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Reinhard Baildon, M.D.

Reinhard Baildon, M.D. Executive Director Clinical Development Pfizer Global Research & Development. Voriconazole. Introduction In vitro and in vivo Data Clinical Pharmacology Efficacy Safety Conclusion. Voriconazole Development Program. First in human: 1991

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Reinhard Baildon, M.D.

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  1. Reinhard Baildon, M.D. Executive Director Clinical Development Pfizer Global Research & Development

  2. Voriconazole • Introduction • In vitro and in vivo Data • Clinical Pharmacology • Efficacy • Safety • Conclusion

  3. VoriconazoleDevelopment Program • First in human: 1991 • IND for oral/IV: 08/95, 04/96 • NDA submitted 11/00 • Extensive, frequent discussion with Division • Collaboration with NIAID Mycoses Study Group (MSG) and European Organisation for Research and Treatment of Cancer (EORTC) • External Data Review Committees (DRCs) for rigorous, blinded efficacy assessments

  4. Craig Brater, MD University of Indiana John Camm, MD St. George’s Hospital George Drusano, MD Albany Medical College Frederick Fraunfelder, MD Casey Eye Institute Willis Maddrey, MD University of Texas, Dallas Thomas Patterson, MD University of Texas, San Antonio Guy Paulus, MD, PhD Consultant John Rex, MD University of Texas, Houston Robert Rubin, MD Harvard University Jeremy Ruskin, MD Massachusetts General Hospital Eugene Schiff, MD University of Miami Thomas Walsh, MD National Cancer Institute Paul Watkins, MD University of North Carolina Andrew Whelton, MDConsultant Sponsor Section

  5. Voriconazole • Superior outcome and survival benefit in primary therapy of acute invasive aspergillosis • Efficacy in patients with Scedosporium and Fusarium infections • Efficacy in Candida infections • Appropriate option for empirical therapy • Better tolerated than amphotericin B formulations • Acceptable overall safety profile • Manageable drug-drug interactions

  6. VoriconazoleClinical Program Invasive Aspergillosis • Global Comparative Aspergillosis Study (307/602) • Non-Comparative Aspergillosis Study (304) • Historical Control Study (1003) Emerging Pathogens • Scedosporium Infections • Fusarium Infections Candida Infections • Esophageal Candidiasis Study (305) • Pooled Efficacy Data Empirical Therapy Study (603/MSG42)

  7. Me F HO HO N N N N N N N N N N N F F F F Voriconazole Fluconazole Voriconazole

  8. Voriconazole • Introduction • In vitro and in vivo Data • Clinical Pharmacology • Efficacy • Safety • Conclusion

  9. Esophageal Candidiasis Study (305)MIC Data for Candida Isolates

  10. Esophageal Candidiasis Study (305)Clinical Isolate Susceptibilities (N = 633) 2 1 0 -1 -2 -3 Voriconazole Susceptibility (Log10 MIC) -1 0 1 2 3 Fluconazole Susceptibility (Log10 MIC)

  11. Organism Number of Isolates Antifungal Agent MIC Range (g/mL) MIC50 (g/mL) MIC90 (g/mL) A. fumigatus 160 Voriconazole Itraconazole Amphotericin B 0.06 - 1 0.03 - 1 0.2 - 2 0.25 0.25 1.0 0.5 0.5 2.0 A. niger 16 Voriconazole Itraconazole Amphotericin B 0.125 - 1.0 0.06 - 0.5 0.25 - 1.0 0.25 0.5 0.25 1.0 0.5 1.0 A. flavus 14 Voriconazole Itraconazole Amphotericin B 0.125 - 0.5 0.03 - 0.25 0.5 - 4.0 0.25 0.12 1.0 0.5 0.25 2.0 A. terreus 15 Voriconazole Itraconazole Amphotericin B 0.125 - 1.0 <0.01 - 0.25 0.5 - 4.0 0.25 0.12 1.0 1.0 0.25 4.0 A. nidulans 5 Voriconazole Itraconazole Amphotericin B 0.06 - 0.125 0.06 - 0.25 0.5 - 1.0 A. glaucus 1 Voriconazole Itraconazole Amphotericin B 0.5 0.5 4.0 A. sydowii 1 Voriconazole Itraconazole Amphotericin B 0.12 0.12 2.0 Global Comparative Aspergillosis Study (307/602)MIC Data for Aspergillus Isolates

  12. VoriconazoleIn Vivo Model Immunocompromised guinea pigs (cyclophosphamide and dexamethasone) • Dunkin Hartley guinea pigs • > 90% reduction in neutrophils • Direct IV inoculation • Efficacy measured • Survival • Cure • Tissue burden

  13. Neutropenic Guinea Pig ModelDisseminated Invasive Aspergillosis Treatment group Dose (mg/kg/day) 1.25 5 10 5 10 Colony Count (mean log10 CFU/g of tissue + SE) Tissue Source: Kirkpatrick et al, AAC, 2000

  14. Voriconazole • In vitro potency against yeasts 60-fold higher than for fluconazole • Cidality against Aspergillus and other moulds • In vitro potency translates into in vivo efficacy in severely immunocompromised animals

  15. Voriconazole • Introduction • In vitro and in vivo Data • Clinical Pharmacology • Efficacy • Safety • Conclusion

  16. VoriconazoleClinical Pharmacology • Absorption and distribution • Metabolism and excretion • Non-linear pharmacokinetics • Loading dose regimen • Factors influencing pharmacokinetic variability • Drug-drug interactions

  17. Voriconazole • Oral bioavailability of 96% • Volume of distribution of 4.6 L/kg • Plasma protein binding 58%

  18. VoriconazoleTissue Distribution in Animals • Concentrations of radioactivity in male rat tissue at 5 minutes post infusion • Cerebrospinal fluid/plasma concentrationratio = 0.8 in guinea pigs at steady state after multiple dosing* *Jezequel et al. 1995, ICAAC

  19. VoriconazoleMetabolism and Excretion • Metabolized primarily by the hepatic cytochrome P450 isoenzymes CYP2C19, CYP2C9 and CYP3A4 • CYP2C19 exhibits genetic polymorphism • Extensive metabolism to a major circulating N-oxide metabolite (72% at 1 hour) and several minor metabolites • Metabolite present in toxicology species,does not contribute to efficacy • Less than 2% of a dose excreted unchanged in the urine

  20. Due to saturation of metabolism (Michaelis-Menten kinetics) Greater than proportional increase in exposure with increasing dose On average, 1.5-fold oral dose escalation from 200 mg q 12 h to 300 mg q 12 h will lead to a 2.5-fold increase in exposure VoriconazoleNon-linear Pharmacokinetics Average Steady State Plasma Concentration (g/ml) Twice Daily Dose (mg)

  21. VoriconazoleLoading Dose Regimen (Study 247) Mean plasma voriconazole concentrations in 17 healthy subjects: oral 400mg q 12 h x 1 d followed by 200mg q 12 h x 9 d Day 1 Day 10 Plasma Voriconazole Concentration (µg/ml) 400mg 400mg 200mg Time Post First Dose (hours)

  22. Voriconazole Factors Influencing Pharmacokinetic Variability • CYP2C19 genotype • Race • Gender and age in adults • Children (2 - < 12 years) • Body weight • Hepatic impairment • Renal impairment • Concomitant medications

  23. Voriconazole Factors Influencing Pharmacokinetic Variability • CYP2C19 genotype • Race • Gender and age in adults • Children (2 - < 12 years) • Body weight • Hepatic impairment • Renal impairment • Concomitant medications No dose adjustment

  24. Voriconazole Factors Influencing Pharmacokinetic Variability • CYP2C19 genotype • Race • Gender and age in adults • Children (2 - < 12 years) • Body weight • Hepatic impairment • Renal impairment • Concomitant medications No dose adjustment

  25. Voriconazole Factors Influencing Pharmacokinetic Variability • CYP2C19 genotype • Race • Gender and age in adults • Children (2 - < 12 years): maintenance dose of 4mg/kg IV q 12 h • Body weight • Hepatic impairment • Renal impairment • Concomitant medications

  26. Voriconazole Factors Influencing Pharmacokinetic Variability • CYP2C19 genotype • Race • Gender and age in adults • Children (2 - < 12 years) • Body weight: under 40 kg halve oral maintenance dose • Hepatic impairment • Renal impairment • Concomitant medications

  27. Voriconazole Factors Influencing Pharmacokinetic Variability • CYP2C19 genotype • Race • Gender and age in adults • Children (2 - < 12 years) • Body weight • Hepatic impairment: halve maintenance dose • Renal impairment • Concomitant medications

  28. Voriconazole Factors Influencing Pharmacokinetic Variability • CYP2C19 genotype • Race • Gender and age in adults • Children (2 - < 12 years) • Body weight • Hepatic impairment • Renal impairment: use oral in patients with serum creatinine > 2.5 mg/dL • Concomitant medications

  29. Voriconazole Factors Influencing Pharmacokinetic Variability • CYP2C19 genotype • Race • Gender and age in adults • Children (2 - < 12 years) • Body weight • Hepatic impairment • Renal impairment • Concomitant medications: drug-drug interactions

  30. VoriconazoleDrug-drug Interactions Explored in 19 studies including 365 volunteers • Effect of nine other drugs on voriconazole • Effect of voriconazole on 11 other drugs Recommendations • Contraindications • Dose adjustments of voriconazole or concomitant medications • Monitor concentrations or effects of concomitant medications • No adjustments needed

  31. VoriconazoleDrug-drug Interactions: Contraindications The following drugs are contraindicated: • Rifampin*, barbiturates (long-acting), carbamazepine (decreased voriconazole exposure) • Sirolimus*, terfenadine, astemizole, cisapride, pimozide, quinidine, ergot alkaloids (voriconazole increases exposure to these medications) * Studied in volunteers, other interactions predicted

  32. Voriconazole Drug-drug Interactions: Dose Adjustment * Studied in volunteers

  33. Voriconazole Drug-drug Interactions: Dose Adjustment * Studied in volunteers, other interactions predicted

  34. Voriconazole Drug-drug Interactions • No dose adjustment required when voriconazole is administered with: • Macrolide antibiotics • Indinavir • Cimetidine • Ranitidine • Digoxin • Mycophenolate • Prednisolone All studied in volunteers

  35. VoriconazoleSummary of Pharmacokinetics • Rapid and consistent absorption with high oral bioavailability (96%) • Large volume of distribution (4.6 L/kg) • Non-linear elimination • Hepatic metabolism by CYP2C19, 2C9 and 3A4 isoenzymes • Increased exposure in cirrhosis • Metabolic drug interactions well-characterized

  36. Voriconazole • Superior outcome and survival benefit in primary therapy of acute invasive aspergillosis • Efficacy in patients with Scedosporium and Fusarium infections • Efficacy in Candida infections • Appropriate option for empirical therapy • Better tolerated than amphotericin B formulations • Acceptable overall safety profile • Manageable drug-drug interactions

  37. VoriconazoleFactors Affecting Dose Selection • Clinical PK • Variability • Dose ranging • Safety: MTD Voriconazole Pathogen Host Immune dysfunction Organ dysfunction Other risk factors Susceptibility Variability Pre-clinical PD

  38. VoriconazoleDose Selection • Target maximum tolerated dose • Aim for plasma concentrations above MIC for common pathogens

  39. VoriconazoleDosage and Administration If patient response is inadequate, increase dose to 4 mg/kg IV or 300 mg oral

  40. Voriconazole • Introduction • In vitro and in vivo data • Clinical Pharmacology • Efficacy • Safety • Conclusion

  41. Voriconazole Safety Database

  42. VoriconazoleOverall Patient Exposure

  43. Voriconazole Target Population • Severe underlying disease • Multiple interventions, eg bone marrow transplant • 26.9% of patients in Global Comparative Aspergillosis Study (307/602) • 49.8% of patients in Empirical Therapy Study (603) • Multiple concomitant medications • Mean of 26 in Global Comparative Aspergillosis Study (307/602) • Mean of 23 in Empirical Therapy Study (603)

  44. Overview of Safety Presentation • Deaths and discontinuations • Adverse events • Special safety topics • Emerging clinical, animal, published data • Thorough investigation

  45. VoriconazoleDeaths - Safety Populations * Median duration 73 days ** Median duration 12 days

  46. Global Comparative Aspergillosis Study (307/602)Time to Death (Safety Population) Voriconazole +/- OLAT Amphotericin B +/- OLAT Probability of Survival Hazard ratio = 0.60 ( 95% CI 0.42 , 0.84) Number of Days of Treatment At Risk (Censored) Vori 196 (0) 179 (0) 166 (0) 158 (0) 151 (0) 146 (0) 140 (0) AMB 185 (0) 161 (0) 139 (0) 124 (0) 119 (0) 112 (0) 107 (0)

  47. Discontinuations Due to Adverse Events and Laboratory Abnormalities

  48. Healthy Volunteers Most Frequent Voriconazole Adverse Events

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