Effects of Altered Formulation on the Bioequivalence of Tacrolimus in Healthy Female and Male Volunteeers

NCT02341274 | Completed Phase 1 DMC

• 1 other identifier: 1409250017
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Bioequivalence

Keywords

Tacrolimus; Drug Formulation; Absorption; Bioavailability; Healthy Volunteer

Outcome Measures

Primary Outcomes (2)

• Bioequivalence using pharmacokinetic endpoint of peak blood concentration (Cmax).

  Ten blood samples (10 mL) will be obtained at zero time (baseline) and at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours after oral administration of 5 mg capsule of tacrolimus. Each healthy volunteer will be given a single oral dose of tacrolimus, 5 mg, on four separate occasions with at least a 2 week washout between study days. The peak exposure will be assessed by measuring the peak blood concentration (Cmax) obtained directly from the data. The treatment arms (aged Prograf®, fresh generic, aged generic) will be compared to fresh Prograf®. If the 90% confidence interval for the ratio of the measures in the treatment arms to the fresh Prograf is within the limits of 0.8 to 1.25 for the Cmax, the treatment measures will be judged bioequivalent.

  24 hours

• Bioequivalence using pharmacokinetic endpoints of the area under the blood concentration vs time curve (AUC).

  Ten blood samples (10 mL) will be obtained at zero time (baseline) and at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours after oral administration of 5 mg capsule of tacrolimus. Each healthy volunteer will be given a single oral dose of tacrolimus, 5 mg, on four separate occasions with at least a 2 week washout between study days. The AUC will be computed using the linear trapezoidal rule. The total exposure will be assessed by comparing the AUC from zero to 24 hours and the AUC from zero to infinity. The treatment arms (aged Prograf®, fresh generic, aged generic) will be compared to fresh Prograf®. If the 90% confidence interval for the ratio of the measures in the treatment arms to the fresh Prograf is within the limits of 0.8 to 1.25 for the AUC, the treatment measures will be judged bioequivalent.

  24 hours

Study Arms (4)

Fresh Brand Name Tacrolimus (Prograf®)

ACTIVE COMPARATOR

Oral administration of 5 mg capsule of fresh brand name tacrolimus (Prograf®) to healthy volunteer on an empty stomach. 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. The volunteers will be allowed to eat a normal lunch 3 hours after taking their tacrolimus dose. After the 24-hour blood sample has been collected, the volunteer will be discharged.

Drug: Tacrolimus

Fresh Generic Tacrolimus

ACTIVE COMPARATOR

Oral administration of 5 mg capsule of fresh generic tacrolimus to healthy volunteer on an empty stomach. 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. The volunteers will be allowed to eat a normal lunch 3 hours after taking their tacrolimus dose. After the 24-hour blood sample has been collected, the volunteer will be discharged.

Drug: Tacrolimus

Low Crystal Generic Tacrolimus

ACTIVE COMPARATOR

Oral administration of 5 mg capsule of 10-30% crystallized generic tacrolimus (Low Crystal) to healthy volunteer on an empty stomach. 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. The volunteers will be allowed to eat a normal lunch 3 hours after taking their tacrolimus dose. After the 24-hour blood sample has been collected, the volunteer will be discharged.

Drug: Tacrolimus

High Crystal Generic Tacrolimus

ACTIVE COMPARATOR

Oral administration of 5 mg capsule of 40-60% crystallized generic tacrolimus (High Crystal) to healthy volunteer on an empty stomach. 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. The volunteers will be allowed to eat a normal lunch 3 hours after taking their tacrolimus dose. After the 24-hour blood sample has been collected, the volunteer will be discharged.

Drug: Tacrolimus

Interventions

Tacrolimus DRUG

Bioequivalence study

Also known as: FK-506, FK506, D016559, WM0HAQ4WNM

Fresh Brand Name Tacrolimus (Prograf®); Fresh Generic Tacrolimus; High Crystal Generic Tacrolimus; Low Crystal Generic Tacrolimus

Eligibility Criteria

• Age: 18 Years - 49 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male and female subjects between 18 and 49 years old.
• Healthy individuals without any significant medical condition.
• Nonsmoker or individuals willing to refrain from smoking or use of tobacco or marijuana for at lest one month prior to and until the completion of the study. The entire study for each volunteer will last for minimum of 42 days.
• Ability to commit the time requested for this study.
• Ability to swallow capsules.

You may not qualify if:

• Underweight (weigh less than 52 kg or 114 lb.) or overweight (body mass index (BMI) greater than 32).
• History or current alcohol or drug abuse (more than 3 alcoholic drinks per day on a regular basis).
• History or current significant health conditions such as heart, liver, or kidney.
• History or current psychiatric illness such as depression, anxiety, or nervousness.
• History or current gastrointestinal disorders such as persistent diarrhea or malabsorption that would interfere with the absorption of orally administered drugs.
• Individuals having a serious infection within the last month.
• Donation of blood within the past two months.
• Blood hemoglobin less than 12.5 mg/dL.
• Individuals who are regularly taking prescriptions, over-the-counter, herbal or dietary supplements, alternative medications, or hormonal agents (i.e. oral contraceptives, intra-uterine device with hormones).
• Females with a positive pregnancy test.
• Breastfeeding.
• Females of child-bearing potential who are unable or unwilling to either practice abstinence or to use two non-hormonal forms of birth control (e.g. condom, contraceptive foam) up until the study completion, which will take a total of 30 days. Participation in a research study or use of an investigational drug in the last two months.
• An employee or student under supervision of any of the investigators of this study.
• Individuals who cannot state a good understanding of this study including risks and requirements; are unable to follow the rules of this study.

Sponsors & Collaborators

• Indiana University: lead
• Food and Drug Administration (FDA): collaborator

Study Sites (1)

Indiana CTSI Clinical Research Center

Indianapolis, Indiana, 46202, United States

Location

Related Publications (11)

• Fahr A, Liu X. Drug delivery strategies for poorly water-soluble drugs. Expert Opin Drug Deliv. 2007 Jul;4(4):403-16. doi: 10.1517/17425247.4.4.403.

  PMID: 17683253 RESULT

• Hancock BC, Parks M. What is the true solubility advantage for amorphous pharmaceuticals? Pharm Res. 2000 Apr;17(4):397-404. doi: 10.1023/a:1007516718048.

  PMID: 10870982 RESULT

• Kwong AD, Kauffman RS, Hurter P, Mueller P. Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus. Nat Biotechnol. 2011 Nov 8;29(11):993-1003. doi: 10.1038/nbt.2020.

  PMID: 22068541 RESULT

• Rumondor AC, Stanford LA, Taylor LS. Effects of polymer type and storage relative humidity on the kinetics of felodipine crystallization from amorphous solid dispersions. Pharm Res. 2009 Dec;26(12):2599-606. doi: 10.1007/s11095-009-9974-3. Epub 2009 Oct 6.

  PMID: 19806435 RESULT

• Baird JA, Taylor LS. Evaluation of amorphous solid dispersion properties using thermal analysis techniques. Adv Drug Deliv Rev. 2012 Apr;64(5):396-421. doi: 10.1016/j.addr.2011.07.009. Epub 2011 Aug 4.

  PMID: 21843564 RESULT

• Zucman D, Camara S, Gravisse J, Dimi S, Vasse M, Goudjo A, Choquet M, Peytavin G. Generic antiretroviral drugs in developing countries: friends or foes? AIDS. 2014 Feb 20;28(4):607-9. doi: 10.1097/QAD.0000000000000170.

  PMID: 24378755 RESULT

• Petan JA, Undre N, First MR, Saito K, Ohara T, Iwabe O, Mimura H, Suzuki M, Kitamura S. Physiochemical properties of generic formulations of tacrolimus in Mexico. Transplant Proc. 2008 Jun;40(5):1439-42. doi: 10.1016/j.transproceed.2008.03.091.

  PMID: 18589125 RESULT

• Momper JD, Ridenour TA, Schonder KS, Shapiro R, Humar A, Venkataramanan R. The impact of conversion from prograf to generic tacrolimus in liver and kidney transplant recipients with stable graft function. Am J Transplant. 2011 Sep;11(9):1861-7. doi: 10.1111/j.1600-6143.2011.03615.x. Epub 2011 Jun 30.

  PMID: 21714845 RESULT

• Pasqualotto AC, Denning DW. Generic substitution of itraconazole resulting in sub-therapeutic levels and resistance. Int J Antimicrob Agents. 2007 Jul;30(1):93-4. doi: 10.1016/j.ijantimicag.2006.11.027. Epub 2007 Apr 6. No abstract available.

  PMID: 17412566 RESULT

• Calahan JL, Zanon RL, Alvarez-Nunez F, Munson EJ. Isothermal microcalorimetry to investigate the phase separation for amorphous solid dispersions of AMG 517 with HPMC-AS. Mol Pharm. 2013 May 6;10(5):1949-57. doi: 10.1021/mp300714g. Epub 2013 Apr 24.

  PMID: 23574401 RESULT

• Pham TN, Watson SA, Edwards AJ, Chavda M, Clawson JS, Strohmeier M, Vogt FG. Analysis of amorphous solid dispersions using 2D solid-state NMR and (1)H T(1) relaxation measurements. Mol Pharm. 2010 Oct 4;7(5):1667-91. doi: 10.1021/mp100205g. Epub 2010 Aug 3.

  PMID: 20681586 RESULT

MeSH Terms

Interventions

Tacrolimus

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Raymond E Galinsky, PharmD

  Indiana University

  PRINCIPAL INVESTIGATOR

• Brian Decker, MD, PharmD

  Indiana University

  PRINCIPAL INVESTIGATOR

• Lynne S Taylor, PhD

  Purdue University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 7, 2015
• First Posted: January 19, 2015
• Study Start: November 11, 2016
• Primary Completion: January 20, 2018
• Study Completion: January 20, 2018
• Last Updated: April 7, 2023

Record last verified: 2017-09

Locations

US (1)