Effects of Genetic Polymorphisms on the Pharmacokinetics of Calcineurin Inhibitors

Kyle N. Utecht; Jon J. Hiles; Jill Kolesar

Disclosures

Am J Health Syst Pharm. 2006;63(23):2340-2348. 

In This Article

Polymorphisms to predict cyclosporine and tacrolimus dosing

Using genetic markers to adjust initial doses of cyclosporine or tacrolimus may prove difficult, considering the variety of polymorphisms known to affect CYP3A4, CYP3A5, and MDR1. The current literature focuses on correlations between metabolic enzyme genotypes and corresponding measures of patient exposure. Several investigators have attempted to test the effects of one or more SNPs on patients’ response to calcineurin inhibitors ( Table 1 ).

The most comprehensive study to date retrospectively examined 174 stable renal transplant recipients at 3 and 12 months posttransplantation. [14] Patients using medications known to interact with the calcineurin inhibitors were excluded. The study gave participants two equally divided doses of cyclosporine (n = 110) or tacrolimus (n = 64) at each patient’s stabilized dose and measured blood drug concentrations before the next administration time to determine the predose concentration. The predose blood drug concentration was then normalized to a 24-hour weight-adjusted dose. Patients’ blood samples were analyzed to determine the genotype of CYP3A4 (CYP3A4*1, CYP3A4*1B, or CYP3A4*3), CYP3A5 (CYP3A5*1, CYP3A5*3, or CYP3A5*6), and MDR1 (ABCB1) (C3435C, C3435T, or T3435T). The authors noted that the pharmacokinetics of cyclosporine were not affected by the polymorphisms studied.[14] Tacrolimus’s predose concentration, however, was 36% lower in CYP3A4*1B allele carriers when compared with patients homozygous for CYP3A4*1 (p < 0.003). Significant results were also found with tacrolimus in CYP3A5*1 carriers as dose-adjusted predose concentrations were 35% lower than in patients homozygous for CYP3A5*3 (p < 0.0001). No correlation was found between the MDR1 (ABCB1) polymorphisms and tacrolimus pharmacokinetics. This study was unable to adequately analyze the patients carrying the CYP3A4*3 allele because the sample size was small (n = 2). Patients carrying both the CYP3A5*3 and CYP3A5*6 alleles were also excluded because their phenotypes could not reliably be predicted. Based on these results, dosage adjustments inversely proportional to these findings can be expected for tacrolimus users who carry either the CYP3A5*1 or CYP3A4*1B alleles.

Another study that retrospectively examined the correlation between metabolic enzyme genotypes and cyclosporine pharmacokinetics included 151 stable kidney and heart transplant recipients using cyclosporine.[11] In an attempt to improve sensitivity, this trial used a two-compartment model to determine pharmacokinetic parameters for statistical testing. Blood samples from patients were tested to determine the genotypes of CYP3A4 (CYP3A4*1, CYP3A4*1B, or CYP3A4*3), CYP3A5 (CYP3A5*1, CYP3A5*3, or CYP3A5*6), and MDR1 (ABCB1) (C3435C, C3435T, or T3435T). After patients took their dose of oral cyclosporine, blood concentrations were drawn and assayed at zero, one, two, three, and four hours for inclusion in the modeling system. Participants were required to have a consistent cyclosporine dosage for at least one month before the study and were not supposed to be taking any medications that could interact with the calcineurin inhibitor. The results of this study showed no correlation between MDR1 (ABCB1) or CYP3A5 polymorphisms and cyclosporine pharmacokinetics. However, this study did find that carriers of the CYP3A4*1B allele had a small (9%) increase in oral cyclosporine clearance compared with patients homozygous for CYP3A4*1 (p < 0.05). The authors attributed this to the increased sensitivity of the two-compartment model used for characterizing cyclosporine pharmacokinetics.[11]

A study of 118 kidney transplant recipients prospectively examined the differences in tacrolimus dose-adjusted blood concentrations at one week, one month, and three months posttransplantation.[26] Tacrolimus dosing began at 0.15 mg/kg/day as divided doses but was adjusted to obtain a target trough concentration of 10 ng/mL initially and 5 ng/mL at three months. Patients taking medications known to interact with calcineurin inhibitors were excluded. Patients’ blood samples were tested to determine the genotype for CYP3A5 (CYP3A5*1 or CYP3A5*3) and MDR1 (ABCB1) (C1236T, G2677T, or C3435T) (C3435C, C3435T, or T3435T). Both CYP3A5*1 homozygotes and heterozygotes showed lower tacrolimus dose-adjusted predose concentrations compared with CYP3A5*3 homozygotes at one week (32.8 and 41.6 ng/mL versus 102.3 ng/mL per mg/kg/day, respectively), one month (33.1 and 46.4 ng/mL versus 103.2 ng/mL per mg/kg/day, respectively), and three months (35.3 and 59 ng/mL versus 150.3 ng/mL per mg/kg/day, respectively) (p < 0.001 for all). Dose-adjusted predose concentrations were 40% and 67% greater for CYP3A5*1 heterozygotes compared with CYP3A5*1 homozygotes at one and three months after transplantation, respectively (p < 0.01). MDR1 (ABCB1) polymorphisms did not affect tacrolimus pharmacokinetics.[26]

Another trial analyzed the pharmacokinetics of cyclosporine in carriers of the CYP3A5*1 and CYP3A5*3 polymorphisms and the MDR1 (ABCB1) T-129C, C1236T, G2677(T,A), and C3435T SNPs in 106 stable renal transplant recipients. [10] The pharmacokinetic parameters studied were dose-adjusted AUC0–4 hr and AUC0–12 hr and doseadjusted maximum concentration (Cmax). All study patients were using cyclosporine and mycophenolate mofetil for immunosuppression but no medications known to alter the pharmacokinetics of calcineurin inhibitors (except for low-dose prednisone). This trial confirmed that there was no association between CYP3A5 polymorphisms and cyclosporine metabolism. Of the four SNPs examined, only the C1236T polymorphism was associated with a 16% decrease in dose-adjusted Cmax and a 14% decrease in dose-adjusted AUC0–4 hr. However, neither of these findings were reported as clinically significant.[10]

Several other studies have been published that either confirm or contradict the findings from the larger studies discussed above. A study of 10 patients found that cyclosporine metabolism was increased by 52% in CYP3A5*1 carriers; however, the correlation may have been confounded by the small sample size and a linkage with the C3435T MDR1 (ABCB1) polymorphism.[27] A study of 50 renal transplant recipients using cyclosporine for immunosuppression found that patients carrying the CYP3A5*1 allele had lower dose-adjusted trough blood concentrations when only considering the second cyclosporine administration of the day (p = 0.037). The difference, however, was not present if the blood concentrations were adjusted to the 24-hour dose (p = 0.062).[28] Kreutz et al.[29] retrospectively studied the effect of CYP3A5 polymorphisms on cyclosporine pharmacokinetics and general renal transplant outcomes (n = 399) but found no difference between carriers and noncarriers of CYP3A5*1 with respect to cyclosporine dose-adjusted predose trough blood concentrations, blood pressure, and transplant survival. Overall, most trials found no correlation between the CYP3A5 allele and cyclosporine pharmacokinetics.

One study of 81 renal transplant recipients found an association between patients homozygous for the MDR1 (ABCB1) C3435T polymorphism and lower dose-adjusted blood tacrolimus concentrations 12 hours after the previous dose at two months posttransplantation (p ≤ 0.02).[23] Numerous other reports, including those discussed above, do not support this finding.[14,20,26,28,30,31]

A retrospective analysis of 180 renal transplant recipients affirmed an increase in tacrolimus clearance in CYP3A5*1 carriers with dose-adjusted blood drug concentrations half those of CYP3A5*3 homozygotes during the first two weeks posttransplantation.[32] A study of 180 renal transplant recipients also found that CYP3A5*1 carriers had lower average blood tacrolimus concentrations during the first two weeks posttransplantation (13.6 μg/L versus 18.4 μg/L for week 1 and 11.2 μg/L versus 14.3 μg/L for week 2, p < 0.0001), took longer to reach goal blood tacrolimus concentrations of 20 μg/L during week 1 and of 15 μg/L during week 2 (39.3% below goal versus 8.2% below goal, p < 0.0001), and had an earlier median time to acute rejection (8 days versus 13 days, p < 0.05) when compared with CYP3A5*3 homozygotes.[33] A final trial of 80 renal transplant patients again confirmed a higher tacrolimus dose requirement for CYP3A5*1 carriers. [34] These studies, in addition to those previously presented, firmly demonstrate an association between increased tacrolimus clearance and the CYP3A5*1 allele.

Carriers of CYP3A5*1 consistently have higher clearance rates of tacrolimus than do CYP3A5*3 homozygotes. The influence of CYP3A5 alleles on cyclosporine metabolism and the MDR1 (ABCB1) C3435T polymorphism on tacrolimus metabolism has been studied but remains controversial. Other drug-allele interactions have not been studied or have yielded inconsistent findings.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....