USO08097607B2 (12) United States Patent (10) Patent No.: US 8,097,607 B2 Cabana et al. (45) Date of Patent: *Jan. 17, 2012 (54) LOW DOSE RIFALAZIL COMPOSITIONS Emori et al., “Evaluation of in Vivo Therapeutic Efficacy of a New Benzoxazinorifamycin, KRM-1648, in SCID Mouse Model for Dis (76) Inventors: Bernard E. Cabana, Montgomery seminated Mycobacterium avium Complex Infection.” International Village, MD (US); Arthur F. Michaelis, Journal of Antimicrobial Agents 10(1):59 (1998). Devon, PA (US); Gary P. Magnant, Fujii et al., “In Vitro and In Vivo Antibacterial Activities of KRM Topsfield, MA (US); Chalom B. 1648 and KRM-1657, New Rifamycin Derivatives.” Antimicrobial Sayada, Luxembourg (LU) Agents and Chemotherapy 38: 1118, (1994). Gidoh et al., “Bactericidal Action at Low Doses of a New Rifamycin (*) Notice: Subject to any disclaimer, the term of this Derivative, 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl) patent is extended or adjusted under 35 Benzoxazinorifamycin (KRM-1648) on Mycobacterium leprae U.S.C. 154(b) by 447 days. Inoculated into Ffootpads of Nude Mice.” Leprosy Review 63(4):319 This patent is Subject to a terminal dis (1992). claimer. Heep et al., “Detection of Rifabutin Resistance and Association of rpoB Mutation S with Resistance to Four Rifamycin Derivatives in Helicobacter pylori.” Journal of Clinical Microbiology & Infectious (21) Appl. No.: 10/668,792 Diseases 21:143 (2002). Hirara et al., “In Vitro and in Vivo Activities of the (22) Filed: Sep. 23, 2003 Benezoxazinorifamycin KRM-1648 Against Mycobacterium tuber (65) Prior Publication Data culosis,” Antimocrobial Agents and Chemotherapy 39 (10):2295 (1995). US 2004/O15784.0 A1 Aug. 12, 2004 Hosoe et al., “Identification and Antimicrobial Activity of Urinary Metabolites of a Rifamycin Derivative in Dog,” Xenoblotica Related U.S. Application Data 26(3):321 (1996). Hosoe et al., “Pharmacokinetics of KRM-1648, a New (60) Provisional application No. 60/412,958, filed on Sep. Benzoxazinorifamycin, in Rats and Dogs.” Antimicrobial and Che 23, 2002. motherapy 40(12):2749 (1996). Ji et al., “How Effective is KRM-1648 in Treatment of Disseminated (51) Int. Cl. Mycobacterium avium Complex Infections in Beige Mice?.” Antimi A6 IK3I/33 (2006.01) crobial Agents and Chemotherapy 40(2):437 (1996). (52) U.S. Cl. ....................................................... S14f183 Kelly et al., “Low-Dose Aerosol Infection Model for Testing Drugs (58) Field of Classification Search ........................ None for Efficacy Against Mycobacterium tuberculosis,” Antimicrobial See application file for complete search history. Agents and Chemotherapy 40(12):2809 (1996). Klemens et al., “Activity of KRM-1648 in Comination with Isoniazid (56) References Cited Against Mycobacterium tuberculosis in a Murine Model.” Antimi crobial Agents and Chemotherapy 40(2):298 (1996). U.S. PATENT DOCUMENTS Lenaerts et al., “Evaluation of Rifalazil in a Combination Treatment 4,983,602 A 1/1991 Yamane et al. ............ 514,229.5 Regimen as an Alternative to Isoniazid-Rifampin Therapy in a Mouse 5,547,683 A 8, 1996 Yano et al. ..... ... 424,501 Tuberculosis Model.” Antimicrobial Agents and Chemotherapy 5,786,349 A 7, 1998 Yamashita et al. ............ 514/183 44(11):3167 (2000). 5,981.522 A 11/1999 Yamashita et al. ......... 514/224.5 Mae et al., “Effect of a New Rifamycin Derivative, Rifalazil, on Liver 6,316,433 B1 1 1/2001 Rose et al. .. ... 514, 183 Microsomal Enzyme Induction in Rat and Dog,” Xenoblotica 6,486,161 B1 1 1/2002 Fujii et al. ............. 514,252.13 6,566,354 B1 5/2003 Montgomery et al. ....... 514, 183 28(8):759 (1998). 2003/0203903 A1 10, 2003 Rose et al. ................. 514,229.8 Mae et al., “Isolation and Identification of Major Metabolites of 2003/0236265 A1* 12/2003 Sayada .................... 514,252.13 Rifalazil in Mouse and Human.” Xenobiotica 29:1073 (1999). 2004/00 14750 A1 1/2004 Michaelis et al. ......... 514,224.5 Roblin et al., “In Vitro Activities of Rifamycin Derivatives ABI-1648 2004.0034021 A1 2/2004 Michaelis et al. 514/310 (Rifazil, KRM-1648), ABI-1657, and ABI-1131 Against Chlamydia 2004/OO77533 A1 4/2004 Sayada ............................. 5148 trachomatis and Recent Clinical Isolates of Chlamydia 2004/0106590 A1* 6/2004 Eisenstein 514, 183 pneumoniae," Antimicrobial Agents and Chemotherapy 47: 1135 2004/O126414 A1 7/2004 Michaelis .................. 514,224.5 (2003). 2004/0176404 A1 9/2004 Sayada .......... 514,252.13 Sano et al., “Therapeutic Effects of Benzoxazinorifamycin KRM 2005, 01371.89 A1* 6, 2005 Van Duzer et al. 514,224.5 1648 Administered Alone or in Combination with a Half-sized Secre 2005/0143409 A1* 6/2005 Michaelis et al. ............ 514,291 tory Leukocyte Protease Inhibitor or the Nonsteroidal Anti-inflam OTHER PUBLICATIONS matory Drug Diclofenac Sodium against Mycobacterium avium Complex Infection in Mice.” Antimicrobial Agents and Chemo Lithander et al., British Journal of Ophthalmology, 2001, 85:371.* therapy 43(2):360 (1999). Remington's Pharmaceutical Sciences, (1975) 15" edition, p. 703.* “Rifalazil PathoGenesis Plans Phase II Studies.” R&D Focus Drug (Continued) News. Jun. 9, 1997. Bermudez et al., “Activity of KRM 1648 Alone or in Combination Primary Examiner — Phyllis G. Spivack with Ethambutolor Clarithromycin Against Mycobacterium avium in (74) Attorney, Agent, or Firm — David Bradin: Steven J. Beige Mouse Model of Disseminated Infection.” Antimicrobial Hultquist; Hultquist IP Agents and Chemotherapy 38(8): 1844 (1994). Dietzeet al., “Safety and Bactericidal Activity of Rifalazil in Patients (57) ABSTRACT with Pulmonary Tuberculosis.” Antimicrobial Agents and Chemo therapy 45(7): 1972 (2001). The invention features low-dosage rifalazil compositions Dhople AM, “In Vivo Susceptibility of Mycobacterium ulcerans to which are useful for the treatment of bacterial infections. KRM-1648, A New Benzoxazinorifamycin, in Comparison with Rifampicin.” Arzneimiiffelforschung 51(6):501 (2001). 4 Claims, 7 Drawing Sheets US 8,097,607 B2 Page 2 OTHER PUBLICATIONS Tomioka et al., “Therapeutic Efficacy of KRM-1648 in Combination with Other Antimicrobials Against M. leprae Infection Induced in Sato et al., “Antimicrobial Activities of Benzoxazinorifamycin Nude Mice.” International Journal of Leprosy and Other Mycobacte KRM-1648, Clarithromycin and Levofloxacin Against Intracellular rial Diseases 61:77A (1993). Mycobacterium avium Complex Phagocytosed by Murine Peritoneal Tomioka et al., “Intramacrophage Passage of Mycobacterium Macrophages,” Journal of Antimicrobial Chemotherapy 41(1):77 tuverculosis and M. avium Complex Alters the drug susceptibilities of te organisms as determined by intracellular SuSeptivility Testing (1998). using Macrophages and Type II Alveolar Epithelial Cells.” Antimi Shimizu et al., “Effects of the Chinese Traditional Medicine Mao crobial Agents and Chemotherapy 46:519 (2002). bushi-saishin-to on Therapeutic Efficacy of a New Wallis et al., “Inhibition of Isoniazid-induced Expression of Benzoxazinorifamycin, KRM-1648, Against Mycobacterium avium Mycobacterium tuberculosis Antigen 85 in Sputum: Potential Surro Infection in Mice.” Antimicrobial Agents and Chemo gate Marker in Tuberculosis Chemotherapy Trials.” Antimicrobial therapy:43(3):514 (1999). Agents and Chemotherapy 45(4): 1302 (2001). Shoen et al., “Evaluation of Rifalazil in Long-term Treatment Regi Yamamoto et al., “In Vitro Bactericidal and in Vivo Therapeutic mens for Tuberculosis in Mice.” Antimicrobial Agents and Chemo Activities of a New Rifamycin Derivative, KRM-1648, Against therapy 44(6): 1458 (2000). Mycobacterium tuberculosis,” Antimicrobial Agents and Chemo Tomioka et al., “Effects of Benzoxazinorifamycin KRM-1648 on therapy 40(2):426 (1996). Cytokine Production at Sites of Mycobacterium avium Complex Yamamoto et al., “Activity of KRM-1648 Alone or in Combination Infection Induced in Mice.” Antimicrobial Agents and Chemotherapy with Both Ethambutol and Kanamycin or Clanthromycin Against 41(2):357 (1997). Mycobacterium intracellulare Infections in Beige Mice.” Antimicro Tomioka et al., “In Vivo Antileprosy Activity of the Newly Synthe bial Agents and Chemotherapy 40(2):429 (1996). sized Benzoxazinorifamycin, KRM-1648.” International Journal of Leprosy 61:255-258 (1993). * cited by examiner U.S. Patent Jan. 17, 2012 Sheet 1 of 7 US 8,097,607 B2 O Observed Values Predicted Values FIG. A O 24 48 72 96 120 144 168 192 216 240 264. 288 312 336 Time (hr) 1 O t = 139 hours FIG. B O 24 48 72 96 120 144 168 192 216 240 264. 288 312 336 Time (hr) U.S. Patent Jan. 17, 2012 Sheet 2 of 7 US 8,097,607 B2 FIG. 2 TWO.COMPARTMENT OPEN MODEL Ka Gract -0. Plasma Compartment Tissue Compartment Drug Elimination (Metabolism & Excretion) U.S. Patent Jan. 17, 2012 Sheet 3 of 7 US 8,097,607 B2 FIG. 3 1 O O - - Amount in Plasma (ng/g) --- Amount in Tissues (ng/g) 10 ' ' ' ' ' ' MIC for C. trachomatis (ng/mL) 0.1 0.01 O 48 96 144 192 240 288 336 384 432 480 Time (hr) U.S. Patent Jan. 17, 2012 Sheet 4 of 7 US 8,097,607 B2 FIG. 4 100 - Amount in Plasma (ng/g) --- Amount in Tissues (nglg) 10 MIC for C. trachomatis (ng/mL) - s r s s - - - * s s s - A. s • *w - a • * * r * - - - a a • - - - - - - - - - - - - - - - - - creas aas - - - - • * r s r * * r * a • - as - - - 0.1 O 48 96 144 192 240 288 336 384. 432 480 Time (hr) U.S. Patent Jan. 17, 2012 Sheet 5 Of 7 US 8,097,607 B2 FIG. 5 Amount in Plasma (ng/g) 0.6 -- Amount in Tissues (ng/g) 0.5 - / MIC for C. Trachomatis (ng/mL) 1G - Series 1 2 0.4 re- Series3 R 5 0.3 /N E E3 0.2 e 0.1 O.O -- --- O 48 96 144 192 240 288 336 384 432 480 Time (h) U.S. Patent Jan. 17, 2012 Sheet 6 of 7 US 8,097,607 B2 FIG. 6 100 - Amount in Plasma (ng/g) --- Amount in Tissues (ng/g) - - - - - - - - - - MIC for C. trachomatis (ng/mL) 10 - tw. a s s - w - - - t a s - - ". 0.1 0.01 O 48 96 144 192 240 288 336 384 432 480 Time (hr) U.S.