Study Shows Value of Investing in Pharmacogenomics Testing for Tacrolimus Dosing in Kidney Transplant Recipients

The cost of pharmacogenomic (PGx) testing is often a barrier to more widespread implementation of preemptive PGx testing in clinical practice, and more cost effectiveness data is crucial in advocating for better insurance coverage in the United States. Currently, PGx testing coverage varies by insurance plan, with many private insurers still classifying PGx testing as “experimental” and placing the entire cost burden on the patient.

Transplant is an area of medicine where preemptive PGx testing can play a crucial role in proper dosing of post-transplant immunosuppressive regimens. The calcineurin inhibitor tacrolimus (Envarsus XR; Veloxis Pharmaceuticals) is a critical part of many solid organ transplant regimens.

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Genetic variation in the CYP3A5 enzyme can influence a transplant patient’s tacrolimus level. The most common allele in patients of European ancestry is the CYP3A5*3 allele, which results in the production of a non-functional CYP3A5 enzyme due to an alternate splicing defect. Patients with 1 or 2 copies of a functional allele, like CYP3A5*1, will metabolize tacrolimus more quickly and require higher initial doses than patients carrying 2 copies of the CYP3A5*3 allele. The frequency of the functional alleles is much higher in patients of non-European ancestry. Frequency rates of the CYP3A5 *3/*3 genotype are as high as 95% in patients of European ethnicity, while around 50% or less in many African ancestry populations.

In order to decrease the risk of initially underdosing or overdosing a transplant patient receiving tacrolimus, PGx testing for the CYP3A5 gene can be performed. This study aimed to assess the cost-utility of performing preemptive CYP3A5 genotype testing prior to starting tacrolimus in kidney transplant patients in Austria. Current US transplant guidelines, like the American Society of Transplantation and the Kidney Disease Improving Global Outcomes, do not have statements endorsing the use of preemptive PGx testing to guide initial tacrolimus dosing in transplant recipients.

Methods

This study used cost-utility and clinical outcomes data from the Preemptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions (PREPARE) study, which was a multisite, prospective, open label, randomized controlled clinical study investigating the impact of PGx testing of a panel of actionable PGx variants on adverse event occurrence. The study included several secondary outcome measures, such as the health care expenditures related to the adverse drug events (ADEs) and quality of life data with the objective to estimate the cost-effectiveness of implementing preemptive PGx testing in kidney transplantation. The study had 269 participants, with 145 patients in the PGx-guided tacrolimus group and 124 patients in the control group, receiving standard tacrolimus dosing without utilizing PGx results.

The inclusion criteria for the study participants were patients 18 years of age or older who received a kidney transplant, had no prior history of PGx testing, were able to follow-up for at least 12 weeks, and able to provide saliva or blood samples. Patients were excluded if they were pregnant or breastfeeding, had no general practitioner following them, or if their estimated life expectancy was less than 3 months. All subjects in both groups were genotyped for CYP3A5 prior to starting tacrolimus. The pharmacogenomic test used included 12 genes and 50 different variants, including CYP3A5*3, CYP3A5*6, and CYP3A5*7. In the PGx-guided tacrolimus dosing group, patients found to have CYP3A5 intermediate or normal metabolizer phenotypes were initiated on higher than standard initial tacrolimus doses. Therapeutic drug monitoring was performed on all patients to guide subsequent tacrolimus dose adjustments.

The tracked cost-utility–related outcomes included direct medical costs and the patient’s quality of life using the Visual Analog Scale (VAS). The VAS scores were taken at the initial (baseline) visit, week 4, week 12, and 18 months from the initial visit. Medical costs included the cost of hospitalization, adverse drug events (ADEs), and PGx testing (applicable only for the PGx-guided tacrolimus dosing arm). The incremental Cost-Effectiveness Ratio (ICER) was classified as the ratio of the difference in costs between PGx-guided group vs control group divided by the difference in Quality-Adjusted Life-Years (QALYs).

Results

The mean hospitalization cost was higher for the control group at €25,587 compared to €21,538 for the PGx-guided tacrolimus dosing group. When the €147 cost of the PGx test was taken into account, the PGx-guided tacrolimus dosing group was more cost effective by €3902 per patient (95% CI: −3544–11,619). The PGx test itself accounted for only 0.7% of the total cost on average for patients in the PGx-guided group. When analyzing ADE rates, the control group experienced higher rates of severe ADEs at 4.8% compared to 2.1% in the PGx-guided group. Shorter length of hospitalization following kidney transplant was also observed in the PGx-guided group with an average of 13.9 days compared to 16.6 days in the hospital for patients in the control group.

In terms of quality-of-life outcomes, the PGx-guided group also had better outcomes compared with the control group. The PGx-guided group had 0.900 QALYs (95% CI: 0.862–0.936) while the control group had 0.851 QALYs (95% CI: 0.814–0.885) for a difference of 0.049 QALYs between the 2 groups. The ICER calculation also supported the PGx-guided group at –€80,992 (95% CI: −444.209–233,248) compared to the control group. Probability analysis favored the PGx-guided group, showing a probability of 82.2% of being less costly and more effective than the control group’s tacrolimus dosing method.

Discussion and Conclusion

The perceived cost of PGx testing is often a barrier to more widespread implementation of pharmacogenomics as a routine part of patient care. The results of this cost-effectiveness analysis in a kidney transplant study demonstrate the monetary value investing in PGx testing can provide for the health care system. PGx-guided tacrolimus dosing based on preemptive PGx testing resulted in a nearly €4000 per patient savings compared to the method of using a standard empiric starting tacrolimus dose. Other cost-effectiveness and quality of life analyses also favored PGx-guided tacrolimus dosing compared to the control group. This study adds to the growing body of literature validating the value PGx testing can bring to the health care system, which hopefully will lead to improved coverage by private insurers in the US.

Reference

Fragoulakis V, Koufaki MI, Joefield-Roka C, Sunder-Plassmann G, Mitropoulou C. Cost-utility analysis of pharmacogenomics-guided tacrolimus treatment in Austrian kidney transplant recipients participating in the U-PGx PREPARE study. Pharmacogenomics J. 2024 Mar 18;24(2):10. doi: 10.1038/s41397-024-00330-5. PMID: 38499549.