Pharmacokinetics, Safety and Tolerability of Escalating Rifapentine Doses in Healthy Volunteers

NCT01162486 | Completed Phase 1 Results DMC

• 1 other identifier: CDC-NCHHSTP-5779
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Tuberculosis; Tuberculosis, Pulmonary

Keywords

Anti-infective agents; Anti-bacterial agents; Rifampin; Rifapentine; Midazolam; Molecular mechanisms of pharmacological action; Antitubercular agents; Pharmacologic actions

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Grade 2 or Higher Adverse Events Over the Course of the 26 Day Trial

  Number of Participants with Grade 2 or higher adverse events over 26 days

  26 days

• Pharmacokinetics (AUC of RPT Over 24 Hours Post-dose)

  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 after a single dose (Day 2) or multiple doses (Day 15)

  days: 2, 15

Secondary Outcomes (3)

• Midazolam, AUC Over 12 Hours Post-dose

  days: 1, 15

• Transporter Genes

  day 3

• Rifapentine Concentrations From Dried Blood Spots

  days 2, 3, 7, 10, 15, 16, 17, 18

Study Arms (6)

Rifampin control

ACTIVE COMPARATOR

Rifampin + midazolam

Drug: Rifampin & midazolam

RPT 1

EXPERIMENTAL

RPT Cohort 1 - 5 mg/kg

Drug: rifapentine & midazolam

RPT 2

EXPERIMENTAL

RPT Cohort 2 - 10 mg/kg

Drug: rifapentine & midazolam

RPT 3

EXPERIMENTAL

RPT Cohort 3 - 15 mg/kg

Drug: rifapentine & midazolam

RPT 4

EXPERIMENTAL

RPT Cohort 4 - 20 mg/kg

Drug: rifapentine and midazolam

RPT 5

EXPERIMENTAL

RPT Cohort 5 - Maximal tolerated dose, if dose limiting toxicities are observed

Drug: rifapentine and midazolam

Interventions

Rifampin & midazolam DRUG

rifampin - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15

Rifampin control

rifapentine & midazolam DRUG

rifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15

RPT 1

rifapentine and midazolam DRUG

rifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15

RPT 4

Eligibility Criteria

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

You may qualify if:

• Ability and willingness to provide written informed consent.
• Age greater than or equal to 18 years, and less than or equal to 65 years.
• Weight of 50-100 kg for enrollment into the RPT cohorts
• Weight of 50-80 kg for enrollment into the RIF cohort
• 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:
• Serum amino aspartate transferase (AST) less than the upper limit of normal
• Total bilirubin level less than the upper limit of normal
• Serum creatinine \<1.5 mg/dL
• Hemoglobin greater than 12.0 for men, greater than 11.0 for women
• Platelet count greater than or equal to 125,000 /cu mm
• Absolute neutrophil count greater than or equal to 1250 /cu mm
• Serum albumin greater than 3.5 g/dL
• HIV antibody test negative
• Hepatitis C antibody negative
• For women of childbearing potential, a negative serum bHCG pregnancy test, performed at screening.

You may not qualify if:

• Pregnant or breastfeeding
• Known intolerance of or allergy to rifamycins
• Allergy to benzodiazepines
• Use of rifamycin antibiotics in the 30 days prior to enrollment
• Inability to take oral medications
• Renal, hepatic, cardiac (except benign heart murmur), or endocrine disorder; or malignancy; or immunocompromise.
• History of any acute or chronic illness that requires current medical therapy.
• Prior gastrointestinal surgery involving stomach, biliary system, pancreas, or small intestine.
• Any medical condition that, in the opinion of the investigator, would interfere with the subject's ability to participate in the protocol.
• 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.
• Current use of any prescription medication(s), including oral contraceptives.
• 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.
• Participation in any other investigational drug study within 30 days prior to study entry and during study.
• Inability to participate in pharmacokinetic visits

Sponsors & Collaborators

• Johns Hopkins University: lead
• Sanofi: collaborator
• Centers for Disease Control and Prevention: collaborator

Study Sites (1)

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Related Publications (1)

• Savic RM, Lu Y, Bliven-Sizemore E, Weiner M, Nuermberger E, Burman W, Dorman SE, Dooley KE. Population pharmacokinetics of rifapentine and desacetyl rifapentine in healthy volunteers: nonlinearities in clearance and bioavailability. Antimicrob Agents Chemother. 2014 Jun;58(6):3035-42. doi: 10.1128/AAC.01918-13. Epub 2014 Mar 10.

  PMID: 24614383 DERIVED

MeSH Terms

Conditions

Tuberculosis; Tuberculosis, Pulmonary

Interventions

Rifampin; Midazolam; rifapentine

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring

Results Point of Contact

• Title: Dr. Kelly E. Dooley
• Organization: Johns Hopkins University School of Medicine

kdooley1@jhmi.edu

410-955-3100

Study Officials

• Kelly Dooley, MD, PhD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

• Susan Dorman, MD

  Johns Hopkins Univeristy

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

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

Study Record Dates

• First Submitted: July 13, 2010
• First Posted: July 14, 2010
• Study Start: April 1, 2010
• Primary Completion: February 1, 2011
• Study Completion: March 1, 2011
• Last Updated: May 7, 2019
• Results First Posted: May 7, 2019

Record last verified: 2019-01

Locations

US (1)