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

Abstract

Background: 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 CYP3A5, MRP2 and UGT1A9 genes in Chilean pediatric kidney recipients using TAC and MPA.Patients and Methods: 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 CYP3A5 polymorphism (ancestral allele *1; variant allele *3) was determined in the entire cohort, while MRP2 -24G > A, UGT1A9 -275T > A, and UGT1A9 -2152C > T polymorphisms were determined in 53 patients. Genotypes were associated with trough drug concentrations (C0), dose requirements normalized by weight (TAC-D mg/kg) or body surface (MPA-D mg/m2), trough levels normalized by dose requirements (C0/D), and area under the curve in 12 h normalized by dose requirements (AUC0–12h/D).Results: The frequencies of the variant alleles CYP3A5*3, MRP2-24A, UGT1A9-275A, and UGT1A9-2152T were 76.9, 22.1, 6.6, and 2.9%, respectively. AUC0–12h/TAC-D were 1.6-fold higher in CYP3A5*3/*3 patients than in CYP3A5*1 carriers (CYP3A5*1/*3 and CYP3A5*1/*1). When analyzing patients with steroid withdrawal, CYP3A5*3/*3 patients had 1.7-fold higher AUC0–12h/TAC-D than the other genotypes. Patients carrying the CYP3A5*3/*3 genotype had higher TAC-C0, lower TAC-D and higher TAC-C0/D, consistently in a 6-months follow-up. Creatinine clearance was stable during the follow-up, regardless of the genotype. No significant differences between MRP2 and UGT1A9 genotypes were observed in MPA-C0, MPA-D or MPA-C0/D. However, patients carrying the UGT1A9-275A allele had lower AUC0–12h/MPA-D than those carrying the UGT1A9-275T ancestral allele.Conclusions: These results support that CYP3A5 and UGT1A9 genotyping in pediatric recipients might be useful and advisable to guide TAC and MPA dosing and monitoring in children that undergo kidney transplantation.

Use of Pharmacogenetics to Optimize Immunosuppressant Therapy in Kidney-Transplanted Patients

“…Moreover, a Chilean study showed that carriers of the UGT1A9-275A allele had lower AUC 0 –12h/MPA-D when compared with UGT1A9-275T carriers. Instead, MRP2 and UGT1A9 genotypes did not show significant differences in MPA C 0 , MPA-D, or MPA C 0 /D in 104 pediatric renal transplant recipients [ 76 ]. These results were confirmed by Mazidi et al [ 77 ] ( Table 1 ).…”

Estudio farmacocinético del ácido micofenólico en el trasplante renal pediátrico: experiencia en el Hospital Dr. Luis Calvo Mackenna

“…Se ha propuesto que la combinación de los polimorfismos en las isoformas UGT1A9, UGT2B7 y MRP2 (ABCC2) pueden ser importantes predictores de variabilidad interindividual del MPA en población pediátrica 22,23 . Resultados en pacientes pediátricos atendidos en nuestro centro, han mostrado que los portadores del alelo variante UGT1A9-275A tenían un ABC 0-12h /dosis MPA más bajo que los pacientes portadores solo del genotipo del alelo ancestral UGT1A9-275T con una diferencia de significación estadística marginal (p = 0,05) 24 . Estos resultados sugieren que los pacientes portadores de aquel polimorfismo, podrían registrar niveles de C0 y ABC de MPA más bajos que los esperados y por consiguiente requerir mayor dosificación a la estandarizadas por superficie corporal.…”

Recent Advances in Therapeutic Drug Monitoring of Voriconazole, Mycophenolic Acid, and Vancomycin: A Literature Review of Pediatric Studies

“…MPA TDM is recommended in pediatric patients, but it is still not a routine practice although numerous studies proved the advantage of dose adjustment based on TDM [66][67][68][69][70][71][72][73]. Our review includes studies on the MPA TDM in children after renal transplantation [67,[74][75][76][77][78][79][80][81], other organ transplantation such as heart [82,83], liver [72], or intestine [65], children after hematopoietic stem cell transplantation [84][85][86][87][88][89] or cord blood transplantation [90], and children with lupus [71,73,[91][92][93][94][95][96], nephrotic syndrome [69,70,[97][98][99][100][101][102][103][104][105]…”

“…There has been a discussion on the pharmacogenetic approach to MPA TDM. A recent study conducted by Krall et al [74] showed that CYP3A5 and UGT1A9 genotyping in pediatric recipients might be useful and advisable to guide the dosing and monitoring of MPA and Tac in children that undergo kidney transplantation. Although no significant differences between MRP2 and UGT1A9 genotypes were observed regarding most MPA pharmacokinetic parameters (C 0 , dose, dose-normalized C 0 ), patients carrying the UGT1A9-275A allele had lower dose-normalized AUC 0-12 than those carrying the UGT1A9-275T ancestral allele.…”

“…Rother et al [117] raised the question whether dosing of MMF every 8 h might be more effective than the common twice a day regimen as they showed that IMPDH activity returned to baseline within 4-8 h of administration of MMF in children after renal transplantation. Krall et al [74] recently published a study in which children after renal transplantation were treated with Tac and MMF at starting doses of 0.15 mg/kg twice per day and 800 mg/m 2 twice per day, respectively. In a study conducted by Berger et al [75], the initial dose of MMF was 400-600 mg/m 2 orally every 12 h (up to a maximum of 2 g per day).…”