CYP3A5 Genotype and Time to Reach Tacrolimus Therapeutic Levels in Renal Transplant Children.
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 = .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 = .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.
Laboratorio de Nefrología y Metabolismo Mineral Óseo, Hospital Infantil de México Federico Gómez, México D.F., México.
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Alvarez-Elías
Laboratorio de Nefrología y Metabolismo Mineral Óseo, Hospital Infantil de México Federico Gómez, México D.F., México.
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García-Roca
Departamento de Nefrología, Hospital Infantil de México Federico Gómez, México D.F., México.
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Velásquez-Jones
Departamento de Nefrología, Hospital Infantil de México Federico Gómez, México D.F., México.
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Valverde
Departamento de Cirugía de Trasplante, Hospital Infantil de México Federico Gómez, México D.F., México.
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Varela-Fascinetto
Laboratorio de Nefrología y Metabolismo Mineral Óseo, Hospital Infantil de México Federico Gómez, México D.F., México; Departamento de Farmacología, Facultad de Medicina, Universidad NacionalAutónoma de México, México D.F., México. Electronic address: medeiro.mara@gmail.com.
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Medeiros
D000293:Adolescent; D017398:Alternative Splicing / Q000235:genetics; D001682:Biological Availability; D002648:Child; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000097:blood / Q000235:genetics*; D006085:Graft Survival / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D011446:Prospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014019:Tissue Donors
D007166:Immunosuppressive Agents; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus