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Pharmacokinetics, Safety and Tolerability of Escalating Rifapentine Doses in Healthy Volunteers (TBTC S29B)

This study has been completed.
Sponsor:
Collaborators:
Sanofi
Information provided by (Responsible Party):
Susan E. Dorman, Johns Hopkins University
ClinicalTrials.gov Identifier:
NCT01162486
First received: July 13, 2010
Last updated: April 1, 2013
Last verified: April 2013
  Purpose

The aim of this study is to evaluate (1) the safety and tolerability of escalating doses of rifapentine (RPT) administered daily by oral; (2) the effect of increasing doses of RPT on cytochrome P450 isoform 3A (CYP3A) enzyme metabolizing activity, using single-dose midazolam (MDZ); and (3) the effect of increasing doses of RPT on autoinduction of RPT metabolism.


Condition Intervention Phase
Tuberculosis
Tuberculosis, Pulmonary
Drug: Rifampin & midazolam
Drug: rifapentine & midazolam
Drug: rifapentine and midazolam
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Dose Escalation Study of the Pharmacokinetics, Safety and Tolerability of Rifapentine and the Effects of Increasing Doses of Rifapentine on Induction of Metabolizing Enzymes in Healthy Volunteers

Resource links provided by NLM:


Further study details as provided by Johns Hopkins University:

Primary Outcome Measures:
  • Safety [ Time Frame: days: 3, 7, 10, 14, 15, 17, 26 ] [ Designated as safety issue: Yes ]
    To determine the safety of escalating doses, from 5 mg/kg to 20 mg/kg of daily rifapentine administered orally for 14 days in healthy volunteers

  • Pharmacokinetics [ Time Frame: days: 2, 3, 7, 10, 15, 16, 17, 18 ] [ Designated as safety issue: No ]
    To determine and compare the steady-state pharmacokinetics and dose linearity of escalating daily doses of rifapentine in dose cohorts of 5 mg/kg, 10 mg/kg, 15 mg/kg and 20 mg/kg in healthy volunteers


Secondary Outcome Measures:
  • autoinduction [ Time Frame: days: 2, 3, 7, 10, 15, 16, 17, 18 ] [ Designated as safety issue: No ]
    To evaluate for evidence of autoinduction of metabolism by rifapentine

  • midazolam [ Time Frame: days: 1, 15 ] [ Designated as safety issue: No ]
    To compare and describe, the pharmacokinetics of single-dose midazolam alone versus midazolam co-administered with either steady-state rifapentine at multiple daily doses (5, 10, 15, and 20 mg/kg) or rifampin at 10 mg/kg daily

  • transporter genes [ Time Frame: day 3 ] [ Designated as safety issue: No ]
    To determine the effects of polymorphisms of transporter genes on rifampin and rifapentine PK parameters

  • dried blood spots [ Time Frame: days 2, 3, 7, 10, 15, 16, 17, 18 ] [ Designated as safety issue: No ]
    To develop methods for determination of rifapentine concentrations from dried blood spots on sampling paper


Enrollment: 37
Study Start Date: April 2010
Study Completion Date: March 2011
Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Rifampin control
Rifampin + midazolam
Drug: Rifampin & midazolam
rifampin - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
Experimental: RPT 1
RPT Cohort 1 - 5 mg/kg
Drug: rifapentine & midazolam
rifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
Experimental: RPT 2
RPT Cohort 2 - 10 mg/kg
Drug: rifapentine & midazolam
rifapentine - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
Experimental: RPT 3
RPT Cohort 3 - 15 mg/kg
Drug: rifapentine & midazolam
rifapentine - tablet, 15 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
Experimental: RPT 4
RPT Cohort 4 - 20 mg/kg
Drug: rifapentine and midazolam
rifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
Experimental: RPT 5
RPT Cohort 5 - Maximal tolerated dose, if dose limiting toxicities are observed
Drug: rifapentine and midazolam
rifapentine - tablet, 2.5 mg/kg lower than previously tolerated dose cohort, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15

Detailed Description:

On day 1, volunteers will receive a single dose of MDZ dosed at 15 mg delivered orally, and a 24-hour PK analysis of MDZ and its metabolite, 1-OH-midazolam (1-OH-MDZ) will be performed. RPT (or RIF) will be given as a single daily dose (5, 10, 15, or 20 mg/kg, depending on the dose cohort) on days 2-15 (14 doses). A 24-hour PK analysis of RPT (or RIF) and its 25-deacetyl metabolite (25-des-RPT) will be performed after the first dose (day 2). On day 15, volunteers receive a second single dose of MDZ. A 72-hour RPT (or RIF) and 24-hour MDZ (and 1-OH-MDZ) PK analysis will be performed after the second dose of MDZ beginning on day 15. The PK sampling will occur both on an in-patient basis in the General Clinical Research Center (GCRC) and on an out-patient basis in the study clinic. Volunteers will undergo assessments for adverse events (AEs) several times throughout the study.

Each dose cohort will contain 6 subjects. RPT dosing will begin at 5 mg/kg (6 volunteers) and increase by 5 mg/kg increments (6 volunteers each at 10, 15, and 20 mg/kg) to a maximum dose of 20 mg/kg unless dose-limiting toxicities (DLT) are seen in two or more patients within a dose cohort, in which case a dose that is 2.5 mg/kg lower than the previous dose will be enrolled to determine the maximal tolerated dose (MTD). In addition, one cohort of 6 subjects will receive RIF at 10 mg/kg daily, rather than RPT, as a comparator arm.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Ability and willingness to provide written informed consent.
  2. Age greater than or equal to 18 years, and less than or equal to 65 years.
  3. Weight of 50-100 kg for enrollment into the RPT cohorts
  4. Weight of 50-80 kg for enrollment into the RIF cohort
  5. Within 28 or fewer days prior to enrollment, a complete blood count with differential, comprehensive serum chemistry profile, HIV antibody test, and Hepatitis C antibody test will be performed, with the following laboratory values:

    1. Serum amino aspartate transferase (AST) less than the upper limit of normal
    2. Total bilirubin level less than the upper limit of normal
    3. Serum creatinine <1.5 mg/dL
    4. Hemoglobin greater than 12.0 for men, greater than 11.0 for women
    5. Platelet count greater than or equal to 125,000 /cu mm
    6. Absolute neutrophil count greater than or equal to 1250 /cu mm
    7. Serum albumin greater than 3.5 g/dL
    8. HIV antibody test negative
    9. Hepatitis C antibody negative
  6. For women of childbearing potential, a negative serum bHCG pregnancy test, performed at screening.
  7. During the study and for 14 days after the last dose of study medication, women of childbearing potential must agree to practice barrier contraception for the duration of the study.

Exclusion Criteria:

  1. Pregnant or breastfeeding
  2. Known intolerance of or allergy to rifamycins
  3. Allergy to benzodiazepines
  4. Use of rifamycin antibiotics in the 30 days prior to enrollment
  5. Inability to take oral medications
  6. Renal, hepatic, cardiac (except benign heart murmur), or endocrine disorder; or malignancy; or immunocompromise.
  7. History of any acute or chronic illness that requires current medical therapy.
  8. Prior gastrointestinal surgery involving stomach, biliary system, pancreas, or small intestine.
  9. Any medical condition that, in the opinion of the investigator, would interfere with the subject's ability to participate in the protocol.
  10. Any illicit drug use within the preceding 2 months. Subjects must agree to abstain from alcohol and illicit drug use during the study. Smokers must agree to abstain from cigarettes or to smoke fewer than 5 cigarettes per day.
  11. Current use of any prescription medication(s), including oral contraceptives.
  12. Planned use, during the study from Day 0 through the last PK blood draw, of any of the following: prescription medication(s), herbal supplement(s), vitamin(s), mineral supplement(s), over-the-counter medication(s), or grapefruit juice. Subjects must agree to abstain from grapefruit juice during the study.
  13. Participation in any other investigational drug study within 30 days prior to study entry and during study.
  14. Inability to participate in pharmacokinetic visits
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01162486

Locations
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287
Sponsors and Collaborators
Johns Hopkins University
Sanofi
Investigators
Principal Investigator: Kelly Dooley, MD, PhD Johns Hopkins University
Principal Investigator: Susan Dorman, MD Johns Hopkins Univeristy
  More Information

No publications provided by Johns Hopkins University

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Susan E. Dorman, Associate Professor, Johns Hopkins University
ClinicalTrials.gov Identifier: NCT01162486     History of Changes
Other Study ID Numbers: CDC-NCHHSTP-5779
Study First Received: July 13, 2010
Last Updated: April 1, 2013
Health Authority: United States: Food and Drug Administration
United States: Federal Government

Keywords provided by Johns Hopkins University:
Anti-infective agents
Anti-bacterial agents
Rifampin
Rifapentine
Midazolam
Molecular mechanisms of pharmacological action
Antitubercular agents
Pharmacologic actions

Additional relevant MeSH terms:
Tuberculosis
Tuberculosis, Pulmonary
Actinomycetales Infections
Bacterial Infections
Gram-Positive Bacterial Infections
Lung Diseases
Mycobacterium Infections
Respiratory Tract Diseases
Respiratory Tract Infections
Midazolam
Molecular Mechanisms of Pharmacological Action
Rifampin
Rifapentine
Adjuvants, Anesthesia
Anesthetics
Anesthetics, General
Anesthetics, Intravenous
Anti-Anxiety Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antitubercular
Antitubercular Agents
Central Nervous System Agents
Central Nervous System Depressants
Enzyme Inhibitors
GABA Agents
GABA Modulators
Hypnotics and Sedatives
Leprostatic Agents
Neurotransmitter Agents

ClinicalTrials.gov processed this record on November 20, 2014