CYP3A5 Genotype and Time to Reach Tacrolimus

CYP3A5 Genotype and Time to Reach Tacrolimus Therapeutic Levels in Renal Transplant Children A.C. Alvarez-Elíasa, P. García-Rocaa, L. Velásquez-Jonesb, S. Valverdeb, G. Varela-Fascinettoc, and M. Medeirosa,d,* a

Laboratorio de Nefrología y Metabolismo Mineral Óseo, Hospital Infantil de México Federico Gómez, México D.F., México; Departamento de Nefrología, Hospital Infantil de México Federico Gómez, México D.F., México; cDepartamento de Cirugía de Trasplante, Hospital Infantil de México Federico Gómez, México D.F., México; and dDepartamento de Farmacología, Facultad de Medicina, Universidad NacionalAutónoma de México, México D.F., México b

ABSTRACT Background. CYP3A5 gene polymorphism rs776746 has been associated with lower tacrolimus dose requirements and bioavailability in both adults and children. This variant causes a loss of CYP3A5 activity owing to a splice site variant leading to a truncated inactive enzyme. The aim of this study was to determine if the rs776746 gene polymorphism is related to the time to reach tacrolimus therapeutic levels in renal transplant children. Methods. A prospective study was performed in renal transplant children receiving tacrolimus as part of their immunosuppressive regime. CYP3A5 genotype was determined by direct sequencing. Tacrolimus trough levels and serum creatinine at 1 week and 1 month after renal transplantation was obtained from clinical chart. Results. A total of 42 patients were included; 19 (45.2%) were female, 23 (54.8%) received living-donor transplants, and 21 patients expressed CYP3A5*1/*1 or CYP3A5*1/*3. Tacrolimus dose was higher in expressers at week 1 (0.13 vs 0.10 mg/kg/d; P ¼ .011), and week 4 after transplantation (0.17 vs 0.09 mg/kg/d; P < .0001). At 4 weeks after renal transplantation, only 9 patients from the expressers group (42.8%) had levels 7 ng/mL, in contrast to 18 in the nonexpressers group (85.7%; Fisher exact P ¼ .008). Conclusions. Tacrolimus dose was significant higher in functional CYP3A5 expressers. Only 42.8% of such expressers had tacrolimus trough levels 7 ng/mL at 1 month after transplantation despite dose adjustments. Long-term follow up is needed to address the consequences of early post-transplantation bioavailability differences due to CYP3A5 genotype.

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ENAL transplantation is the best therapeutic option for children with end-stage renal disease. Transplant recipients receive long-term immunosuppression to prevent graft rejection [1]. Tacrolimus is a widely used calcineurin inhibitor, it has a therapeutic index where small differences in dose or blood concentration may lead to graft rejection or adverse reactions. Tacrolimus therapeutic drug monitoring is recommended to adjust levels to attain the target level, it is metabolized by cytochrome P450 enzymes, mainly CYP3A4 and CYP3A5, and CYP3A5 gene polymorphism rs776746 (T>C) has been associated with lower tacrolimus dose requirements and bioavailability in both adults and ª 2016 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

Transplantation Proceedings, 48, 631e634 (2016)

children [2,3]. This variant, also known as CYP3A5*3, causes a loss of CYP3A5 activity owing to a splice site variant leading to a truncated inactive enzyme [4]. The aim Funding: Fondos Federales. HIM/2013/030. A.C. Alvarez-Elías is a CONACYT fellow and received support from Programa de Maestria y Doctorado en CienciasMédicas, Facultad de Medicina UNAM. *Address correspondence to Mara Medeiros, MD, PhD, Hospital Infantil de México Federico Gómez, Dr Márquez 162 Col Doctores, México, DF CP 06720, México. E-mail: medeiro.mara@ gmail.com 0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2016.02.024

631

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ALVAREZ-ELÍAS, GARCÍA-ROCA, VELÁSQUEZ-JONES ET AL Table 1. Patient Demographics

Sex, n (%) Male Female Age, y, median (IQR) Graft source (n%) Living donor Deceased donor CMV risk, n (%) High Medium Low Cause of renal disease, n (%) Unknown CAKUT Glomerulonephritis Interstitial nephritis

All (n ¼ 42)

CYP3A5 Expressers (n ¼ 21)

CYP3A5 Nonexpressers (n ¼ 21)

23 (54.8%) 19 (45.2%) 15 (12.7e17)

12 (57.1%) 9 (42.9%) 15 (12e17)

11 (52.4%) 10 (47.6%) 14.5 (13.5e16.5)

23 (54.8%) 19 (45.2%)

13 (61.9%) 8 (38.1%)

10 (47.6%) 11 (52.4%)

13 (30.9%) 28 (66.7%) 1 (2.4%)

5 (23.8%) 16 (76.2%) d

8 (38.1%) 12 (57.1%) 1 (4.8%)

22 11 8 1

10 (47.6%) 7 (33.4%) 4 (19%) d

12 4 4 1

P Value*

1.0

.71 .53

.32

.57 (52.4%) (26.2%) (19%) (2.4%)

(57.1%) (19%) (19%) (4.8%)

Abbreviations: IQR, interquartile range; CMV, cytomegalovirus, CAKUT, congenital anomalies of kidney and urinary tract. *Fisher exact test or chi-square as appropriate.

of the present study was to determine if the rs776746 gene polymorphism is related to the time to reach tacrolimus therapeutic levels in renal transplant children.

Patients with the homozygous CYP3A5*1/*1 or heterozygous CYP3A5*1/*3 genotype were considered to be expressers of the functional CYP3A5 protein, whereas children exhibiting the homozygous CYP3A5*3/*3 genotype were considered to be nonexpressers.

PATIENTS AND METHODS Pediatric patients in the renal transplant waiting list at the Hospital Infantil de México Federico Gómez were invited to participate, and a blood sample for CYP3A5 genotyping was obtained. The study was conducted according to the principles of the revised World Medical Association’s Declaration of Helsinki 2008 and was approved by the Institutional Internal Review Board and Ethics Committee. Parental written informed consent and assent of the patient were obtained in every case. Patients aged