Effect of CYP3A5 Genetic Polymorphisms on the Blood Drug Concentration of Tacrolimus in Patients With Lupus Nephritis and the Relationship With Patient Prognosis
Abstract
To evaluate the effect of cytochrome P450 3A5 (CYP3A5) genetic polymorphism on the blood drug concentration of tacrolimus (TAC) in patients with lupus nephritis (LN), to determine the appropriate initial dose for LN patients of different genotypes and the differences in time to remission, and to analyze factors associated with LN prognosis.
Methods
Patients with active LN attending the outpatient clinic of the Department of Rheumatology and Immunology, West China Hospital, Sichuan University were enrolled. Their CYP3A5 genotypes were determined. According to the different genotypes, the patients were assigned to two groups, the AA + GA group, or the rapid metabolism group with the genotype CYP3A5*1/*1, i.e., AA + CYP3A5*1/*3, and the GG group, or the slow metabolism group with the genotype CYP3A5*3/*3. The basic information, clinical manifestations, history of other diseases, and medication history of the enrolled patients were collected. According to the principle of simple random grouping, patients in each group were randomly divided into two subgroups, receiving TAC at initial doses of 0.05 mg/(kg·d) and 0.075 mg/(kg·d), respectively. Data on laboratory test indicators, including TAC blood drug concentration, blood pressure, and other relevant clinical follow-up indicators, were collected each month from each group. Patients were also evaluated each month for their clinical remission status. When patients in the 0.05 mg/(kg·d) initial dose group did not achieve clinical remission after 2 months, the TAC dose was increased to 0.075 mg/(kg·d), and the patients were observed until the end of the 6th month. Patients in the 0.075 mg/(kg·d) initial dose group were observed for 6 months, regardless of their remission status.
Results
In the LN patient subgroups receiving TAC at the same initial dose, the cumulative remission rate of patients with the GG genotype was higher than that of patients with the AA+GA genotype, but only in the 0.05 mg/(kg·d) initial dose group, the difference in cumulative remission rate between the two genotypes was statistically significant (P < 0.05). According to a comparison of patients with the same genotype who received TAC at different initial doses, the remission rate of patients receiving 0.075 mg/(kg·d) initial dose was higher than that of the 0.05 mg/(kg·d) initial dose group, but only in patients with AA + GA genotype, the difference in remission rate between the two initial dose groups was statistically significant (P < 0.05). Whether it was different genotypes in the same TAC initial dose group or different TAC initial doses of the same genotype, there was no statistically significant difference in the time to achieve complete remission (P > 0.05). Regardless of the different initial TAC doses, patients with the GG genotype maintained higher TAC blood concentrations than those with the AA + GA genotype throughout the course of treatment. TAC blood concentration during treatment (OR = 1.941; 95% CI, 1.47-2.563; P < 0.001), CYP3A5*1 genotype carrier status (OR = 0.161; 95% CI, 0.053-0.492; P = 0.001), and the initial TAC dose (OR = 0.205; 95% CI, 0.113-0.371; P < 0.001) were all significant factors influencing treatment efficacy. When TAC blood concentration was higher, patients with the GG genotype receiving TAC at an initial dose of 0.075 mg/(kg·d) were more likely to achieve clinical remission. There were no statistically significant differences in the incidence of adverse reactions between subgroups with the same genotype but receiving TAC at different initial doses (P > 0.05).
Conclusion
The efficacy of TAC in treating LN patients is correlated with CYP3A5 genotypes, TAC blood drug concentration, and TAC initial dose. The blood drug concentration of TAC is influenced by CYP3A5 genotypes, with the TAC blood drug concentrations of the slow metabolism group being higher than that of the fast metabolism group. When the TAC blood drug concentration reaches 6-10 ng/mL, it is more likely for LN patients to achieve clinical remission.
Keywords: Lupus nephritis, Tacrolimus blood drug concentration, CYP3A5 gene polymorphism
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