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2016 - IPTA Fellows Meeting


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Mini Oral Abstract Presentations

18.66 - Time to reach trough levels of tacrolimus with dosing based on CYP3A5 polymorphisms:
Interim results from a clinical trial in pediatric kidney transplantation

Presenter: Ana Catalina, Alvarez-Elías, Mexico City, Mexico
Authors: Ana Alvarez-Elías, Pilar García-RocaPhD, Luis Velasquez-JonesMD, Saúl Valverde-RosasMD, Gustavo Varela-FascinettoSD, Peter KotankoMD, Mara MedeirosPhD

Time to reach trough levels of tacrolimus with dosing based on CY3A5 polymorphisms: Interim results from a clinical trial in pediatric kidney transplantation

Ana Alvarez-Elías1, Pilar García-Roca PhD2, Luis Velasquez-Jones MD3, Saúl Valverde-Rosas MD4, Gustavo Varela-Fascinetto SD5, Peter Kotanko MD6, Mara Medeiros PhD7.

1Laboratory of Pediatric Nephrology. Bone and Mineral Metabolism, Hospital Infantil de México. Federico Gómez, Mexico, , Mexico; 2Laboratory of Pediatric Nephrology. Bone and Mineral Metabolism, Hospital Infantil de México. Federico Gómez, Mexico, , Mexico; 3Pediatric Nephrology Clinical Department, Hospital Infantil de México. Federico Gómez, Mexico, , Mexico; 4Pediatric Nephrology Clinical Department, Hospital Infantil de México. Federico Gómez, Mexico, , Mexico; 5Transplantation Surgical Deparment , Hospital Infantil de México. Federico Gómez, Mexico, , Mexico; 6Research, Renal Research Institute, New York, NY, United States; 7Laboratory of Pediatric Nephrology. Bone and Mineral Metabolism, Hospital Infantil de México. Federico Gómez, Mexico, , Mexico

Protocol: HIM/2013/030 Introduction: Tacrolimus bioavailability depends on the expression of CYP3A5 isoenzymes; function and activity of these proteins vary markedly between individuals and have been linked to the presence of genetic polymorphisms. CYP3A5 gene polymorphism rs776746, also known as CYP3A5*3 has been associated with lower tacrolimus dose requirements and bioavailability in both adults and children The aim of the study was to identify whether providing a dose of tacrolimus according to CYP3A5 genotype improves the time to reach target tacrolimus trough levels in pediatric kidney transplant recipients. Methods: A a single-blinded randomized clinical trial was performed in a cohort of pediatric renal transplant recipients. CYP3A5 genotype was determined by direct sequencing before transplantation. We included all patients who received tacrolimus. The initial doses of tacrolimus were asigned as follows: Conventional Group: maximum dose of 0.10 mg/kg/day, regardless of genotype. Genotype-guided Dose Group: (dosing according to allelic variant), CYP3A5 *1*1, at least 0.20 mg/kg/day. CYP3A5*1*3: at least 0.15 mg/kg/day, CYP3A5*3*3, at least 0.10 mg/kg/day; the subsequent doses were adjusted to achieve target trough levels of at least 8 ng/mL. Results: 74 patients were enrolled and followed up for one month. Mean age was 13.6 3.2 years, 38 were males. Genotype distribution in the Conventional Group (n = 44) was as follows: CYP3A5*1*1 4.5%, CYP3A5*1*3 29.5% CYP3A5*3*3 66.0%. In the Genotype-guided Dose Group (n = 30) CYP3A5*1*1, 13.3%, CYP3A5*1*3 56.6%, CYP3A5*3*3 30.0%. The tacrolimus trough levels reached between expressers, were higher in the Genotype-guided Dose group until the fourth week of follow up (Conventional Group: CYP3A5*1*1: 5.35 2.19, CYP3A5*1*3: 8.30 3.37; Genotype-guided Dose Group: CYP3A5*1*1: 8.67 2.06, CYP3A5*1*3: 10.02 5.44 [p=0.046]). The median time to reach target trough levels of tacrolimus (Kaplan-Meier ITT analysis) were: Conventional Group: CYP3A5*1*1: 4 weeks, CYP3A5 *1*3: 2 weeks, CYP3A5*3*3: 1 week; Genotype-guided Dose Group: CYP3A5*1*1: 2 weeks, CYP3A5*1*3: 2 weeks, CYP3A5*3*3: 1 week, without showing differences between groups (p = 0.123). Discussion and Conclusions: The frequency of polymorphisms corroborates previous data in Mexican population distribution. Subjects expressing the enzyme achiveve higher tacrolimus levels if the initial dose is guided by genotype. It is premature to determine the effectiveness of the genotype-guided dosing strategy since the calculated sample size is 110 patients Long term follow up of this cohort will further elucidate the utility of this dosing strategy and the impact of these polymorphisms long-term graft survival.

1Universidad Nacional Autónoma de México. Postgraduate Unit..

References:

[1] Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology--drug disposition, action, and therapy in infants and children. N Engl J Med 2003;349:1157-67.
[2] Medeiros-Domingo M, Romero-Navarro B, Valverde-Rosas S, Delgadillo R, Varela-Fascinetto G, Munoz-Arizpe R. [Renal transplantation in children]. Rev Invest Clin 2005;57:230-6.
[3] Wallemacq PE, Verbeeck RK. Comparative clinical pharmacokinetics of tacrolimus in paediatric and adult patients. Clin Pharmacokinet 2001;40:283-95.
[4] Niioka T, Kagaya H, Saito M, Inoue T, Numakura K, Habuchi T, Satoh S, Miura M. Capability of utilizing CYP3A5 polymorphisms to predict therapeutic dosage of tacrolimus at early stage post-renal transplantation. Int J Mol Sci. 2015 Jan 14;16(1):1840-54. doi: 10.3390/ijms16011840. PMID: 25594874
[5] Shilbayeh S, Zmeili R, Almardini RI. The impact of CYP3A5 and MDR1 polymorphisms on tacrolimus dosage requirements and trough concentrations in pediatric renal transplant recipients. Saudi J Kidney Dis Transpl. 2013 Nov;24(6):1125-36. doi: 10.4103/1319-2442.121268. PMID: 24231473
[6] Tsuchiya N, Satoh S, Tada H, Li Z, Ohyama C, Sato K, Suzuki T, Habuchi T, Kato T. Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantation 2004; 78: 1182-1187 [PMID: 15502717]


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