Effects of Altered Formulation on the Bioequivalence of Tacrolimus in Healthy Female and Male Volunteeers
Condition: Bioequivalence
Study type: Interventional
Phase: Phase 1

Summary: 
      Amorphous solid dispersion (ASD) formulations are increasingly used by the pharmaceutical
      industry to develop poorly water-soluble drugs into effective oral dosage forms. Examples
      include the antifungal drug itraconazole, the HIV protease inhibitor combination,
      lopinavir/ritonavir and the immunosuppressive, tacrolimus. There is potential for significant
      variation in bioavailability of ASD and thus heightened concern regarding the therapeutic
      efficacy as generic versions of these poorly water-soluble compounds become approved. The
      variation in bioavailability is to be expected because of our limited understanding of the
      precise physical chemistry of drug polymer amorphous solid dispersion formulations.
    

Detailed description: 
      The specific aim is to conduct a randomized, single dose, four-treatment, four-period
      cross-over bioequivalence (BE) study in 24 healthy normal adult volunteers (males and
      non-gravid females) to evaluate the in vivo performance of fresh and aged brand name and
      generic amorphous solid dispersion (ASD) preparations of tacrolimus. The pharmacokinetics of
      tacrolimus as fresh Prograf® and aged Prograf®, fresh generic tacrolimus capsules and aged
      generic tacrolimus capsule will be determined and compared in healthy volunteers. The
      hypothesis to be tested is that the tacrolimus in the amorphous solid dispersion formulation
      will be partially crystalized upon treatment with controlled heat and humidity and will
      demonstrate lower absorption (lower relative bioavailability) compared to the fresh product.
      Moreover, the expectation is that the heat- and humidity-stressed generic formulations will
      not be robust to crystallization as the stressed brand name drug and will demonstrate a
      decreased in vivo performance and loss of bioequivalence.

      A total of 24 healthy female and male volunteers (age 18 to 49 years old) will be recruited
      to participate in this study. Volunteers will be determined to be free of significant medical
      conditions as assessed by medical history, physical examination, and blood and urine tests.
      Volunteers will be randomly allocated to receive one of the four treatment sequence groups
      and, on each occasion, receive one of the following: Fresh Prograf (RLD), fresh generic
      tacrolimus, 10-30% crystallized generic (Low Crystal), and 40-60% crystallized generic (High
      Crystal) tacrolimus. There will be a minimum 2-week washout between treatments. On each
      occasion, healthy volunteers will be administered tacrolimus, 5 mg, as a single capsule
      orally on an empty stomach with approximately 240 mL of water. Blood samples will be
      collected from the indwelling venous catheter (∼10 ml) after 0.5, 1, 2, 3, 4, 6, 8, 12 and 24
      hours after dosing. Subjects will be regularly monitored during this time. The volunteers
      will be allowed to eat a normal lunch 3 hours after taking their tacrolimus dose.

      The primary endpoints will be the maximum blood concentration (Cmax) and the area under the
      curve (AUC) from zero to 24 hours and the AUC extrapolated from zero to infinity for
      tacrolimus for this bioequivalence study as recommended by the FDA guidance for industry. We
      will compute the AUC (from zero to 24 hours) to the last time point with measurable
      concentration using the linear trapezoidal rule and the AUC from time zero to time infinity
      with extrapolation computed as the quotient of the last measurable concentration and the
      terminal slope of the log concentration vs. time curve. In addition, we will report half-life
      of tacrolimus estimated from the terminal slope of the concentration vs. time plot determined
      by linear least squares regression. The peak blood tacrolimus concentration (Cmax,) and the
      time to Cmax (Tmax,) will be determined by visual inspection of the individual subject
      concentration-time curves.

      A treatment will be considered bioequivalent if the geometric least square mean ratios and
      90% confidence interval for Cmax and AUC fall between 0.80 to 1.25 of the fresh Prograf®.
    

Intervention name(s): Tacrolimus
Intervention type(s): Drug
Intervention description(s): Bioequivalence study
Other intervention name(s): FK-506, FK506, D016559, WM0HAQ4WNM
Intervention MeSH terms: Tacrolimus
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Tacrolimus; Drug Formulation; Absorption; Bioavailability; Healthy Volunteer