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Why Another Antibiotic for Respiratory Tract Infections ?

Why Another Antibiotic for Respiratory Tract Infections ?. C. Couturier. Community Acquired Pneumonia. No./an USA. Incidence 2–3 millions Hospitalisations 500 000 (env. 1/5) Mortalité 45 000 (env. 1/50). Bartlett et al. Clin Infect Dis 1998;26:811–38. Incidence increases with age.

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Why Another Antibiotic for Respiratory Tract Infections ?

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  1. Why Another Antibiotic for Respiratory Tract Infections? C. Couturier

  2. Community Acquired Pneumonia No./an USA Incidence 2–3 millions Hospitalisations 500 000 (env. 1/5) Mortalité 45 000 (env. 1/50) Bartlett et al. Clin Infect Dis 1998;26:811–38

  3. Incidence increases with age Age (years) 16–19 20–29 30–39 40–49 50–59 60–69 70–79 0 20 40 60 80 100 120 140 Cases per 1000 population/year MacFarlane et al. Lancet 1993;341:511–14

  4. Community Acquired Pneumopathy Etiology Other bacteria (12.5%) Viral (12.6%) H. influenzae(14.3%) Mycoplasma (6.7%) Legionella (5.2%) Chlamydia (3.7%) S. pneumoniae(44.9%) Analysis of 16 studies of >3300 hospitalized patients (1960–1987) LaForce. Clin Infect Dis 1992;14 (Suppl. 2):S233–7

  5. Why Another Antibiotic for RTIS. pneumoniae Resistance Rates % Resistance Antimicrobial US Worldwide agent (N=10,103) (N=16,672) Penicillin G 24.2 22.3 Erythromycin A 31.7 30.7 Azithromycin 31.5 30.9 Clarithromycin 31.3 30.6 Clindamycin 13.6 8.6 Cotrimoxazole 31.1 33.9 Tetracycline 22.1 15.9 Levofloxacin 0.9 0.8 Source: PROTEKT US

  6. Penicillin-resistant S. pneumoniae tend to be resistant to other -lactams MIC distribution for ceftriaxone against S. pneumoniae % isolates 80 70 Penicillin-sensitive (MIC 0.06 mg/L) 60 Penicillin-resistant (MIC 2 mg/L) 50 40 Penicillin-intermediate (MIC 0.12–1 mg/L) 30 20 10 0 0.004 0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 MIC (mg/L) Goldstein et al. J Antimicrob Chemother 1996;38(Suppl. A):71–84

  7. Tailored activity against pathogens from community RTIs: common & atypicals Excellent antipneumococcal activity SPN is the leading organism in frequency and morbidity includes activity against ERSP and PRSP Telithromycin – R&D Target Ketolides are developed in response to Bacterial Resistance

  8. Macrolides Target the 50S Subunit of the Bacterial Ribosome AA-tRNA Peptidyl tRNA 50S Subunit 23S and 5S rRNA + 32 proteins mRNA Exit site for the growing peptide 30S Subunit 16S rRNA + 20 proteins J. Zhu, et al., J Struct Biol. 1997 118:197-219 • Macrolide binding inhibits protein synthesis by interfering with elongation of peptide synthesis and preventing 50S subunit assembly

  9. Telithromycin Mechanism of Action 23S rRNA Domain V 5S rRNA 30S Domain II Pocket: peptidyl transferase site 50S Erythromycin A Telithromycin V V 2058 2058 5S rRNA O O 5S rRNA -cladinose O O O O II II 752 752

  10. Consequence of Double Binding to 23S rRNA Erythromycin A Telithromycin V V 2058 2058 (methylation) (methylation) x x O O 5S rRNA 5S rRNA -cladinose O O O O II II 752 752 No link with domain V Link with domain II Resistance to erythromycin A Telithromycin retains activity against erythromycin A- resistant organisms

  11. Ribosomal Depletion • Inhibition of ribosomal subunit formation 30S 50S 50S 30S Erythromycin A 30S Depletion of ribosome in the bacterial cells Telithromycin

  12. Macrolide Resistance • Inactivating Enzymes • Staphylococci • Gram Negative Rods • Efflux • Wildly distributed • Multi drug activity • Target modification • 23S Methylases • 23 S Mutations • r-Proteins Mutations

  13. erm(A) S. pneumoniae are Inducibly Resistant to ML Antibiotics • Telithromycin activity is not altered by inducible methylases in S.pneumoniae erm(A)

  14. In vitro Activity of Telithromycin Against S. pneumoniae MIC (µg/mL) Resistance Phenotype (N) MIC50 MIC90 Range Macrolide-susceptible (11,384) 0.015 0.015 0.004 - 1 Macrolide-resistant (5,288) 0.12 1.0 0.008 - 8 erm(B) (657) 0.06 0.5 0.008 - 8 mef(A) (436) 0.12 0.5 0.008 - 1 mef(A)+erm(B) (71) 0.5 0.5 0.06 - 1 Penicillin-resistant (4,027) 0.12 1.0 0.004 - 8 Levofloxacin-resistant (154) 0.03 0.5 0.004 - 1 Multi-drug resistant (1,500) a 0.12 1.0 0.008 - 8 a resistant to the macrolides, penicillin, cotrimoxazole, and tetracycline Data from PROTEKT Worldwide, N = 16,672

  15. Activities of Telithromycin and Macrolides Erythromycin-Resistant S. pneumoniae (N=3,131) 2500 2000 1500 Number of Isolates 1000 Azithromycin 500 Clarithromycin Erythromycin 0 Telithromycin 1 2 4 8 0.5 0.03 0.06 0.12 0.25 16 0.015 MIC (µg/mL) Data from PROTEKT US 2000/2001

  16. Control TEL at 2x MIC (0–0.6 mg/L) TEL at 4x MIC (0–12 mg/L) TEL at 8x MIC (0–25 mg/L) AZI at 2x MIC (0–25 mg/L) AZI at 4x MIC (0–5 mg/L) AZI at 8x MIC (1 mg/L) Bactericidal activity of telithromycin in vitro Counts (log10 CFU/mL) 10 9 PenS EryS S. pneumoniae 8 7 6 5 4 3 2 1 0 -5 0 5 10 15 20 25 30 -5 Time (hours) Starting inoculum 105 CFU/mL Felmingham et al. 38th ICAAC 1998

  17. 0 µg/mL 0.06 0.125 0.25 0.5 1 2 4 8 16 Bactericidal Activity of telithromycin Against Macrolide-Resistant S. pneumoniae S. pneumoniae Strain 5467 mef(A) S.pneumoniae Strain 5991 erm(B) 10 10 8 8 LOG10cfu/mL LOG10cfu/mL 6 6 4 4 2 2 0 2 4 6 8 12 0 2 4 6 8 12 Hours Hours

  18. In vitro Activity of Telithromycin Organism (N) MIC50 MIC90 Range S. pneumoniae (10,103) 0.015 0.5 0.015 - 8 H. influenzae (2,706) 2.0 4.0 0.12 - 32 (-lactamase positive; 769) 2.0 4.0 0.12 - 16 M. catarrhalis (1,896) a 0.06 0.12 0.004 - 0.5 S. pyogenes (3,918) 0.03 0.03 0.015 - 16 MIC (µg/mL) Data from PROTEKT US; a PROTEKT Worldwide, 2000-2001

  19. Telithromycin Selection of Antibiotic Resistance • Telithromycin does not induce MLSB resistance in pneumococci • In serial passage experiments, telithromycin was less efficient in selecting resistant mutants of pneumococci than azithromycin, clarithromycin, erythromycin, or clindamycin • Selection of resistant strains of viridans group streptococci and other usual oropharyngeal flora less efficient with telithromycin than azithromycin • Selection of resistant strains of viridans group streptococci and intestinal enterococci less efficient with telithromycin than clarithromycin

  20. Telithromycin • Ketolide antibiotic, derived from macrolides • Novel mechanism of action • Tailored activity against pathogens from community RTIs: common & atypicals • Excellent antipneumococcal activity: • leading organism in frequency and morbidity • includes activity against ERSP and PRSP • Short, simple course of treatment

  21. Global development ( +Japan specificities) Sharing indications Only one Database Resulting in 2 dossiers FDA & EMEA Telithromycin – Development Strategy

  22. In vitro studies PK PK/PD animal Telithromycin – Development Strategy Dose Ranging Phase II study was not performed Short duration treatment choosen

  23. Indications • Community-acquired pneumonia (CAP) • Acute exacerbation of chronic bronchitis (AECB) • Acute sinusitis (AS)

  24. Antibacterial studies difficulties • Bacteriological End Point difficult to monitor • Strains are fastidious • Efficacy results in absence of sputum

  25. Large number of Patients >> few Strains CAP Studies • mITT • PPc • S. pneumoniae • ERSP • PRSP 2511 1925 318 50 27

  26. Human Pharmacology Program • Clinical pharmacokinetics of telithromycin have been studied extensively: • studies on plasma PK, studies on tissue penetration • interaction studies • special population studies (elderly; renal, hepatic, and multiple impairment)

  27. Pharmacokinetics of Oral Telithromycin in Healthy Subjects 800 mg single dose 800 mg multiple dose (7 d) tmax (h) 1.0 a [0.5-4] 1.0 a [0.5-3] Cmax (mg/L) 1.9 (42) 2.3 (31) C24h (mg/L) 0.03 (45) 0.07 (72) AUC(0-24h) (mg.h/L) 8.3 (31) 12.5 (43) t½,z (h) 7.2 (19) 9.8 (20) Data are mean (CV%) [Min-Max], N = 18 a Median

  28. Tissue and Fluid Penetration of Telithromycin in Patients Mean (CV%) telithromycin concentration after 800 mg dose (mg/L) Tissue 2-3h 12h 24h Epithelial lining fluid a 14.9 3.3 0.8 (76) (51) (62) Alveolar macrophages a 69.3 318.1 161.6 (60) (73) (59) Tonsils(µg/g) b 4.0 0.9 0.7 (13) (56) (40) a Data from Honeybourne and Wise, N = 5-7 b Data from Gehanno, N = 6-8

  29. Pathways of Telithromycin Disposition Oral administration ( 90% absorbed, <10% unabsorbed) First pass effect Metabolism in liver and GI tract (33%) Systemic bioavailability (57%) GI tract/biliary Renal excretion Hepatic excretion (37%) (7%) (13%) Unchanged drug in feces Unchanged drug in urine Metabolized drug* ½ ½ CYP3A4-mediated Non-P450 mediated * Telithromycin is not metabolized by CYP2D6

  30. PK Modifications Under Various Conditions Comparisons with Healthy Control Subjects Cmax AUC Renal impairment CLCR <30 mL/min 1.5 x  2.0 x  30-80 1.1 x  1.2 x  CYP3A4 inhibition Ketoconazole 1.5 x  2 x  Itraconazole 1.2 x  1.5 x  Grapefruit juice  Hepatic impairment   Renal impairment+ ketoconazole CLCR <30 mL/min 3.4 x  4.5 x  30-80 1.7 x  2.7 x 

  31. (41) (31) AUC(0-24)(mg.h/L) 112.2 33.4 51.7, 61.6 Cmax,ss (mg/mL) 6.2 (36) 3.6 (22) 5.4, 8.8 Effects of Multiple Impairments (Elderly, Renal, +Ketoconazole) Clarithromycin Telithromycin 30-80 N=6 30-80 N=10 <30 N=2 Creatinine clearance (mL/min) Data are mean (CV%).

  32. Telithromycin Interaction with CYP3A4 Substrate: Midazolam Change in exposure Midazolam Parameter TEL CLA KET Intravenous AUC 2.2 x 2.7 x 5 x  Oral AUC 6.1 x  7 x  16 x  Dose of iv midazolam was 2 mg for TEL and KET and 0.05 mg/kg for CLA Dose of oral midazolam was 6 mg for TEL and KET and 4 mg for CLA TEL = Telithromycin; CLA = Clarithromycin; KET = Ketoconazole

  33. Summary of Human Pharmacology • PK of telithromycin have been well characterized, and are reproducible or predictable under various conditions • Telithromycin rapidly achieved targeted plasma and respiratory tissue concentrations • Multiple elimination pathways limit the potential for increased exposure in special populations. CYP3A4 metabolism accounts for a small fraction of total drug clearance • Similar inhibition of CYP3A4 to clarithromycin and erythromycin but for less time because of the short treatment duration

  34. Telithromycin Dosage Regimens in Phase III Studies CAP 800 mg qd 7-10 days AECB 800 mg qd 5 days Acute sinusitis 800 mg qd 5 days 800 mg qd 10 days Indication Dosage Duration

  35. Visit 1 (Day 1) Visit 2 (Day 3 to 5) Visit 3 (Day 10 to 13) Visit 4 (Day 17 to 21) Visit 5 (Day 31 to 36) TEL: 5 days Placebo: 5 days End of Therapy Posttherapy/TOC Late Posttherapy Pretherapy/ Entry Telithromycin: 10 days Comparator: 10 days On Therapy Off Therapy Generalized Study Design

  36. Clinical Efficacy of Telithromycin • Clinical efficacy by indication: • community-acquired pneumonia (CAP) • acute exacerbation of chronic bronchitis (AECB) • acute sinusitis

  37. CAP: Phase III Controlled Studies • 4 randomized, controlled, double-blind, comparative trials (Western countries) Study No. Treatment N (mITT) 3001 TEL 10 d 800 mg qd 199 AMX 10 d 1000 mg tid 205 3006 TEL 10 d 800 mg qd 204 CLA 10 d 500 mg bid 212 3009 TEL 7-10 d 800 mg qd 100 TVA 7-10 d 200 mg qd 104 4003 TEL 5 d 800 mg qd 187 TEL 7 d 800 mg qd 191 CLA 10 d 500 mg qd 181 TEL = Telithromycin; AMX = Amoxicillin; CLA = Clarithromycin; TVA = Trovafloxacin

  38. CAP: Other Studies • 4 Phase III open-label studies (Western countries) Study No. Treatment N (mITT) 3000 TEL 7-10 d 800 mg qd 240 3009 OL TEL 7-10 d 800 mg qd 212 3010 TEL 7 d 800 mg qd 418 3012 TEL 7 d 800 mg qd 538 • 2 Phase II/III comparative studies (Japan) 2105 TEL 7 d 600 mg qd 46 TEL 7 d 800 mg qd 50 3107 TEL 7 d 600 mg qd 126 LVX 7 d 100 mg tid 111 LVX = Levofloxacin

  39. TEL (7-10 d) Comparator (10 d) TEL (5 d) CAP: Clinical Cure at TOC, PPc (Controlled Western Studies) [–9.7; 4.7] a,b [–2.1; 11.1] a [–7.9; 7.5] a [–13.6; 5.2] a [–10.2; 4.3] a,c 100% 95% 94% 92% 90% 90% 89% 88% 89% 89% 80% 60% 40% 141149 137152 143162 138156 7280 8186 20% 142159 143161 134146 0% 4003 vs CLA 3001 vs AMX 3006 vs CLA 3009 vs TVA c TEL (7 d) vs CLA a 95% confidence intervals b TEL (5 d) vs CLA

  40. CAP: Clinical Cure at Test Of Cure, PerProtocol(clinical)(Uncontrolled Western Studies) TEL Study n/N (%) 3000 183/197 (93) 3009 OL 175/187 (94) 3010 332/357 (93) 3012 424/473 (90)

  41. CAP: Clinical Cure by Pathogen(All Western Studies) TEL Comparators a All Cultures: n/N (%) n/N (%) Key pathogens (PPb at TOC) S. pneumoniae 300/318 (94) 63/70 (90) H. influenzae 206/229 (90) 42/44 (95) M. catarrhalis 44/50 (88) 7/9 (78) Atypical pathogens (PPc at TOC) M. pneumoniae 36/37 (97) 20/22 (91) C. pneumoniae 34/36 (94) 18/19 (95) L. pneumophila 13/13 (100) 2/3 (67) a Study 3001: Amoxicillin; Studies 3006 and 4003: Clarithromycin; Study 3009: Trovafloxacin

  42. CAP: Clinical Cure for Resistant S. pneumoniae Isolates TEL: PPb population at TOC (Western + Japanese studies) n/N (%) Subjects Single and multiple pathogens PRSP 24/27 (89) ERSP 44/50 (88) PRSP and ERSP 16/19 (84) Single pathogens PRSP 15/16 (94) ERSP 29/32 (91) PRSP and ERSP 9/10 (90) PRSP = Penicillin G-resistant (MIC 2.0 µg/mL); ERSP = Erythromycin A (macrolide)-resistant (MIC 1.0 µg/mL) a Excludes strains that are both PRSP and ERSP

  43. CAP: Clinical Cure for Erythromycin-Resistant S. pneumoniae by genotype TEL: PPb population at TOC (Western + Japanese studies) n/N (%) Subjects Single and multiple pathogens ERSP 44/50 (88) erm(B) 24/28 (86) mef(A) 16/18 (89) erm(B)/mef(A) 3/3 (100) Negative for erm(B) and mef(A) 1/1 (100) PRSP = Penicillin G-resistant (MIC 2.0 µg/mL); ERSP = Erythromycin A (macrolide)-resistant (MIC 1.0 µg/mL)

  44. Summary of Efficacy in CAP • Effective in outpatients at risk for complications (elderly, pneumococcal bacteremia, Legionella) • Treatment with telithromycin 800 mg once daily for 7 to 10 days is effective in CAP due to: Common pathogens • S. pneumoniae • Pen-R strains • Ery-R strains • H. influenzae • M. catarrhalis Atypical pathogens • M. pneumoniae • C. pneumoniae • L. pneumophila

  45. Summary of Efficacy in RTIs (1) • Efficacy of telithromycin demonstrated in 14 studies in 3 indications: • 5-day treatment for AECB and acute sinusitis • 7- to 10-day treatment for CAP • Effective in subjects at risk for complications: • CAP: elderly, pneumococcal bacteremia • AECB: elderly, significant obstruction (FEV1/FVC < 60%)

  46. Summary of Efficacy in RTIs (2) • Effective against S. pneumoniae resistant to penicillin G and macrolides (erythromycin A) • Effective against atypical and intracllular organisms: • C. pneumoniae • M. pneumoniae • L. pneumophila

  47. Clinical Safety of Telithromycin • Phase III clinical efficacy studies • Large study in usual care setting (Study 3014) • Post-marketing experience

  48. Current Extent of Exposure • Significant global exposure to TEL: • 4,472 subjects in 16 Phase III clinical efficacy studies • 12,159 subjects in large comparative study in usual care setting (Study 3014) • >24,000 patients in post-marketing survey • >750 000 global post-marketing exposures* • * based upon Aventis internal sales data to retail and outpatient pharmacies as of 09 July 2002 (PSUR n°2 submitted September 9, 2002)

  49. Subjects (%) with Treatment-Emergent Adverse Events (2%) (Controlled Efficacy Studies) TEL Comparator N=2702 N=2139 Subjects with TEAEs 1348 (49.9) 1035 (48.4) Diarrhea 292 (10.8) 184 (8.6) Nausea 213 (7.9) 99 (4.6) Dizziness (excl vertigo) 99 (3.7) 57 (2.7) Vomiting 79 (2.9) 48 (2.2) Loose stools 63 (2.3) 33 (1.5) Headache 148 (5.5) 125 (5.5) Dysguesia 43 (1.6) 77 (3.6)

  50. Deaths in Clinical Efficacy Studies • Reports of deaths balanced between TEL and comparators: • TEL: 7 (0.3%), comparators: 9 (0.4%) • (uncontrolled studies: 10; 0.6%) • No treatment related deaths

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