What He Said: Rifampin versus Rifapentine

Transcription

1 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

2 Rifampin vs. Rifapentine: PK factors Rifampin Rifapentine Minimum inhibitory concentration 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

3 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

4 Comparative efficacy

5 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 R 20 HZ R 40 HZ P 10 HZ 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

6 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/ % 152/ % (-5.7, 13.2) solid 152/ % 182/ % (-3.6, 9.6) Dorman et al. JID 2012

7 Comparative activity of RIF and RPT in BALB/c and C3HeB/FeJ mice over 4 wks of treatment CFU count (log 10 /lung) BALB/c CFU count (log 10 /lung) 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

8 TBTC 29X: RPT Dose Finding AJRCCM :333

9 RPT (daily, with food) 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

10 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 ( ) HR 35 ZE 1.99 ( ) 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

11 Safety & tolerability

12 Safety & Tolerability: TBTC 29X

13 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 Change in treatment due to protocol defined liver toxicity 2 (2%) 3 (5%) 0 From PanACEA MAMS trial

14 Enzyme induction

15 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 : 881; see also AAC :6366

16 Effect of Rifapentine on Moxifloxacin Rifapentine Moxifloxacin Dose AUC 0-24 (mcg*h/ml) C max (mcg/ml) Rifaquin None Healthy vol None Rifaquin 1200 mg once weekly mg twice weekly Healthy vol 900 mg three times weekly RioMAR mg daily RioMar: Conde et al PLoS One (2016) 11:e

17 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 mg once daily (with HZE and H, respectively) ACTG A5279

18 Drug penetration

19 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

20 Model parameters Drug Rifampin n/n Rifapentine n/n Parameter Plasma 38/8 49/11 CL (L/h/kg) (3) (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 (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

21 Subgroups

22 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] > Africa 40 [20, 56] 66 [20, >120] > 350 < 4 Not Africa 79 [70, 87] 39 [12, 76] > Not Africa 48 [30, 70] 57 [17, 111] < 300 < 4 Africa 37 [27, 48] 68 [21, > 120] < Africa 37 [25, 49] 68 [21, > 120] < 300 < 4 Not Africa 47 [28, 63] 58 [18, 114] < Not Africa 44 [22, 72] 58 [18, 114] Submitted; see also AJRCCM :333

23 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

24 Prevention of resistance

25 Pathway to resistance Cohen et al (2015) PLoS Medicine

26 Rifampin vs. Rifapentine: You the Jury Efficacy Safety Enzyme induction (DDI) Protection against resistance Benefit for all pts with DS-TB Rifampin Rifapentine Favors