AUTHOR=Krall Paola , Yañez Dominique , Rojo Angélica , Delucchi Ángela , Córdova Miguel , Morales Jorge , Boza Pía , de la Rivera Alonso , Espinoza Natalie , Armijo Natalia , Castañeda Luis E. , Farfán Mauricio J. , Salas Carolina 

TITLE=CYP3A5 and UGT1A9 Polymorphisms Influence Immunosuppressive Therapy in Pediatric Kidney Transplant Recipients

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.653525

DOI=10.3389/fphar.2021.653525

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> Tacrolimus (TAC) and mycophenolic acid (MPA) are the main immunosuppressive drugs used in pediatric kidney transplantation. Single nucleotide polymorphisms (SNPs) in metabolizing enzymes and transporters might influence plasma levels of these drugs. Herein, we sought to determine the influence of SNPs on <italic>CYP3A5</italic>, <italic>MRP2</italic> and <italic>UGT1A9</italic> genes in Chilean pediatric kidney recipients using TAC and MPA.</p><p><bold>Patients and Methods:</bold> A prospective study was performed on 104 pediatric kidney recipients that used TAC and MPA for immunosuppression. The median age at the time of transplantation was 8.1 years [Q1–Q3 4.5–11.6 years] and the main clinical diagnosis was a structural anomaly. In a subgroup of patients, a complete steroid withdrawal was made at day 7. The <italic>CYP3A5</italic> polymorphism (ancestral allele *1; variant allele *3) was determined in the entire cohort, while <italic>MRP2</italic> -24G &gt; A, <italic>UGT1A9</italic> -275T &gt; A, and <italic>UGT1A9</italic> -2152C &gt; T polymorphisms were determined in 53 patients. Genotypes were associated with trough drug concentrations (C<sub>0</sub>), dose requirements normalized by weight (TAC-D mg/kg) or body surface (MPA-D mg/m2), trough levels normalized by dose requirements (C<sub>0</sub>/D), and area under the curve in 12 h normalized by dose requirements (AUC<sub>0–12h</sub>/D).</p><p><bold>Results:</bold> The frequencies of the variant alleles <italic>CYP3A5*3</italic>, <italic>MRP2-24A</italic>, <italic>UGT1A9-275A</italic>, and <italic>UGT1A9-2152T</italic> were 76.9, 22.1, 6.6, and 2.9%, respectively. AUC<sub>0–12h</sub>/TAC-D were 1.6-fold higher in <italic>CYP3A5*3/*3</italic> patients than in <italic>CYP3A5*1</italic> carriers (<italic>CYP3A5*1/*3</italic> and <italic>CYP3A5*1/*1</italic>). When analyzing patients with steroid withdrawal, <italic>CYP3A5*3/*3</italic> patients had 1.7-fold higher AUC<sub>0–12h</sub>/TAC-D than the other genotypes. Patients carrying the <italic>CYP3A5*3/*3</italic> genotype had higher TAC-C<sub>0</sub>, lower TAC-D and higher TAC-C<sub>0</sub>/D, consistently in a 6-months follow-up. Creatinine clearance was stable during the follow-up, regardless of the genotype. No significant differences between <italic>MRP2</italic> and <italic>UGT1A9</italic> genotypes were observed in MPA-C<sub>0</sub>, MPA-D or MPA-C<sub>0</sub>/D. However, patients carrying the <italic>UGT1A9-275A</italic> allele had lower AUC<sub>0–12h</sub>/MPA-D than those carrying the <italic>UGT1A9-275T</italic> ancestral allele.</p><p><bold>Conclusions:</bold> These results support that <italic>CYP3A5</italic> and <italic>UGT1A9</italic> genotyping in pediatric recipients might be useful and advisable to guide TAC and MPA dosing and monitoring in children that undergo kidney transplantation.</p>