requirement after adult kidney transplantation. Eur J Clin Pharmacol 68, 671–680 (2012). https://doi.org/10.1007/s00228-011-1150-0

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