Wiener klinische Wochenschrift

, Volume 125, Issue 13, pp 393–395

The role of CYP2C8 genotypes in dose requirement and levels of everolimus after heart transplantation

Authors

    • Department of Surgery, Division of TransplantationMedical University Graz
  • Doris Wagner
    • Department of Surgery, Division of TransplantationMedical University Graz
  • Andrä Wasler
    • Department of Surgery, Division of TransplantationMedical University Graz
  • Karl-Heinz Tscheliessnigg
    • Department of Surgery, Division of TransplantationMedical University Graz
  • Wilfried Renner
    • Clinical Institute of Medical and Chemical Laboratory Diagnostics
original article

DOI: 10.1007/s00508-013-0387-2

Cite this article as:
Kniepeiss, D., Wagner, D., Wasler, A. et al. Wien Klin Wochenschr (2013) 125: 393. doi:10.1007/s00508-013-0387-2

Summary

Everolimus is an immunosuppressive drug metabolized by enzymes of the CYP family. A common variant of the CYP2C8 gene, CYP2C8*3, results in strongly decreased CYP2C8 activity, but its role for the pharmacogenetics of everolimus remains unclear. Aim of the present study was to examine the role of CYP2C8 variants in everolimus dose and drug levels after heart transplantation.

The present study comprised 30 patients with everolimus based maintenance therapy after heart transplantation. CYP2C8 genotypes were determined and correlated with clinical data.

In all, 21 subjects carried the CYP2C8 *1/*1 genotype and 9 subjects carried the CYP2C8 *1/*3 genotype. Neither everolimus dose nor everolimus levels were associated with CYP2C8 genotype at any point of time (p < 0.05). During follow-up, graft rejection reactions were observed in two patients and infections were observed in seven patients. In one patient, type 2 diabetes was diagnosed during follow-up. None of these adverse events were significantly associated with CYP2C8 genotypes.

We conclude that in adult patients after heart transplantation, CYP2C8 genotypes are not associated with dose requirements or levels of everolimus.

Keywords

Heart transplantationImmunosuppressionGenotypes

Einfluss von CYP2C8 Genotypen auf Dosis und Spiegel von Everolimus nach Herztransplantation

Zusammenfassung

Everolimus ist ein Immunsuppressivum, welches durch Enzyme der Cytochrom P450 Familie metabolisiert wird. Eine Variante des CYP2C8 Gens, das CYP2C8*3, hat eine deutlich verminderte Aktivität. Der Einfluss der verschiedenen CYP2C8 Varianten auf die Pharmakokinetik von Everolimus ist derzeit noch unklar. Ziel dieser Studie war es, den Einfluss der CYP2C8 Varianten auf Dosis und Spiegel von Everolimus bei Patienten nach Herztransplantation zu überprüfen.

Dreißig Patienten mit Everolimus als Erhaltungstherapie nach Herztransplantation wurden in die Studie eingeschlossen. Die CYP2C8 Genotypen wurden bestimmt und mit den klinischen Daten korreliert.

Bei 21 Patienten wurde der CYP2C8 *1/*1 Genotyp nachgewiesen, bei 9 Patienten der CYP2C8 *1/*3 Genotyp. Weder die Everolimus Dosis noch der Everolimus Spiegel korrelierten mit dem CYP2C8 Genotyp (< 0,05). Während des Follow-ups traten bei 2 Patienten Abstoßungen auf und bei 7 Patienten Infektionen. Bei einem Patienten wurde ein Typ 2 Diabetes diagnostiziert. Keine dieser Komplikationen war mit den CYP2C8 Genotypen assoziiert.

Zusammenfassend kann man sagen, dass bei Patienten nach Herztransplantation der CYP2C8 Genotyp weder mit der Dosis noch mit dem Spiegel von Everolimus korreliert.

Schlüsselwörter

HerztransplantationImmunsuppressionGenotypen

Introduction

Everolimus is worldwide used as immunosuppressive agent in heart transplant recipients to prevent allograft rejection [1]. However, everolimus has a narrow therapeutic range and shows highly inter-individual differences in metabolism [2]. Overdosing may lead to toxic side-effects, such as infection, malignant diseases, or renal dysfunction. Drug levels below the therapeutic range result in suboptimal immunosuppression and increased risk of acute rejection. Intensive drug monitoring is necessary to achieve drug levels within therapeutic range. Therapeutic drug monitoring may maximize the benefit of everolimus by optimizing immunosuppressive efficacy and reducing side-effects [3].

Everolimus is metabolized by cytochromes P450 2C8 (CYP2C8), 3A4 (CYP3A4) and 3A5 (CYP3A5) [2]. Sequences and metabolic activities of these enzymes are similar, but the expression of CYP2C8 is polymorphic [4].

The role of CYP2C8 genotypes in metabolism and dose requirements of everolimus in heart transplant recipients is currently unknown. The objective of our study was to examine and compare the association between CYP2C8 genotypes and dose and drug levels of everolimus in adult heart transplant recipients.

Material and methods

Heart transplant recipients transplanted at the Medical University Graz were invited to participate in the study.

Immunosuppression

During the first week after heart transplantation, all patients received an induction therapy with antilymphocyte globulin. Calcineurin inhibitors and Mycophenolate Mofetil (MMF) were initiated on days 2–4. As maintenance therapy, all patients received triple drug immunosuppression consisting of a calcineurininhibitor, MMF, and prednisolone. Beginning with the year 2004, about 30 patients received everolimus in combination with Cyclosporine and Prednisolon. The switch to everolimus was performed in patients with impaired renal function. Everolimus was administered for blood levels between 5 and 8 ng/ml. Cyclosporine levels in combination with everolimus were between 70 and 90 ng/ml.

Data collection

Clinical and laboratory data at various time points (1 month, 3 months, 1 year and 3 years after start of medication with everolimus) were evaluated retrospectively. Clinical data included body weight, body mass index, blood pressure, history of smoking, assessment of general condition of the patient (completed questionnaire from each patient), and evaluation of co-morbidities (e.g. diabetes mellitus, hypertension, renal dysfunction, need for dialysis). Furthermore, doses of immunosuppression were noted and a screening of all concomitant medications with possible CYP2C8 interaction was performed. Clinical adverse events, including drug related side effects, rejection, infection, and laboratory abnormalities were collected at each time point.

Results

The present study comprised a total of 30 patients with everolimus based maintenance therapy after heart transplantation (Table 1). CYP2C8 genotypes were successfully determined in all subjects and did not deviate from the Hardy-Weinberg equilibrium. In all, 21 subjects carried the CYP2C8 *1/*1 genotype and 9 subjects carried the CYP2C8 *1/*3 genotype (Table 1). Neither everolimus dose nor everolimus levels were associated with CYP2C8 genotype at any point of time (p < 0.05).
Table 1.

Characteristics of patients at the time of heart transplantation

 

CYP2C8 genotype

*1/*1

*1/*3

Number of patients

21

9

Male/female

16/5

9/0

Age at transplantation, years

47 ± 16

52 ± 8

Dose, 1 month (n)

1.4 ± 0.7 (21)

1.6 ± 1.0 (9)

Dose, 2 months (n)

1.4 ± 0.6 (21)

2.0 ± 1.6 (9)

Dose, 12 months (n)

1.3 ± 0.5 (20)

1.5 ± 1.1 (9)

Dose, 36 months (n)

1.5 ± 0.6 (9)

1.5 ± 0.5 (3)

Level, 1 month (n)

6.8 ± 2.9 (21)

6.9 ± 2.8 (9)

Level, 2 month (n)

6.5 ± 2.3 (21)

5.9 ± 3.0 (9)

Level, 12 months (n)

6.0 ± 1.8 (20)

5.7 ± 1.7 (9)

Level, 36 months (n)

5.2 ± 1.5 (9)

5.6 ± 1.2 (3)

Infections during follow-up

n = 5

n = 2

Graft rejection reactions

n = 2

New diabetes diagnosed during follow-up

n = 1

Dose (mg/day) and levels (ng/ml) of everolimus are given at different points of time after medication start. Values are mean standard deviation, numbers in brackets indicate patients for whom follow-up data were available.

During follow-up, graft rejection reactions were observed in four patients (two patients with grade 2 rejection and two patients with grade 3 rejection) and infections were observed in a total of eight patients. In two patients, type 2 diabetes was diagnosed during follow-up. None of these adverse events were significantly associated with CYP2C8 genotypes (Table 1).

Discussion

The primary aim of immunosuppressive therapy following heart transplantation is to reach and maintain the optimal combination of efficacy and tolerability. Understanding the large inter-individual variability of immunosuppressive drugs is of high importance for optimizing the clinical outcome after transplantation and to minimize adverse events.

In the present study, we analyzed 30 adult heart transplant recipients and evaluated the role of CYP2C8 genetic polymorphisms for maintenance doses of everolimus.

To the best of our knowledge, data on the potential role of CYP2C8 genotypes in the pharmacogenetics of everolimus have not been available yet. The main finding of our study revealed no association between CYP2C8 genotypes and dose requirements or levels of everolimus. Our data indicate that inter-individual differences in everolimus dose requirements are not related to CYP2C8 activity. Polymorphisms in other candidate genes, such as multidrug resistance 1 (MDR1 or ABCB1) or CYP3A4, might contribute to the pharmacokinetics of everolimus.

Furthermore, CYP2C8 genotypes were not related to adverse events. We suppose that therapeutic drug monitoring as performed in the local clinical setting was sufficient to keep dose maintenance levels within the therapeutic range. Nevertheless, the study size was obviously too small to analyze the potential association of CYP2C8 genotypes with adverse events.

We would like to emphasize that the aim of the present retrospective study was to investigate the associations of CYP2C8 genotypes with dose requirement of everolimus in patients after heart transplantation. Comparison of clinical safety and efficacy of everolimus and other immunosuppressive drugs with different CYP genotypes requires adequate prospective randomized double-blind studies. Nevertheless, the knowledge that everolimus dosing is not related to CYP2C8 genotypes should be incorporated in the interpretation of such studies.

Conflict of interest

There is no conflict of interest and no funding sources and relevant disclosures for any of the authors.

Copyright information

© Springer-Verlag Wien 2013