Bioequivalence Study of Tacrolimus in Healthy Volunteers

NCT04725682 | Completed Phase 1 Results FDA Drug

• 1 other identifier: Protocol 2521
• Study Type: interventional
• Target: 67
• Locations: 1 country
• Sites: 1

Brief Summary

This is an in-vivo study to investigate the bioequivalence of generic tacrolimus and its reference listed drug (RLD). The objective of this study is to investigate the bioequivalence of generic Tacrolimus and RLD in healthy male and non-pregnant, non-lactating female volunteers under fasting conditions. The outcome of this study will help further understanding about pharmacokinetic (PK) performance of tacrolimus in a healthy volunteer population and improve review standards for bioequivalence of narrow therapeutic index (NTI) drugs.

Conditions

Healthy Volunteers

Keywords

generic drug; tacrolimus; bioequivalence; reference listed drug; fasting condition

Outcome Measures

Primary Outcomes (2)

• Area Under the Concentration (AUC 72)

  Measurement of whole blood tacrolimus prior to dosing and up to 72 hours post-dose

  72 hours

• Maximum Plasma Concentration (Cmax)

  Measurement of whole blood tacrolimus prior to dosing and up to 144 hours post-dose

  0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00, 72.00, 96.00, 120.00, 144.00 hours

Secondary Outcomes (3)

• Time at Maximum Plasma Concentration (Tmax)

  0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00, 72.00, 96.00, 120.00, 144.00 hours

• Area Under the Concentration (AUC Inf)

  Estimated using the last measurable concentration (144 hours)

• Area Under the Concentration (AUC 0-t)

  To the last measurable concentration or last sampling time t, whichever occurs first. (0 to 144 hours post-dose)

Study Arms (2)

Sequence 1 (TRTR)

ACTIVE COMPARATOR

Each subject is scheduled to receive each treatment twice by the end of the study in the order of TRTR. Treatment T (Test): 1 × 1mg Test tacrolimus capsules (Applicant holder: Accord Healthcare, Inc.); Treatment R (Reference): 1 × 1mg RLD tacrolimus capsules

Drug: Tacrolimus

Sequence 2 (RTRT)

ACTIVE COMPARATOR

Each subject is scheduled to receive each treatment twice by the end of the study in the order of RTRT. Treatment T (Test): 1 × 1mg Test tacrolimus capsules (Applicant holder: Accord Healthcare, Inc.); Treatment R (Reference): 1 × 1mg RLD capsules

Drug: Tacrolimus

Interventions

Tacrolimus DRUG

a single dose of 1 mg capsule per period

Sequence 1 (TRTR); Sequence 2 (RTRT)

Eligibility Criteria

• Age: 18 Years - 59 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Males and female volunteers, 18 -59 years of age (inclusive).
• BMI that is within 18.5-33.0 kg/m², inclusive.
• Healthy, according to medical history, ECG, vital signs, laboratory results and physical examination as determined by the PI/Sub-Investigator.
• Capable of giving written informed consent prior to receiving any study medication.
• Availability to volunteer for the entire study duration and willing to adhere to all protocol requirements.
• Smokers: Capable of refraining from smoking for the duration of the confinement.
• Female subjects must be non-pregnant, non-lactating and fulfill at least one of the following:
• Be surgically sterile for a minimum of 6 months
• Post-menopausal for a minimum of 12 months; Menopause defined as 12 months of amenorrhea without any other obvious pathological or physiological cause.
• Agree to avoid pregnancy and use medically acceptable method of contraception from at least 30 days prior to the study until 30 days after the study has ended (last study procedure).
• Medically acceptable methods of contraception include non-hormonal intrauterine device or double barrier method (foam or vaginal spermicidal suppository in conjunction with a male condom, diaphragm with spermicide in conjunction with a male condom). Abstinence as a method of contraception is acceptable if it is in line with the preferred and usual lifestyle of the study participant.
• If a female subject becomes pregnant during participation in the study or within 30 days after she has completed her last tacrolimus administration (whichever was administered last), she must inform BPSUSA staff immediately.
• Males who are able to father children must agree to use medically acceptable methods of contraception and not to donate sperm during the study and for 30 days after the end of the study.
• Medically acceptable methods of contraception include using a condom with a female partner of child-bearing potential who is using: oral contraceptives, hormonal patch, implant or injection, intrauterine device, or diaphragm with spermicide.
• If a male subject's partner becomes pregnant during his participation in the study or within 30 days after he has completed his last tacrolimus administration (whichever was administered last), he must inform BPSUSA staff immediately.

You may not qualify if:

• Known history and/or presence of any clinically significant hepatic (e.g., hepatitis, jaundice, hepatic failure, hepatic necrosis, hepatic encephalopathy, biliary tract diseases, cirrhosis), renal/genitourinary (e.g., urethral stricture, any renal impairment), gastrointestinal, cardiovascular (e.g., hypotension including orthostatic hypotension, cor pulmonale, congenital long QT, congestive heart failure, bradyarrhythmias), cerebrovascular, pulmonary (e.g., chronic obstructive pulmonary disease, decreased respiratory reserve, hypoxia, pre-existing respiratory depression), endocrine (e.g., myxedema, hypothyroidism, adrenal cortical insufficiency), immunological, musculoskeletal (e.g., kyphoscoliosis), neurological (e.g., CNS depression or coma, increased cerebrospinal pressure), psychiatric (e.g., psychosis, depression, hallucinations, delirium tremens, suicidal thoughts or behavior), dermatological or hematological (e.g., thrombocytopenic purpura) disease or condition unless determined as not clinically significant by the PI/Sub- Investigator.
• History or presence of any clinically significant gastrointestinal pathology (e.g., chronic diarrhea, inflammatory bowel disease), unresolved gastrointestinal symptoms (e.g., diarrhea, vomiting), or other conditions known to interfere with the absorption, distribution, metabolism or excretion of the drug experienced within 7 days prior to first tacrolimus administration, as determined by the PI/Sub-Investigator.
• Systolic blood pressure outside 90-130 mmHg, inclusive, and diastolic blood pressure outside 55-80 mmHg, inclusive, and heart rate between 50-100 bpm, inclusive, unless deemed otherwise by the PI/Sub-Investigator.
• QTc interval ≥ 440 milliseconds for males and ≥ 460 milliseconds for females, unless deemed otherwise by the PI/Sub-Investigator.
• Abnormal clinical laboratory values unless values are deemed by the PI/Sub- Investigator as "Not Clinically Significant".
• Abnormal vital signs (blood pressure \[BP\], heart rate \[HR\], respiratory rate \[RR\], pulse oximetry and temperature) measurements, unless deemed otherwise by the PI/Sub-Investigator.
• Presence of any clinically significant illness within 30 days prior to first dosing, as determined by the PI/Sub-Investigator.
• Presence of any significant physical or organ abnormality as determined by the PI/Sub-Investigator.
• A positive test result for any of the following: HIV, Hepatitis B surface antigen, Hepatitis C, drugs of abuse (marijuana, amphetamines, barbiturates, cocaine, opiates, phencyclidine and benzodiazepines), and alcohol test. Positive serum or urine pregnancy test for female subjects.
• Known history or presence of:
• Alcohol abuse or dependence within one year prior to first study drug administration;
• Drug abuse or dependence;
• Hypersensitivity or idiosyncratic reaction to tacrolimus, its excipients, and/or related substances;
• Lymphoma and other malignancies (particularly of the skin);
• Bacterial, viral, fungal and protozoal infections (e.g., polyoma virus- associated nephropathy \[PVAN\] due to BK virus infection, JC virus associated progressive multifocal leukoencephalopathy \[PML\], Epstein Barr Virus (EBC) associated Post transplant lymphoproliferative disorder \[PTLD\], cytomegalovirus (CMV) infections associated CMV viremia and CMV disease);

Sponsors & Collaborators

• Food and Drug Administration (FDA): lead
• BioPharma Services Inc.: collaborator

Study Sites (1)

BioPharma Services USA

St Louis, Missouri, 63141, United States

Location

MeSH Terms

Interventions

Tacrolimus

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Wei-Jhe Sun, Ph.D.
• Organization: FDA/CDER/OGD

ORSHSR@fda.hhs.gov

301-796-6176

Study Officials

• Artan Markollari, MD

  BioPharma Services Inc.

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

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

Model Details: a single-dose, randomized, open-label, four-period, two-sequence, two- treatment, single-center, crossover, bioequivalence study

Study Record Dates

• First Submitted: January 15, 2021
• First Posted: January 27, 2021
• Study Start: January 5, 2021
• Primary Completion: May 14, 2021
• Study Completion: June 17, 2021
• Last Updated: September 21, 2023
• Results First Posted: September 21, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Beginning 3 months and ending 5 years following article publication.
• Access Criteria: Researchers who provide a methodologically sound proposal.

Locations

US (1)