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

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).

Study Overview

• Status: Completed
• Conditions: Kidney Transplantation
• Intervention / Treatment: Drug: tacrolimus extended release

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).

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois Hospital & Health Sciences System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: IBW; tacrolimus extended release 0.15 mg/kg/day based on Ideal Body Weight (IBW)	Drug: tacrolimus extended release; Other Names: Astagraf XL
EXPERIMENTAL: ABW; tacrolimus extended release 0.15 mg/kg/day based on adjusted Body Weight (aBW)	Drug: tacrolimus extended release; Other Names: Astagraf XL

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in Tacrolimus Exposure (AUC-0-24)) in Obese Patients Who Received an Initial TAC -ER Dose of 0.15 mg/kg Using aBW Versus IBW	Difference in tacrolimus exposure (area under the concentration-time curve from time 0 to 24 hours (AUC-0-24)) in obese patients who received an initial TAC -ER dose of 0.15 mg/kg using aBW versus IBW	Days 1-14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in Time to Therapeutic Level	Difference in the time to a therapeutic tacrolimus trough level in the aBW group compared to the IBW group.	Days 1 to 7

Collaborators and Investigators

• Sponsor: University of Illinois at Chicago
• Collaborators: Astellas Pharma US, Inc.

Publications and helpful links

General Publications

• Conley MM, McFarlane CM, Johnson DW, Kelly JT, Campbell KL, MacLaughlin HL. Interventions for weight loss in people with chronic kidney disease who are overweight or obese. Cochrane Database Syst Rev. 2021 Mar 30;3(3):CD013119. doi: 10.1002/14651858.CD013119.pub2.
• Jasiak-Panek NM, Wenzler E, Patel S, Thielke JJ, Progar K, Patel S, Brandt S, Huang YJ, Benedetti E, West-Thielke PM. A randomized, open-label pharmacokinetic trial of tacrolimus extended-release dosing in obese de novo kidney transplant recipients. Clin Transplant. 2019 Aug;33(8):e13640. doi: 10.1111/ctr.13640. Epub 2019 Jul 1.

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (ACTUAL): February 28, 2017
• Study Completion (ACTUAL): June 9, 2017

Study Registration Dates

• First Submitted: November 20, 2014
• First Submitted That Met QC Criteria: May 11, 2015
• First Posted (ESTIMATE): May 14, 2015

Study Record Updates

• Last Update Posted (ACTUAL): November 7, 2018
• Last Update Submitted That Met QC Criteria: November 6, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: Immunosuppression; Transplant; Kidney
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: 2014-XXXX