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A New CYP3A5*3 and CYP3A4*22 Cluster Influencing Tacrolimus Target Concentrations: A Population Approach

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Abstract

Background

Single nucleotide polymorphisms (SNPs) in the CYP3A5 and CYP3A4 genes have been reported to be an important cause of variability in the pharmacokinetics of tacrolimus in renal transplant patients. The aim of this study was to merge all of the new genetic information available with tacrolimus pharmacokinetics to generate a more robust population model with data from renal transplant recipients.

Methods

Tacrolimus exposure data from 304 renal transplant recipients were collected throughout the first year after transplantation and were simultaneously analyzed with a population pharmacokinetic approach using NONMEM® version 7.2.

Results

The tacrolimus whole-blood concentration versus time data were best described by a two-open-compartment model with inter-occasion variability assigned to plasma clearance. The following factors led to the final model, which significantly decreased the minimum objective function value (p < 0.001): a new genotype cluster variable combining the CYP3A5*3 and CYP3A4*22 SNPs defined as extensive, intermediate, and poor metabolizers; the standardization of tacrolimus whole blood concentrations to a hematocrit value of 45%; and age included as patients <63 years versus patients ≥63 years. External validation confirmed the prediction ability of the model with median bias and precision values of 1.17 ng/mL (95% confidence interval [CI] –3.68 to 4.50) and 1.64 ng/mL (95% CI 0.11–5.50), respectively. Simulations showed that, for a given age and hematocrit at the same fixed dose, extensive metabolizers required the highest doses followed by intermediate metabolizers and then poor metabolizers.

Conclusions

Tacrolimus disposition in renal transplant recipients was described using a new population pharmacokinetic model that included the CYP3A5*3 and CYP3A4*22 genotype, age, and hematocrit.

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Acknowledgements

We are especially grateful to the transplant assistant, Carmen Fernández-Gámiz, for her support in the collection of clinical variables.

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Authors and Affiliations

  1. Laboratory 4122, Nephrology Service and Laboratory of Experimental Nephrology, University of Barcelona, Campus Bellvitge, Pavelló de Govern, Feixa Llarga, s/n, L’Hospitalet de Llobregat, 08907, Barcelona, Spain

    Franc Andreu, Oriol Bestard, Joan Torras, Josep M. Cruzado, Josep M. Grinyó & Nuria Lloberas

  2. Biopharmaceutics and Pharmacokinetics Unit, Department of Pharmacy and Pharmaceutical Technology Department, School of Pharmacy, University of Barcelona, Barcelona, Spain

    Franc Andreu & Helena Colom

  3. Department of Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics (PMGK), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCL), Brussels, Belgium

    Laure Elens

  4. Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    Teun van Gelder & Dennis A. Hesselink

  5. Department of Hospital Pharmacy, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    Teun van Gelder & Ronald H. N. van Schaik

  6. Department of Clinical Chemistry, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    Laure Elens, Teun van Gelder, Ronald H. N. van Schaik & Dennis A. Hesselink

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  1. Franc Andreu
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  2. Helena Colom
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  3. Laure Elens
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  4. Teun van Gelder
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  5. Ronald H. N. van Schaik
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  6. Dennis A. Hesselink
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  7. Oriol Bestard
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  10. Josep M. Grinyó
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  11. Nuria Lloberas
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Corresponding author

Correspondence to Nuria Lloberas.

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Funding

Nuria Lloberas is a researcher from Instituto de Salud Carlos III Miguel Servet (CP06/00067) and REDinREN RD12/0021/003. This study was supported by Grants from Instituto de Salud Carlos III and Ministerio de Sanidad y Consumo (PI12/01564, PI15/00871), (EC10-144), and Fondo Europeo de Desarrollo Regional (FEDER).

Conflict of Interest

Franc Andreu, Helena Colom, Laure Elens, Teun van Gelder, Ronald H. N. van Schaik, Dennis A. Hesselink, Oriol Bestard, Joan Torras, Josep M. Cruzado, Josep M. Grinyó and Nuria Lloberas declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

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Andreu, F., Colom, H., Elens, L. et al. A New CYP3A5*3 and CYP3A4*22 Cluster Influencing Tacrolimus Target Concentrations: A Population Approach. Clin Pharmacokinet 56, 963–975 (2017). https://doi.org/10.1007/s40262-016-0491-3

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