BioequivalencePhase 1ASDBioequivNCT02341274
Effects of Altered Formulation on the Bioequivalence of Tacrolimus in Healthy Female and Male Volunteeers
A Phase 1 study testing Tacrolimus in people with Bioequivalence, run by Indiana University at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 49 yearsHealthy volunteers can take part
- Conditions the study is for
- Bioequivalence
- What is being tested?
- Tacrolimus
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteUnited States
- Study dates
- 11 Nov 2016to 20 Jan 2018
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 49 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 14Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Indiana CTSI Clinical Research Center
Indianapolis, Indiana, 46202
About this study
Official title: Effects of Altered Formulation on the Bioequivalence of Tacrolimus in Healthy Female and Male Volunteers
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.
Read the 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®.
- Conditions
- Bioequivalence
- Being tested
- Tacrolimus
- Keywords
- Tacrolimus, Drug Formulation, Absorption, Bioavailability, Healthy Volunteer
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TacrolimusDrug
Also called FK-506, FK506, D016559, WM0HAQ4WNM
Bioequivalence study
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: Drug: Tacrolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 24 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jan 2015 (estimated)
- Study start11 Nov 2016
- Primary completion20 Jan 2018
- Study completion20 Jan 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for BioequivalenceStudies of the same condition, open and under way.
- More trials run by Indiana UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- Indiana University
- Sponsor type
- University, hospital or other
- Collaborators
- Food and Drug Administration (FDA)
- Responsible party
- Sponsor
- Investigators
- Raymond E Galinsky, PharmD, Principal investigator, Indiana UniversityBrian Decker, MD, PharmD, Principal investigator, Indiana UniversityLynne S Taylor, PhD, Principal investigator, Purdue University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02341274
- Sponsor's protocol ID
- 1409250017
- Acronym
- ASDBioequiv
- Status last verified
- Sep 2017
- First submitted
- 7 Jan 2015
- Last updated
- 7 Apr 2023
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Publications
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.
PubMed 17683253Hancock 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.
PubMed 10870982Kwong 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.
PubMed 22068541Rumondor 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.
PubMed 19806435Baird 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.
PubMed 21843564Zucman 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.
PubMed 24378755Petan 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.
PubMed 18589125Momper 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.
PubMed 21714845Pasqualotto 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.
PubMed 17412566Calahan 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.
PubMed 23574401Pham 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.
PubMed 20681586Taylor LS, Trasi NS, Purohit HS, Sun D, Kinjo M, Ni Z, Mahjabeen S, Feng KK, Sun WJ, Matta MK, Decker B, Galinsky RE. Changes in drug crystallinity in a commercial tacrolimus amorphous formulation result in variable pharmacokinetics. J Pharm Sci. 2025 Jan;114(1):313-322. doi: 10.1016/j.xphs.2024.09.025. Epub 2024 Oct 15.
PubMed 39414078
Study at a glance
From the registry record, last updated by the sponsor on 7 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects of Altered Formulation on the Bioequivalence of Tacrolimus in Healthy Female and Male Volunteers
- ClinicalTrials.gov ID
- NCT02341274
- Acronym / sponsor ID
- ASDBioequiv / 1409250017
- Conditions
- Bioequivalence
- Keywords
- Tacrolimus, Drug Formulation, Absorption, Bioavailability, Healthy Volunteer
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- Indiana UniversityUniversity, hospital or other
- Collaborators
- Food and Drug Administration (FDA)
- Study start
- 11 Nov 2016 (actual)
- Primary completion
- 20 Jan 2018 (actual)
- Study completion
- 20 Jan 2018 (actual)
- First posted
- 19 Jan 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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®.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Fresh Brand Name Tacrolimus (Prograf®) | Active comparator | Drug: TacrolimusOral 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. |
| Fresh Generic Tacrolimus | Active comparator | Drug: TacrolimusOral 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. |
| Low Crystal Generic Tacrolimus | Active comparator | Drug: TacrolimusOral 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. |
| High Crystal Generic Tacrolimus | Active comparator | Drug: TacrolimusOral 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. |
Who may qualify
- Ages
- 18 to 49 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (14 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TacrolimusAlso: FK-506, FK506, D016559, WM0HAQ4WNMBioequivalence study | Drug | Fresh Brand Name Tacrolimus (Prograf®), Fresh Generic Tacrolimus, High Crystal Generic Tacrolimus, Low Crystal Generic Tacrolimus |
Primary outcome
Bioequivalence using pharmacokinetic endpoint of peak blood concentration (Cmax).
Time frame: 24 hours
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.
Bioequivalence using pharmacokinetic endpoints of the area under the blood concentration vs time curve (AUC).
Time frame: 24 hours
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.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Apr 2023.
- Results publication: PubMed 17683253Fahr 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.
- Results publication: PubMed 10870982Hancock 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.
- Results publication: PubMed 22068541Kwong 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.
- Results publication: PubMed 19806435Rumondor 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.
- Results publication: PubMed 21843564Baird 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.
- Results publication: PubMed 24378755Zucman 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.
- Results publication: PubMed 18589125Petan 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.
- Results publication: PubMed 21714845Momper 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.
- Results publication: PubMed 17412566Pasqualotto 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.
- Results publication: PubMed 23574401Calahan 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.
- Results publication: PubMed 20681586Pham 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.
- Derived from this study: PubMed 39414078Taylor LS, Trasi NS, Purohit HS, Sun D, Kinjo M, Ni Z, Mahjabeen S, Feng KK, Sun WJ, Matta MK, Decker B, Galinsky RE. Changes in drug crystallinity in a commercial tacrolimus amorphous formulation result in variable pharmacokinetics. J Pharm Sci. 2025 Jan;114(1):313-322. doi: 10.1016/j.xphs.2024.09.025. Epub 2024 Oct 15.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Raymond E Galinsky, PharmD principal investigator
Indiana University
Brian Decker, MD, PharmD principal investigator
Indiana University
Lynne S Taylor, PhD principal investigator
Purdue University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Tacrolimus in people with Bioequivalence, run by Indiana University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Bioequivalence using pharmacokinetic endpoint of peak blood concentration (Cmax). (time frame: 24 hours). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02341274, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Apr 2023.