What He Said: Rifampin versus Rifapentine Charles A. Peloquin, Pharm.D. Director Infectious Disease Pharmacokinetics Laboratory Professor, College of Pharmacy & The Emerging Pathogens Institute University of Florida
Rifampin vs. Rifapentine: PK factors Rifampin Rifapentine Minimum inhibitory concentration 0.25 0.06 Half-life 2h 15h Protein binding 80-85% 99% Food requirement No Yes Kinetics Nonlinear (Michaelis-Menten) Nonlinear (Saturable absorption) Flat vs. mg/kg dosing mg/kg? Flat Access Global Limited, but growing Favors
And Another Thing-- What She Said: Rifampin versus Rifapentine Kelly Dooley, MD, PhD Divisions of Clinical Pharmacology and Infectious Diseases Center for TB Research Johns Hopkins University School of Medicine Baltimore, MD, USA
Comparative efficacy
Rifapentine (P) is 4x more potent than rifampin (R) in BALB/c mice Log 10 CFU per Lung 8 R 10 HZ 7 R 15 HZ 6 5 4 3 2 1 R 20 HZ R 40 HZ P 10 HZ 0 0 2 4 6 8 10 12 Treatment duration (weeks) Drug regimen Percentage (proportion) of mice with positive cultures 3 months after stopping treatment for: 8 weeks 10 weeks 12 weeks R 20 HZ ND 100% (15/15) 67% (10/15) P 5 HZ ND 100% (15/15) 67% (10/15) R 40 HZ ND 27% (4/15) 0% (0/15) P 10 HZ 100% (15/15) 33% (5/15) 0% (0/15) Slide from Eric Nuermberger Rosenthal et al, AAC 2012; 56:4331 5
TBTC 29: Efficacy of RIF (10 mg/kg) vs. RPT (10 mg/kg) % of subjects having negative sputum cultures at end of intensive phase in the Protocol Correct analysis group Culture Medium Rifampin Rifapentine p Difference (95% CI) liquid 128/179 71.5% 152/202 75.3% 0.48 3.7 (-5.7, 13.2) solid 152/171 88.9% 182/198 91.9% 0.42 3.0 (-3.6, 9.6) Dorman et al. JID 2012
Comparative activity of RIF and RPT in BALB/c and C3HeB/FeJ mice over 4 wks of treatment CFU count (log 10 /lung) 10 8 6 4 2 BALB/c CFU count (log 10 /lung) 10 8 6 4 2 C3HeB/FeJ A 6 weeks 10 weeks 14 weeks Subsequent relapse experiments suggest: 2-mo Rx shortening with RPT in Balb/C 1-mo Rx shortening with RPT in C3H3B/FeJ S B 0 D0 RIF RPT Regimens PZA 0 D0 MTZ RIF RPT Regimens PZA MTZ
TBTC 29X: RPT Dose Finding AJRCCM 2015 191:333
RPT (daily, with food) 10-20 mg/kg vs. RIF 10 mg/kg: Rifapentine wins!! n.b. Time to first of two consecutive negative cultures at least two weeks apart without subsequent positive cultures
Or is it actually Rifampin that is winning??: PanACEA MAMS-TB Covariate-adjusted hazard ratios (c/w control) over 8 weeks: HR 20 ZM 1.69 (1.02-2.80) HR 35 ZE 1.99 (1.21-3.29) Two-month culture conversion (solid culture): 83% in HR 20 ZM 88% in HR 35 ZE 81% in control arm (HRZE) *n.b.: time to first of two consecutive negative cultures Slide from PanACEA, adapted
Safety & tolerability
Safety & Tolerability: TBTC 29X
Safety and tolerability- high dose RIF Control (HR 10 ZE) HR 35 ZE HR 20 ZM Grade 3, 4, 5 drug related AE 1 (1%) 3 (5%) 4 (6%) Death 0 1 0 Change in treatment due to protocol defined liver toxicity 2 (2%) 3 (5%) 0 From PanACEA MAMS trial
Enzyme induction
Is rifapentine a potent inducer of metabolizing enzymes? MDZ alone MDZ + RIF MDZ +RPT *Midazolam is a CYP3A4 probe drug How will efavirenz (CYP2B6or dolutegravir fare with high-dose RIF or RPT? The model estimated that RIF induced MDZ CL int (due to CYP3A) about 6 fold, and RPT twice as much. Also C Lint of OH-MDZ (UDP glucuronidation) was found enhanced, 3 fold by RIF and 4.5 by RPT. CPT 2012 91: 881; see also AAC 2013 57:6366
Effect of Rifapentine on Moxifloxacin Rifapentine Moxifloxacin Dose AUC 0-24 (mcg*h/ml) C max (mcg/ml) Rifaquin None 50.8 3.8 Healthy vol None 41.9 4.0 Rifaquin 1200 mg once weekly 46.2 2.9 900 mg twice weekly 45.3 2.8 Healthy vol 900 mg three times weekly 34.4 3.3 RioMAR 300-450 mg daily 28.0 2.5 RioMar: Conde et al PLoS One (2016) 11:e0154778
Effect of High Dose RPT or RIF on HIV drug exposures Rifampin Rifapentine Rifavirenz Dolutegravir TBTC 31 Dolutegravir Note: EFV is okay with Rifampicin 600 mg daily or rifapentine given at 300-600 mg once daily (with HZE and H, respectively) ACTG A5279
Drug penetration
Caseum penetration of RPT v RIF Single Multiple RPT Ion count ratio 2 1,5 1 0,5 Caseum/cavity wall (MALDI) 0 RIF 2h RPT 2h RIF 6h RPT 6h RIF 2h RPT 2h RIF 12h RPT 12h RIF Single-dose Multi-dose In collaboration with Brendan Prideaux, Veronique Dartois at Rutgers, submitted
Model parameters Drug Rifampin n/n Rifapentine n/n Parameter Plasma 38/8 49/11 CL (L/h/kg) 0.175 (3) 0.087 (26) V (L/kg) 0.54 (5) 0.67 (11) Residual error, plasma, CV (%) 34 (5) 23 (15) IIV (CL), CV (%) 42 (17) 65 (30) IIV (V), CV (%) - 30 (42) Correlation CL-V - 0.59 (27) Uninvolved lung 15/5 42/11 Ratio, plasma uninvolved lung 0.78 (12) 0.71 (12) Cellular lesion 20/5 19/6 Ratio, plasma cellular lesion 1.12 (5) 1.1 (14) Tissue surrounding lesion 12/5 15/6 Ratio, plasma tissue surrounding lesion 1.01 (16) 1.05 Cavity caseum 9/3 13/4 Ratio, plasma cavity caseum 1.11 (21) 0.25 (21) Cavity wall 7/2 16/4 Ratio, plasma cavity wall 0.98 (8) 1.01 (8) Model by Rada Savic
Subgroups
Patients with cavitary lung disease may not benefit from rifapentine Rifapentine AUC 0-24 * (μg*h/ml) Aggregate Cavity Size on Chest Radiograph (cm) Geographic Origin of Study Site Percent of Participants With Negative Cultures in Liquid Media at 8 Weeks Mean [95% CI] Time (d) Calculated For 50% Participants to Develop Stable Conversion to Negative Cultures [range: 5%, 95% participants] > 350 < 4 Africa 67 [53, 83] 45 [14, 88] > 350 4 Africa 40 [20, 56] 66 [20, >120] > 350 < 4 Not Africa 79 [70, 87] 39 [12, 76] > 350 4 Not Africa 48 [30, 70] 57 [17, 111] < 300 < 4 Africa 37 [27, 48] 68 [21, > 120] < 300 4 Africa 37 [25, 49] 68 [21, > 120] < 300 < 4 Not Africa 47 [28, 63] 58 [18, 114] < 300 4 Not Africa 44 [22, 72] 58 [18, 114] Submitted; see also AJRCCM 2015 191:333
Which patients are at highest risk of poor outcomes with RIF-based treatment? RAFA trial Immediate ART vs. Delayed ART vs. Delayed ART but RIF 15 mg/kg IAS 2016
Prevention of resistance
Pathway to resistance Cohen et al (2015) PLoS Medicine
Rifampin vs. Rifapentine: You the Jury Efficacy Safety Enzyme induction (DDI) Protection against resistance Benefit for all pts with DS-TB Rifampin Rifapentine Favors