A Pharmacokinetic Analysis of Tacrolimus ER Dosing in Obese Kidney Transplant Recipients

Tacrolimus exhibits significant inter- and intra-individual variability of its absorption and
metabolism. Because of this variability, standard dosing is not an accurate predictor of drug
exposure. In clinical use, tacrolimus whole blood trough concentrations are measured to
ensure efficacy and safety. Furthermore, the relatively low bioavailability of tacrolimus is
thought to be a result of the combination of poor water-solubility, pre-systemic metabolism
of tacrolimus in the gastrointestinal tract and activity of the P-glycoprotein efflux pump
found in the enterocytes of the GI tract. Tacrolimus is extensively metabolized by the
cytochrome P-450 system (CYP3A). The plasma protein binding of tacrolimus is approximately
99%. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein. The distribution of
tacrolimus between blood and plasma depends on several factors including hematocrit,
temperature at the time of plasma separation, drug concentration, and plasma protein
concentration.

Pharmacodynamic studies have revealed that, depending on time following transplantation,
maintaining whole blood trough levels between 5 and 20 ng/mL provides adequate protection
against acute rejection and limits the occurrence of adverse events. The management of
tacrolimus blood levels is complicated by variable intra- and inter-patient absorption,
interaction with food and concomitant medications, and the relatively low bioavailability of
tacrolimus from the Prograf formulation (17 ± 10% in adult kidney transplant patients).

Previous studies examining immunosuppressants have shown that drug levels in the immediate
post-transplant period are a major determinant of subsequent acute cellular rejection. It is
known that tacrolimus (TAC) < 10 ng/mL is associated with increased rates of acute cellular
rejection by one month post-transplant.

There is controversy regarding the appropriate dosing weight to use for immunosuppressants
(IS). Weights use range from ideal body weight (IBW) to total body weight (TBW) depending on
the institution and drug being dosed. This becomes particularly important in the obese
population when there are significant differences between IBW and TBW. Our institution has
always used IBW for the dosing of all IS due to concerns for nephrotoxicity with initial high
blood levels of tacrolimus. The concern in obese patients is that the investigators are
underdosing this population that could be at higher risk for rejection due to higher
circulating concentrations of pro-inflammatory cytokines. The introduction of the novel use
of a robotic transplantation procedure at our institution for this patient population has led
to increasing numbers of transplant in obese recipients; therefore, the investigators decided
to re-evaluate our dosing protocol. Data from an internal study at UIC show that our use of
IBW for tacrolimus dosing is not sufficient for the obese population (body mass index [BMI]
≥30). The dose used through month 3 was closer to 0.1 mg/kg/day when total body weight was
utilized. However, the use of an adjusted body weight (aBW) is common for medication dosing
in obese patients. Adjusted body weight is calculated if the TBW is greater than 30% of the
calculated IBW. aBW = IBW + 0.4(TBW - IBW). There is limited data available supporting the
use of either IBW or aBW in dosing tacrolimus within obese patients as these patients are
typically excluded from most clinical trials, particularly the pharmacokinetic trials. In
addition, no literature is available comparing the two dosing weights to determine which
leads to therapeutic concentrations most effectively.

Summary and Present Study Tacrolimus extended release (Astagraf) has recently been approved
by the FDA as a once a day dosing regimen. This formulation has the potential to improve
compliance. Current dosing recommendation for the extended release formulation in renal
transplant is 0.15 mg/kg/day administered once daily in the morning. There are no
specifications on appropriate dosing in obese patients or on whether to use actual, ideal or
and adjusted weight. It will be advantageous to understand the pharmacokinetics of this
medication in the obese to determine the appropriate dosing regimen. In this study, obese
patients will be randomized to receive tacrolimus extended release 0.15 mg/kg/day based on
either ideal body weight (IBW) or adjusted body weight (aBW).

Inclusion Criteria:

1. The subject is a recipient of a living donor or deceased donor kidney only transplant

2. Subject is > 18 years of age

3. BMI≥30 on POD 0

Exclusion Criteria:

1. Multi-organ transplant

2. Subjects taking tacrolimus pre-transplant (i.e. positive crossmatch transplants or
re-transplants)

3. Patients undergoing simultaneous sleeve gastrectomy at the time of transplant.