Pharmacokinetic and Pharmacodynamic Study of High-Dose Rifapentine and Moxifloxacin for Treatment of Tuberculosis

NCT02563327 | Completed Phase 3

• 1 other identifier: CDC-NCHHSTP-6719
• Study Type: interventional
• Target: 53
• Locations: 3 countries
• Sites: 3

Brief Summary

The Tuberculosis Trials Consortium (TBTC) phase 3 treatment trial, Study 31, will investigate the efficacy and safety of daily rifapentine (1200 mg daily) with or without moxifloxacin as part of multidrug treatment regimens for drug-sensitive pulmonary TB. The proposed study (Study 31 PK/PD) will examine the population pharmacokinetics and pharmacodynamics (PK/PD) of high-dose daily rifapentine with and without moxifloxacin given for 17 weeks. Two different PK sampling procedures are required for the population PK/PD assessments involving rifapentine and moxifloxacin: (1) intensive sampling of 6 samples/participant on one occasion plus subsequent sparse sampling for a subset of Study 31 participants who are invited to co-enroll in Study 31 PK/PD; and (2) sparse sampling of 2-3 samples/participant for all other Study 31 trial participants (these data will be collected as part of the Study 31 treatment protocol). Herein, we describe the PK sampling to be conducted among those Study 31 participants who are co-enrolled to Study 31 PK/PD (n=60). Intensive PK sampling is needed in some participants to estimate the population PK model parameters with no bias and satisfactory precision (relative standard error \< 20%). PK and outcomes data from all participants in Study 31 will be merged to build the population PK/PD models to evaluate PK/PD parameters. Details regarding these planned analyses are also provided in this Study 31 PK/PD protocol. Primary Objectives:

1. 1.Characterize the population pharmacokinetics of rifapentine and 25-desacetyl rifapentine, using sparse PK data from Study 31 and intensive PK data from Study 31 PK/PD. Using the population PK model, determine post-hoc Bayesian estimates of individual-level PK parameters.
2. 2.Examine the relationship between rifapentine PK parameters of interest and treatment efficacy. PK parameters will include area under the concentration time curve (AUC0-24), peak concentration (Cmax), time above the mean inhibitory concentration (MIC), and AUC/MIC. The treatment outcome of interest will be time to culture conversion and time to treatment failure or relapse.
3. 3.Among the Study 31 participants in the lowest 10% for rifapentine AUC0-24, examine the PK/PD effect on culture conversion of sputa after completion of 4 months of daily rifapentine therapy.
4. 4.Examine the relationship between safety outcomes (Grade 3 or higher adverse events) and rifapentine PK parameters (AUC0-24, Cmax, AUC0-24/MIC and time above MIC).
5. 5.Characterize the population PK of moxifloxacin, and then estimate moxifloxacin AUC0-24 and Cmax when moxifloxacin is administered with rifapentine given at a daily dose of 1200 mg.
6. 6.Examine the relationships between moxifloxacin PK and treatment outcomes (as described in objective 2 for rifapentine) and moxifloxacin PK and safety (as described in objective 4 for rifapentine).

Conditions

Tuberculosis

Keywords

Pharmacokinetics

Outcome Measures

Primary Outcomes (2)

• TB disease-free survival at twelve months after study treatment assignment

  Twelve months after treatment assignment

• Proportion of participants with grade 3 or higher adverse events during study drug treatment

  Four or six months

Study Arms (3)

Standard Therapy

ACTIVE COMPARATOR

Eight weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol, followed by Eighteen weeks of daily treatment with rifampin and isoniazid. All drugs are administered orally, seven days/week, directly observed by a health care worker at least five of the seven days each week. Pyridoxine (vitamin B6), 25 or 50 mg, is administered with each study dose. Study drug doses: rifampin, 600 mg; isoniazid, 300 mg; pyrazinamide, \< 55kg 1000 mg, \>= 55-75 kg 1500 mg, \>75 kg 2000 mg; ethambutol, \< 55kg 800 mg, \>= 55-75 kg 1200 mg, \>75 kg 1600 mg.

Drug: Rifampin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol; Dietary Supplement: Pyridoxine

Rifapentine-containing Regimen

EXPERIMENTAL

Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and ethambutol, followed by Nine weeks of daily treatment with rifapentine and isoniazid. All drugs are administered orally, seven days/week, directly observed by a health care worker at least five of the seven days each week. Pyridoxine (vitamin B6), 25 or 50 mg, is administered with each study dose. Study drug doses: rifapentine 1200 mg; isoniazid, 300 mg; pyrazinamide, \< 55kg 1000 mg, \>= 55-75 kg 1500 mg, \>75 kg 2000 mg; ethambutol, \< 55kg 800 mg, \>= 55-75 kg 1200 mg, \>75 kg 1600 mg.

Drug: Rifapentine; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol; Dietary Supplement: Pyridoxine

Rifapentine- and Moxifloxacin-containing Regimen

EXPERIMENTAL

Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and moxifloxacin, followed by Nine weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin. All drugs are administered orally, seven days/week, directly observed by a health care worker at least five of the seven days each week. Pyridoxine (vitamin B6), 25 or 50 mg, is administered with each study dose. Study drug doses: rifapentine 1200 mg; isoniazid, 300 mg; pyrazinamide, \< 55kg 1000 mg, \>= 55-75 kg 1500 mg, \>75 kg 2000 mg; moxifloxacin, 400 mg.

Drug: Rifapentine; Drug: Moxifloxacin; Drug: Isoniazid; Drug: Pyrazinamide; Dietary Supplement: Pyridoxine

Interventions

Rifapentine DRUG

A rifamycin with activity against Mycobacterium tuberculosis

Also known as: Priftin

Rifapentine- and Moxifloxacin-containing Regimen; Rifapentine-containing Regimen

Moxifloxacin DRUG

A fluoroquinolone

Rifapentine- and Moxifloxacin-containing Regimen

Rifampin DRUG

A rifamycin with activity against Mycobacterium tuberculosis

Standard Therapy

Isoniazid DRUG

An anti-tuberculosis agent

Rifapentine- and Moxifloxacin-containing Regimen; Rifapentine-containing Regimen; Standard Therapy

Pyrazinamide DRUG

An anti-tuberculosis agent

Rifapentine- and Moxifloxacin-containing Regimen; Rifapentine-containing Regimen; Standard Therapy

Ethambutol DRUG

An anti-tuberculosis agent

Rifapentine-containing Regimen; Standard Therapy

Pyridoxine DIETARY_SUPPLEMENT

An essential vitamin

Also known as: Vitamin B6

Rifapentine- and Moxifloxacin-containing Regimen; Rifapentine-containing Regimen; Standard Therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 years or greater
• Enrolled in TBTC Study 31
• Randomized to receive one of the rifapentine treatment regimens.
• Willingness to be sampled 6 times during 1 PK sampling session and 2 - 3 times during another PK sampling session at an outpatient clinic, a clinical research center, or a hospital.
• Written informed consent given for the Study 31 PK/PD study

You may not qualify if:

• Hematocrit \< 25% most recent value, measured within 30 days before PK/PD study enrollment

Sponsors & Collaborators

• Centers for Disease Control and Prevention: lead
• Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections: collaborator

Study Sites (3)

University of Texas Health Science Center at

San Antonio, Texas, United States

Location

Joint Clinical Research Centre/ Makerere Univ Med Sch

Kampala, Uganda

Location

National TB Program

Hanoi, Vietnam

Location

Related Publications (23)

• Ballow C, Lettieri J, Agarwal V, Liu P, Stass H, Sullivan JT. Absolute bioavailability of moxifloxacin. Clin Ther. 1999 Mar;21(3):513-22. doi: 10.1016/S0149-2918(00)88306-X.

  PMID: 10321420 BACKGROUND

• Burman WJ, Gallicano K, Peloquin C. Comparative pharmacokinetics and pharmacodynamics of the rifamycin antibacterials. Clin Pharmacokinet. 2001;40(5):327-41. doi: 10.2165/00003088-200140050-00002.

  PMID: 11432536 BACKGROUND

• Conde MB, Efron A, Loredo C, De Souza GR, Graca NP, Cezar MC, Ram M, Chaudhary MA, Bishai WR, Kritski AL, Chaisson RE. Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase II trial. Lancet. 2009 Apr 4;373(9670):1183-9. doi: 10.1016/S0140-6736(09)60333-0.

  PMID: 19345831 BACKGROUND

• Dooley K, Flexner C, Hackman J, Peloquin CA, Nuermberger E, Chaisson RE, Dorman SE. Repeated administration of high-dose intermittent rifapentine reduces rifapentine and moxifloxacin plasma concentrations. Antimicrob Agents Chemother. 2008 Nov;52(11):4037-42. doi: 10.1128/AAC.00554-08. Epub 2008 Sep 2.

  PMID: 18765687 BACKGROUND

• Dooley KE, Bliven-Sizemore EE, Weiner M, Lu Y, Nuermberger EL, Hubbard WC, Fuchs EJ, Melia MT, Burman WJ, Dorman SE. Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers. Clin Pharmacol Ther. 2012 May;91(5):881-8. doi: 10.1038/clpt.2011.323.

  PMID: 22472995 BACKGROUND

• Dorman SE, Goldberg S, Stout JE, Muzanyi G, Johnson JL, Weiner M, Bozeman L, Heilig CM, Feng PJ, Moro R, Narita M, Nahid P, Ray S, Bates E, Haile B, Nuermberger EL, Vernon A, Schluger NW; Tuberculosis Trials Consortium. Substitution of rifapentine for rifampin during intensive phase treatment of pulmonary tuberculosis: study 29 of the tuberculosis trials consortium. J Infect Dis. 2012 Oct 1;206(7):1030-40. doi: 10.1093/infdis/jis461. Epub 2012 Jul 30.

  PMID: 22850121 BACKGROUND

• Dorman SE, Savic RM, Goldberg S, Stout JE, Schluger N, Muzanyi G, Johnson JL, Nahid P, Hecker EJ, Heilig CM, Bozeman L, Feng PJ, Moro RN, MacKenzie W, Dooley KE, Nuermberger EL, Vernon A, Weiner M; Tuberculosis Trials Consortium. Daily rifapentine for treatment of pulmonary tuberculosis. A randomized, dose-ranging trial. Am J Respir Crit Care Med. 2015 Feb 1;191(3):333-43. doi: 10.1164/rccm.201410-1843OC.

  PMID: 25489785 BACKGROUND

• Horne DJ, Royce SE, Gooze L, Narita M, Hopewell PC, Nahid P, Steingart KR. Sputum monitoring during tuberculosis treatment for predicting outcome: systematic review and meta-analysis. Lancet Infect Dis. 2010 Jun;10(6):387-94. doi: 10.1016/S1473-3099(10)70071-2.

  PMID: 20510279 BACKGROUND

• Keung AC, Eller MG, Weir SJ. Single-dose pharmacokinetics of rifapentine in women. J Pharmacokinet Biopharm. 1998 Feb;26(1):75-85. doi: 10.1023/a:1023276808298.

  PMID: 9773393 BACKGROUND

• Lettieri J, Vargas R, Agarwal V, Liu P. Effect of food on the pharmacokinetics of a single oral dose of moxifloxacin 400mg in healthy male volunteers. Clin Pharmacokinet. 2001;40 Suppl 1:19-25. doi: 10.2165/00003088-200140001-00003.

  PMID: 11352438 BACKGROUND

• Nijland HM, Ruslami R, Suroto AJ, Burger DM, Alisjahbana B, van Crevel R, Aarnoutse RE. Rifampicin reduces plasma concentrations of moxifloxacin in patients with tuberculosis. Clin Infect Dis. 2007 Oct 15;45(8):1001-7. doi: 10.1086/521894. Epub 2007 Sep 4.

  PMID: 17879915 BACKGROUND

• Pranger AD, Kosterink JG, van Altena R, Aarnoutse RE, van der Werf TS, Uges DR, Alffenaar JW. Limited-sampling strategies for therapeutic drug monitoring of moxifloxacin in patients with tuberculosis. Ther Drug Monit. 2011 Jun;33(3):350-4. doi: 10.1097/FTD.0b013e31821b793c.

  PMID: 21544017 BACKGROUND

• Rustomjee R, Lienhardt C, Kanyok T, Davies GR, Levin J, Mthiyane T, Reddy C, Sturm AW, Sirgel FA, Allen J, Coleman DJ, Fourie B, Mitchison DA; Gatifloxacin for TB (OFLOTUB) study team. A Phase II study of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2008 Feb;12(2):128-38.

  PMID: 18230244 BACKGROUND

• 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 BACKGROUND

• Soman A, Honeybourne D, Andrews J, Jevons G, Wise R. Concentrations of moxifloxacin in serum and pulmonary compartments following a single 400 mg oral dose in patients undergoing fibre-optic bronchoscopy. J Antimicrob Chemother. 1999 Dec;44(6):835-8. doi: 10.1093/jac/44.6.835.

  PMID: 10590288 BACKGROUND

• Stass H, Dalhoff A, Kubitza D, Schuhly U. Pharmacokinetics, safety, and tolerability of ascending single doses of moxifloxacin, a new 8-methoxy quinolone, administered to healthy subjects. Antimicrob Agents Chemother. 1998 Aug;42(8):2060-5. doi: 10.1128/AAC.42.8.2060.

  PMID: 9687407 BACKGROUND

• Stass H, Kubitza D. Pharmacokinetics and elimination of moxifloxacin after oral and intravenous administration in man. J Antimicrob Chemother. 1999 May;43 Suppl B:83-90. doi: 10.1093/jac/43.suppl_2.83.

  PMID: 10382880 BACKGROUND

• Stass H, Kubitza D, Schuhly U. Pharmacokinetics, safety and tolerability of moxifloxacin, a novel 8-methoxyfluoroquinolone, after repeated oral administration. Clin Pharmacokinet. 2001;40 Suppl 1:1-9. doi: 10.2165/00003088-200140001-00001.

  PMID: 11352436 BACKGROUND

• Stass H, Kubitza D. Effects of dairy products on the oral bioavailability of moxifloxacin, a novel 8-methoxyfluoroquinolone, in healthy volunteers. Clin Pharmacokinet. 2001;40 Suppl 1:33-8. doi: 10.2165/00003088-200140001-00005.

  PMID: 11352440 BACKGROUND

• Sullivan JT, Woodruff M, Lettieri J, Agarwal V, Krol GJ, Leese PT, Watson S, Heller AH. Pharmacokinetics of a once-daily oral dose of moxifloxacin (Bay 12-8039), a new enantiomerically pure 8-methoxy quinolone. Antimicrob Agents Chemother. 1999 Nov;43(11):2793-7. doi: 10.1128/AAC.43.11.2793.

  PMID: 10543767 BACKGROUND

• Tam CM, Chan SL, Lam CW, Leung CC, Kam KM, Morris JS, Mitchison DA. Rifapentine and isoniazid in the continuation phase of treating pulmonary tuberculosis. Initial report. Am J Respir Crit Care Med. 1998 Jun;157(6 Pt 1):1726-33. doi: 10.1164/ajrccm.157.6.9707037.

  PMID: 9620898 BACKGROUND

• Weiner M, Bock N, Peloquin CA, Burman WJ, Khan A, Vernon A, Zhao Z, Weis S, Sterling TR, Hayden K, Goldberg S; Tuberculosis Trials Consortium. Pharmacokinetics of rifapentine at 600, 900, and 1,200 mg during once-weekly tuberculosis therapy. Am J Respir Crit Care Med. 2004 Jun 1;169(11):1191-7. doi: 10.1164/rccm.200311-1612OC. Epub 2004 Feb 12.

  PMID: 14962821 BACKGROUND

• Weiner M, Burman W, Luo CC, Peloquin CA, Engle M, Goldberg S, Agarwal V, Vernon A. Effects of rifampin and multidrug resistance gene polymorphism on concentrations of moxifloxacin. Antimicrob Agents Chemother. 2007 Aug;51(8):2861-6. doi: 10.1128/AAC.01621-06. Epub 2007 May 21.

  PMID: 17517835 BACKGROUND

MeSH Terms

Conditions

Tuberculosis

Interventions

rifapentine; Moxifloxacin; Rifampin; Isoniazid; Pyrazinamide; Ethambutol; Pyridoxine; Vitamin B 6

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Heterocyclic Compounds, 1-Ring; Pyrazines; Ethylenediamines; Diamines; Polyamines; Amines; Picolines

Study Officials

• Rada Savic, PhD

  University of San Francisco School of Pharmacy, San Francisco, CA

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 15, 2015
• First Posted: September 30, 2015
• Study Start: May 30, 2016
• Primary Completion: August 30, 2021
• Study Completion: August 30, 2021
• Last Updated: September 19, 2025

Record last verified: 2025-09

Locations

UG (1); US (1); VN (1)