Study of Pharmacogenomic-Guided Tacrolimus Dosing and Monitoring in Kidney Transplant Recipients

Participants: All new kidney transplant recipients aged 18 to 65 years who are admitted at
UNC-CH and provided informed consent will be included in this study (Unless they meet the
exclusion criteria specified). A total of 260 subjects will be included in the study, 130 of
which will be included in the pharmacogenomic group and the remaining 130 will be in the
control group.

Procedures (methods): The pharmacogenomic group will partake in a 12-month study comprising
of two periods, Genotype-Guided Initial Dosing Intervention and Follow-up.

Briefly, patients on transplant waitlist will be screened for eligibility. At the
pre-intervention assessment (Study Day 0), buccal swab samples for genotyping will be
collected on all eligible patients who provided informed consent (performed in real time).
Results of the genotyping test will be incorporated into electronic medical record (EMR). The
initial tacrolimus dose will be based on genotype: 0.1 mg/kg/day (non- expressers) or 0.2
mg/kg/day, with maximum of 20 mg/day (expressers) given in 2 divided doses. Eligible patients
who consented to receive genotype-guided tacrolimus dose will enter the pharmacogenomic group
and will receive the initial tacrolimus dosing based on genotype results following kidney
transplantation (Study Day 1). Subsequent tacrolimus dosing will then be adjusted according
to trough concentrations (C0) and therapeutic target concentrations. The genotype-guided
dosing recommendation for tacrolimus only refers to the initial tacrolimus dose. All patients
in the pharmacogenomic group will be followed from Study Day 2 and up to 12 months to assess
long-term outcome.

Age-, race-, and disease-matched patients who had previously received kidney transplantation
with standard tacrolimus dosing from 2010 to present will also be asked to give consent for
genotyping (historical controls). These patients will be included in the control group and
their safety and efficacy data will be collected retrospectively for up to 12 months from the
initiation of first tacrolimus dose.

As there are confounding variables, including age, race and disease state that may impact the
results of the study, our study design incorporates an overall matching strategy, so that we
can identify a well-matched control group. First, to control for differences in care over
time, patients in the pharmacogenomic group will be matched to controls enrolled from 2010 to
present. This time period was selected as there had been no major changes in standard of care
or treatment regimen since 2010. After eligibility is met, control patients will be selected
to match the pharmacogenomic group using a computerized matching algorithm that has been
optimized to match baseline demographic and disease characteristics that have been identified
a priori as likely to influence the treatment response to tacrolimus. To balance the
trade-off between minimizing bias and maximizing matched sample size, a systematic approach
will be conducted to identify the number of matched control patients for each patient in the
pharmacogenomic group. This approach will include the following steps: 1) run the desired
matching algorithm, starting with 1:1 (one control to one patient in the pharmacogenomic
group) matching and iterating until the maximum desired number of potential controls per
treated subject is reached; 2) for each iteration, test for covariate balance; and (3)
generate numeric summaries and graphical plots of the balance statistics across all
iterations in order to determine the optimal number.

The selection of patients for the control group using a matching algorithm will be conducted
by an independent statistician in a blinded and unbiased manner. The statistician will have
no knowledge of survival outcome, other outcome data, and genotype. The algorithm will not be
used to guide treatment in any way.

Inclusion Criteria:

- All new kidney transplant recipients aged 18 to 65 years who are admitted at UNC-CH
and provided informed consent will be included in this study.

Exclusion Criteria:

- Patients will be excluded from participating in the study to receive genotype-guided
tacrolimus dosing if he/she meets any of the exclusion criteria described below.

- Recipients who did not consent to participate in the study.

- Highly sensitized patients (ie, pretransplant T or B cell flow crossmatch positive)

- Recipients of ABO incompatible kidney transplant

- Recipients with preformed donor-specific antibodies (DSA)

- Human Leukocyte Antigen (HLA) identical kidney transplant

- Recipients of non-kidney transplant

- Recipients of repeat transplant if they are on immunosuppression at the time of
transplant

- Patients using medications that have known pharmacokinetic (PK) drug interaction with
tacrolimus

- Patients in whom tacrolimus therapy is contraindicated