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

Discussion

Trials evaluating the pharmacogenetics of calcineurin inhibitors have inconsistent methods, which may be a contributing factor to the largely inconsistent results. Trials vary in their pharmacokinetic methods, dosing strategies, times when plasma concentrations are assessed, and patient populations and polymorphisms evaluated. In addition, the approaches used to account for patient ethnicity differ among trials. Some authors conduct subgroup analysis of certain ethnic groups; others do not discuss the topic beyond demographics. None of the studies reviewed attempted to predict the combined effect of the many polymorphisms. Each study focused on the effect that one polymorphism had on final calcineurin inhibitor concentrations, while the drug concentration is likely related to a number of polymorphisms. Overall, a large, prospective, randomized trial in the United States studying both cyclosporine and tacrolimus with a comprehensive panel of polymorphisms, or haplotypes, using the AUC during the first weeks posttransplantation would provide greater insight into pharmacokinetic variations from metabolic gene polymorphisms. In addition, trials prospectively comparing calcineurin inhibitor dosing using genotype with traditional regimens would provide definitive evidence for the use of pharmacogenetics to adjust cyclosporine or tacrolimus dosages after renal transplantation.

Most research regarding pharmacogenetic variation and cyclosporine pharmacokinetics has not produced consistent results. In addition, studies comparing tacrolimus pharmacokinetics to CYP3A4 and a variety of MDR1 (ABCB1) polymorphisms have not been consistent. However, several studies have shown an increase in tacrolimus metabolism, and thus decreased daily weight-adjusted dosing requirements, in carriers of the CYP3A5*1 allele.[14,26,31,33,34] Disregarding racial differences, approximately 35% of the population may carry the CYP3A5*1 allele. The literature shows that the tacrolimus clearance in a CYP3A5*1 carrier may be 25-45% greater than its clearance in a CYP3A5*3 homozygote. Thus, the weight-adjusted tacrolimus dosage of a CYP3A5*3 homozygote may be 55-75% lower than that of a CYP3A5*1 carrier.

Preemptive dosage adjustments may lead to cost savings and improved clinical outcomes. However, savings in drug costs must be balanced with the costs of the laboratory tests involved. Laboratory tests to determine the SNP of a single gene can be inexpensive in a facility with the appropriate resources. The cost of a single assay is less than $2 without considering technician time or instrumentation.[35] The recently approved Amplichip, manufactured by Roche, can determine a patient’s CYP2D6 and CYP2C19 SNPs for $350-$400, not including markup, technician time, and other associated costs.[36] If a genetic test can confirm that a patient will require lower doses to achieve target blood concentrations, the cost of the genetic test would be offset by reduced drug costs.

Other costs to be considered are the financial costs and risk to life associated with graft rejection, which has been correlated with not achieving target blood concentrations of the calcineurin inhibitors within days of transplantation.[9] It has also been shown to be more difficult to reach target blood concentrations in CYP3A5*1 carriers.[31] Therefore, an inexpensive CYP3A5 SNP analysis would provide greater guidance for initial dosing requirements of tacrolimus and is potentially an economical and clinically wise inclusion in pre-operative testing for patients about to undergo renal transplantation.

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