A Pharmacokinetic Analysis of Tacrolimus ER Dosing in Obese Kidney Transplant Recipients
Condition: Kidney Transplantation
Study type: Interventional
Phase: Phase 4

Summary: 
      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).
    

Detailed description: 
      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).
    

Intervention name(s): tacrolimus extended release
Intervention type(s): Drug
Other intervention name(s): Astagraf XL
Intervention MeSH terms: Tacrolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Kidney; Immunosuppression; Transplant