Tuberculosis, Tuberculosis, Pulmonary
Conditions
Keywords
Anti-infective agents, Anti-bacterial agents, Rifampin, Rifapentine, Midazolam, Molecular mechanisms of pharmacological action, Antitubercular agents, Pharmacologic actions
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.
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.
Interventions
DRUGRifampin & midazolam
rifampin - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
DRUGrifapentine & midazolam
rifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
DRUGrifapentine and midazolam
rifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15
Sponsors
Sanofi
Centers for Disease Control and Prevention
Johns Hopkins University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Grade 2 or Higher Adverse Events Over the Course of the 26 Day Trial | 26 days | Number of Participants with Grade 2 or higher adverse events over 26 days |
| Pharmacokinetics (AUC of RPT Over 24 Hours Post-dose) | days: 2, 15 | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Midazolam, AUC Over 12 Hours Post-dose | days: 1, 15 | To compare and describe, the pharmacokinetics of single-dose midazolam alone (Day 1) 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 (Day 15) |
| Transporter Genes | day 3 | To determine the effects of polymorphisms of transporter genes on rifampin and rifapentine PK parameters |
| Rifapentine Concentrations From Dried Blood Spots | days 2, 3, 7, 10, 15, 16, 17, 18 | To develop methods for determination of rifapentine concentrations from dried blood spots on sampling paper |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rifampin Control Rifampin + midazolam
Rifampin & midazolam: rifampin - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15 | 8 |
| RPT 1 RPT Cohort 1 - 5 mg/kg
rifapentine & midazolam: rifapentine - tablet, 5 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15 | 7 |
| RPT 2 RPT Cohort 2 - 10 mg/kg
rifapentine & midazolam: rifapentine - tablet, 10 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15 | 7 |
| RPT 3 RPT Cohort 3 - 15 mg/kg
rifapentine & midazolam: rifapentine - tablet, 15 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15 | 7 |
| RPT 4 RPT Cohort 4 - 20 mg/kg
rifapentine and midazolam: rifapentine - tablet, 20 mg/kg, daily 15 days midazolam - liquid syrup, 15 mg, days 1 and 15 | 8 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | elevated LFTs | 0 | 0 | 1 | 0 | 0 |
| Overall Study | low ANC | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Pregnancy | 0 | 0 | 0 | 1 | 0 |
| Overall Study | vomited Rifampin/ gagged with midazolam | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | RPT 1 | RPT 2 | RPT 3 | Rifampin Control | RPT 4 | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 7 Participants | 7 Participants | 8 Participants | 8 Participants | 37 Participants |
| Age, Continuous | 50 years | 44 years | 41 years | 39 years | 47 years | 44 years |
| Region of Enrollment United States | 7 participants | 7 participants | 7 participants | 8 participants | 8 participants | 37 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 3 Participants | 1 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 4 Participants | 7 Participants | 7 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 7 | 0 / 6 |
| other Total, other adverse events | 5 / 8 | 2 / 6 | 3 / 6 | 4 / 7 | 2 / 6 |
| serious Total, serious adverse events | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 7 | 0 / 6 |
Outcome results
Primary
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
Time frame: 26 days
Population: Four withdrew prior to receiving study rifamycin so were not included in the safety population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rifampin Control | Number of Participants With Grade 2 or Higher Adverse Events Over the Course of the 26 Day Trial | 1 Participants |
| RPT 1 | Number of Participants With Grade 2 or Higher Adverse Events Over the Course of the 26 Day Trial | 0 Participants |
| RPT 2 | Number of Participants With Grade 2 or Higher Adverse Events Over the Course of the 26 Day Trial | 1 Participants |
| RPT 3 | Number of Participants With Grade 2 or Higher Adverse Events Over the Course of the 26 Day Trial | 1 Participants |
| RPT 4 | Number of Participants With Grade 2 or Higher Adverse Events Over the Course of the 26 Day Trial | 0 Participants |
Primary
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)
Time frame: days: 2, 15
Population: These patients completed PK visits on Day 2 and 15 (Three participants in this non-control group - subdivided into 4- did not complete the study). Reasons provided in the participant flow session
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Rifampin Control | Pharmacokinetics (AUC of RPT Over 24 Hours Post-dose) | RPT AUC, Day 2 single dose | 128 (mcg*h/ml) |
| Rifampin Control | Pharmacokinetics (AUC of RPT Over 24 Hours Post-dose) | RPT AUC, Day 15 multiple dose | 218 (mcg*h/ml) |
| RPT 1 | Pharmacokinetics (AUC of RPT Over 24 Hours Post-dose) | RPT AUC, Day 15 multiple dose | 330 (mcg*h/ml) |
| RPT 1 | Pharmacokinetics (AUC of RPT Over 24 Hours Post-dose) | RPT AUC, Day 2 single dose | 242 (mcg*h/ml) |
| RPT 2 | Pharmacokinetics (AUC of RPT Over 24 Hours Post-dose) | RPT AUC, Day 2 single dose | 363 (mcg*h/ml) |
| RPT 2 | Pharmacokinetics (AUC of RPT Over 24 Hours Post-dose) | RPT AUC, Day 15 multiple dose | 560 (mcg*h/ml) |
| RPT 3 | Pharmacokinetics (AUC of RPT Over 24 Hours Post-dose) | RPT AUC, Day 2 single dose | 403 (mcg*h/ml) |
| RPT 3 | Pharmacokinetics (AUC of RPT Over 24 Hours Post-dose) | RPT AUC, Day 15 multiple dose | 483 (mcg*h/ml) |
Secondary
Midazolam, AUC Over 12 Hours Post-dose
To compare and describe, the pharmacokinetics of single-dose midazolam alone (Day 1) 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 (Day 15)
Time frame: days: 1, 15
Population: 29 participants completed both midazolam PK visits; one person in RPT1 visit was not analyzed because his samples were zero and was found to have been non-compliant with regimen
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Rifampin Control | Midazolam, AUC Over 12 Hours Post-dose | AUC 0-12 Midazolam alone (Day 1) | 151 ng*h/ml |
| Rifampin Control | Midazolam, AUC Over 12 Hours Post-dose | AUC 0-12 Midazolam with RIF (Day 15) | 26.9 ng*h/ml |
| RPT 1 | Midazolam, AUC Over 12 Hours Post-dose | AUC 0-12 Midazolam alone (Day 1) | 150 ng*h/ml |
| RPT 1 | Midazolam, AUC Over 12 Hours Post-dose | AUC 0-12 Midazolam with RIF (Day 15) | 14.2 ng*h/ml |
| RPT 2 | Midazolam, AUC Over 12 Hours Post-dose | AUC 0-12 Midazolam alone (Day 1) | 114 ng*h/ml |
| RPT 2 | Midazolam, AUC Over 12 Hours Post-dose | AUC 0-12 Midazolam with RIF (Day 15) | 10.2 ng*h/ml |
| RPT 3 | Midazolam, AUC Over 12 Hours Post-dose | AUC 0-12 Midazolam with RIF (Day 15) | 14.0 ng*h/ml |
| RPT 3 | Midazolam, AUC Over 12 Hours Post-dose | AUC 0-12 Midazolam alone (Day 1) | 204 ng*h/ml |
| RPT 4 | Midazolam, AUC Over 12 Hours Post-dose | AUC 0-12 Midazolam alone (Day 1) | 173 ng*h/ml |
| RPT 4 | Midazolam, AUC Over 12 Hours Post-dose | AUC 0-12 Midazolam with RIF (Day 15) | 11.7 ng*h/ml |
Secondary
Rifapentine Concentrations From Dried Blood Spots
To develop methods for determination of rifapentine concentrations from dried blood spots on sampling paper
Time frame: days 2, 3, 7, 10, 15, 16, 17, 18
Population: This outcome was not assessed because data was not collected
Secondary
Transporter Genes
To determine the effects of polymorphisms of transporter genes on rifampin and rifapentine PK parameters
Time frame: day 3
Population: This outcome was not assessed because data was not collected