Evaluating the Pharmacokinetics of High-Dose Rifapentine When Given as a Single Dose or in Divided Doses to Healthy Adults

NCT01574638 | Completed Phase 1 DMC

• 4 other identifiers: A531111859ACTG5311ACTG 5311
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 4

Brief Summary

This study will evaluate two different ways to give rifapentine (RPT), a drug that may help shorten treatment duration for tuberculosis (TB) disease.

Conditions

Tuberculosis

Outcome Measures

Primary Outcomes (3)

• RPT PK parameter: area under the curve over 24 hours (AUC 0 to 24h)

  Measured in Group 1, when given at a dose of 20 mg/kg once daily (Arm 1B) and when given at a dose of 10 mg/kg twice daily (Arm 1A)

  Measured at Days 14 and 56

• RPT PK parameter: AUC 0 to 24h

  Measured in Group 2, when RPT is given at a dose of 15 mg/kg once daily with a boiled egg (Arm 2A) and at a dose of 15 mg/kg once daily with a low-fat meal (Arm 2B)

  Measured at Days 14 and 56

• Grade 2 or higher signs and symptoms observed while on study beginning with the first dose of study drug and continuing through the follow-up period

  Measured through Day 84

Secondary Outcomes (31)

• RPT PK parameter: maximum observed plasma concentrations (Cmax)

  Measured at Days 14 and 56

• Cmin (trough) values

  Measured at Days 1, 7, 14, 43, 49, 56, 64, and 70

• Metabolizer status of human genetic variants/polymorphisms in gene SLCO1B1 and possibly other genes that are thought to affect PK of RIF

  Measured at Day 0

• RPT PK parameter: minimum observed plasma concentration (Cmin)

  Measured at Days 14 and 56

• RPT PK parameter: oral clearance (CL/F)

  Measured at Days 14 and 56

Study Arms (4)

Arm 1B

EXPERIMENTAL

Participants in Arm 1B will receive RPT based on weight at entry, at a dose of 20 mg/kg once daily with a low-fat breakfast, on Days 1 to 14. Participants will not receive RPT on Days 15 to 42 and will resume receipt of RPT on Days 43 to 56, at a dose of 10 mg/kg twice daily with low-fat meals.

Drug: Rifapentine (RPT)

Arm 1A

EXPERIMENTAL

Participants in Arm 1A will receive RPT based on weight at entry, at a dose of 10 mg/kg twice daily with low-fat meals, on Days 1 to 14. Participants will not receive RPT on Days 15 to 42 and will resume receipt of RPT on Days 43 to 56, at a dose of 20 mg/kg once daily with a low-fat breakfast.

Drug: Rifapentine (RPT)

Arm 2A

EXPERIMENTAL

Participants in Arm 2A will receive RPT based on weight at entry, at a dose of 15 mg/kg once daily with a boiled egg, on Days 1 to 14. Participants will not receive RPT on Days 15 to 42 and will resume receipt of RPT on Days 43 to 70, at a dose of 15 mg/kg once daily with a low-fat breakfast.

Drug: Rifapentine (RPT)

Arm 2B

EXPERIMENTAL

Participants in Arm 2B will receive RPT based on weight at entry, at a dose of 15 mg/kg once daily with a low-fat breakfast, on Days 1 to 14. Participants will not receive RPT on Days 15 to 42 and will resume receipt of RPT on Days 43 to 56, at a dose of 15 mg/kg once daily with a boiled egg.

Drug: Rifapentine (RPT)

Interventions

Rifapentine (RPT) DRUG

Participants will receive 150-mg RPT tablets orally either once or twice daily, with total tablet number/dosage amount varying according to weight at entry and arm assignment and following dosing tables in the protocol.

Arm 1A; Arm 1B; Arm 2A; Arm 2B

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Weight of 50 to 100 kg, inclusive
• Absence of HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit within 21 days prior to study entry. NOTE: The term "licensed" refers to a U.S. FDA-approved kit.
• Females of reproductive potential (defined as women who have not been postmenopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, and do not have documentation of having undergone a sterilization procedure \[e.g., hysterectomy or bilateral oophorectomy or salpingectomy\]) must have a negative serum or urine beta-human choriogonadotropin (β-HCG) pregnancy test performed within 48 hours prior to entry. The urine test must have a sensitivity of at least 25 mlU/mL and be performed at a laboratory with Clinical Laboratory Improvement Amendment (CLIA) certification or its equivalent.
• If participating in sexual activity that could lead to pregnancy, females must agree to use at least one reliable form of contraceptive while receiving the protocol-specified medications and for 1 week after stopping study medications. At least one (but preferably two) of the following contraceptives MUST be used appropriately:
• Condoms (male or female) with or without a spermicidal agent
• Diaphragm or cervical cap with spermicide
• Intrauterine device (IUD)
• NOTE: Hormone-based contraceptives are contraindicated with RPT and therefore may not be used as a form of contraception during this study.
• Ability and willingness of volunteer to provide written informed consent
• Laboratory values obtained within 21 days prior to entry:
• Serum alanine aminotransferase (ALT) less than or equal to 1.2 times the upper limit of normal (ULN)
• Total bilirubin level less than or equal to 1.2 times the ULN
• Serum creatinine less than or equal to 1.5 mg/dL
• Hemoglobin greater than or equal to 12.0 g/dL for men, greater than or equal to 11.0 g/dL for women
• Platelet count greater than or equal to 125,000/mm\^3

You may not qualify if:

• Breastfeeding
• Within 30 days prior to entry, use of any prescription medication known to inhibit or induce cytochrome P (CYP)3A metabolizing enzymes (refer to the manufacturers' package inserts for individual drugs). See list posted on the A5311 protocol-specific webpage (PSWP).
• Known intolerance of or allergy to chicken eggs
• Use of rifamycin antibiotics within 60 days prior to entry
• Planned use during the study of prescription medications, herbal supplements, nutritional supplements, or over-the-counter medications except as follows: multivitamins, acetaminophen (up to 650 mg every 6 hours as an analgesic), ibuprofen (up to 600 mg twice daily), naproxen (up to 500 mg twice daily for pain or headache), and Benadryl (diphenhydramine, up to 25 mg daily for insomnia or seasonal allergies) are permitted. The use of topical or locally-acting drugs (e.g., eye drops, IUDs, skin ointments) will be considered on a case-by-case basis.
• Within 14 days prior to study entry, hospitalization for any reason or pharmacotherapy for serious illness
• Within 14 days prior to study entry, use of any prescription medication(s)
• Receipt of any investigational study drug within 21 days prior to study entry
• Known allergy/sensitivity or any hypersensitivity to rifamycins, including rifampin, rifabutin, and rifapentine
• Presence of any condition interfering with normal gastrointestinal anatomy or motility that could interfere with drug absorption or excretion (including cholecystectomy, peptic ulceration, inflammatory bowel disease, or pancreatitis)
• History or evidence of clinically significant (as determined by site investigator) cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, psychiatric, endocrine, or immunologic disease(s)
• Any medical condition that, in the opinion of the site investigator, would interfere with the participant's ability to participate in the study
• Active illicit drug use or dependence or alcohol dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements
• History of TB infection or site investigator suspicion of current active TB
• Inability to abstain from grapefruit and grapefruit juice for the duration of the study

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (4)

UCSD Antiviral Research Center CRS

San Diego, California, 92103, United States

Location

Johns Hopkins University CRS

Baltimore, Maryland, 21205, United States

Location

Chapel Hill CRS

Chapel Hill, North Carolina, 27599, United States

Location

Vanderbilt Therapeutics (VT) CRS

Nashville, Tennessee, 37204, United States

Location

Related Publications (3)

• Zvada SP, Van Der Walt JS, Smith PJ, Fourie PB, Roscigno G, Mitchison D, Simonsson US, McIlleron HM. Effects of four different meal types on the population pharmacokinetics of single-dose rifapentine in healthy male volunteers. Antimicrob Agents Chemother. 2010 Aug;54(8):3390-4. doi: 10.1128/AAC.00345-10. Epub 2010 Jun 1.

  PMID: 20516273 BACKGROUND

• Benator D, Bhattacharya M, Bozeman L, Burman W, Cantazaro A, Chaisson R, Gordin F, Horsburgh CR, Horton J, Khan A, Lahart C, Metchock B, Pachucki C, Stanton L, Vernon A, Villarino ME, Wang YC, Weiner M, Weis S; Tuberculosis Trials Consortium. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet. 2002 Aug 17;360(9332):528-34. doi: 10.1016/s0140-6736(02)09742-8.

  PMID: 12241657 BACKGROUND

• Dooley KE, Savic RM, Park JG, Cramer Y, Hafner R, Hogg E, Janik J, Marzinke MA, Patterson K, Benson CA, Hovind L, Dorman SE, Haas DW; ACTG A5311 Study Team. Novel dosing strategies increase exposures of the potent antituberculosis drug rifapentine but are poorly tolerated in healthy volunteers. Antimicrob Agents Chemother. 2015;59(6):3399-405. doi: 10.1128/AAC.05128-14. Epub 2015 Mar 30.

  PMID: 25824215 DERIVED

MeSH Terms

Conditions

Tuberculosis

Interventions

rifapentine

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 6, 2012
• First Posted: April 10, 2012
• Study Start: June 1, 2012
• Primary Completion: June 1, 2013
• Study Completion: June 1, 2013
• Last Updated: November 5, 2021

Record last verified: 2015-10

Locations

US (4)