Influence of CYP3A5 polymorphism on tacrolimus maintenance doses and serum levels after renal transplantation: Age dependency and pharmacological interaction with steroids

Abstract

TAC, MMF and MP are used in pediatric kidney tx. The cytochrome P450 (CYP)3A5 enzyme appears to play a role in TAC metabolism. The aims of this study were to investigate CYP3A5 polymorphism's effect on TAC dosing and the age dependency of TAC dosing by testing blood concentrations, and the interaction between steroids and TAC during the first year after tx. Genomic DNA was extracted and amplified with specific primers. CYP3A5 alleles were confirmed by direct sequencing of PCR products on an automated AB13100 capillary sequencer. We studied 48 renal transplant patients (age at tx 12±0.5yr, 22 boys) receiving TAC, MMF, MP. Of these, 79% were CYP3A5*3/*3 (non-expressers homozygotes) and 21% were CYP3A5*1/*3 (expressers). TAC trough levels were 7.1±0.4ng/mL in CYP3A5*3/*3 patients and 6.5±0.7ng/mL in CYP3A5*1/*3 group (p=0.03). CYP3A5*1/*3 patients had lower levels of dose-adjusted TAC (36.7±5.8ng/mL/mg/kg/day) to achieve target blood concentration and required higher daily dose per weight (0.21±0.03mg/kg/day) than CYP3A5*3/*3 patients, 72.4±8.0ng/mL/mg/kg/day and 0.13±0.01mg/kg/day (p<0.001). Prepubertal patients with different CYP3A5 polymorphisms required significant higher TAC doses and achieved lower dose-normalized concentration compared with pubertal patients. Both TAC dose and adjusted-dose correlated with daily MP dose in CYP3A5*1*3 (r: 0.4, p<0.03 and r: 0.4, p<0.03) and in CYP3A5*3*3 (r: 0.6, p<0.01 and r: 0.47, p<0.001) patients. CYP3A5 polymorphism performed before tx could contribute to a better individualization of TAC therapy. The higher TAC dose in prepubertal patients and the pharmacological interactions between MP and TAC may not be fully explained by different CYP3A5 polymorphisms.

The interactions of age, sex, body mass index, genetics, and steroid weight-based doses on tacrolimus dosing requirement after adult kidney transplantation

“…Our data also confirm literature reports on clinical factors associated with slow tacrolimus metabolizers: male sex [40], age [41,42], HCV positivity [43], and higher BMI [44].…”

Tacrolimus Dose Requirement in Pediatric Liver Transplantation: Influence of CYP3A5 Gene Polymorphism

“…Additional factors such as age of the recipient, baseline histological score of the graft and treatment with the CYP3A4 inhibitor, fluconazole, were also found to have an influence. n CYP3A5 polymorphism Whereas CYP3A5 genetic polymorphism has been clearly demonstrated to influence tacrolimus disposition during renal and heart transplantation [6,7,[19][20][21], less information is available regarding pediatric liver transplantation [5,8,22]. Two studies found that donor CYP3A5 genotype influenced tacrolimus dose requirements [5,8].…”

Therapeutic concentration achievement and allograft survival comparing usage of conventional tacrolimus doses and CYP3A5 genotype‐guided doses in renal transplantation patients

“…CYP3A5 diplotypes, i.e., CYP3A5*1/*1 , CYP3A5*1/*3 and CYP3A5*3/*3 determine the phenotype of TAC metabolism as extensive, intermediate and poor metabolizers . Individuals who express the CYP3A5*3/*3 allele, therefore, require lower TAC doses than CYP3A5*1/*1 and CYP3A5*1/*3 alleles to keep the desired TR . A previous study by the current authors demonstrated that the average dose of TAC for the induction phase in those who have CYP3A5*3/*3 , CYP3A5*1/*3 and CYP3A5*1/*1 genotypes were 0.077, 0.097 and 0.142 mg/kg/day .…”