Reinhard Baildon, M. D. Executive Director

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

• 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

Sponsor Section

• 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, MD Consultant

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

Voriconazole Clinical 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)

Voriconazole

Voriconazole

• Introduction

• In vitro and in vivo Data

• Clinical Pharmacology

• Efficacy

• Safety

• Conclusion

Esophageal Candidiasis Study (305) MIC Data for Candida Isolates

Esophageal Candidiasis Study (305) Clinical Isolate Susceptibilities (N = 633)

Global Comparative Aspergillosis Study (307/602) MIC Data for Aspergillus Isolates

Voriconazole In 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

Neutropenic Guinea Pig Model Disseminated Invasive Aspergillosis

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

Voriconazole

• Introduction

• In vitro and in vivo Data

• Clinical Pharmacology

• Efficacy

• Safety

• Conclusion

Voriconazole Clinical Pharmacology

• Absorption and distribution

• Metabolism and excretion

• Non-linear pharmacokinetics

• Loading dose regimen

• Factors influencing pharmacokinetic variability

• Drug-drug interactions

Voriconazole

• Oral bioavailability of 96%

• Volume of distribution of 4.6 L/kg

• Plasma protein binding 58%

Voriconazole Tissue Distribution in Animals

• Concentrations of radioactivity in male rat tissue at 5 minutes post infusion

• Cerebrospinal fluid/plasma concentration ratio = 0.8 in guinea pigs at steady state after multiple dosing*

Voriconazole Metabolism 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

Voriconazole Non-linear Pharmacokinetics

• 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

Voriconazole Loading Dose Regimen (Study 247)

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

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

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

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

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

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

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

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

Voriconazole Drug-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

Voriconazole Drug-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)

Voriconazole Drug-drug Interactions: Dose Adjustment

Voriconazole Drug-drug Interactions: Dose Adjustment

Voriconazole Drug-drug Interactions

• No dose adjustment required when voriconazole is administered with:

• Macrolide antibiotics
• Indinavir
• Cimetidine
• Ranitidine
• Digoxin
• Mycophenolate
• Prednisolone

Voriconazole Summary 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

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

Voriconazole Factors Affecting Dose Selection

Voriconazole Dose Selection

• Target maximum tolerated dose

• Aim for plasma concentrations above MIC for common pathogens

Voriconazole Dosage and Administration

Voriconazole

• Introduction

• In vitro and in vivo data

• Clinical Pharmacology

• Efficacy

• Safety

• Conclusion

Voriconazole Safety Database

Voriconazole Overall Patient Exposure

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)

Overview of Safety Presentation

• Deaths and discontinuations

• Adverse events

• Special safety topics

• Emerging clinical, animal, published data
• Thorough investigation

Voriconazole Deaths - Safety Populations

Global Comparative Aspergillosis Study (307/602) Time to Death (Safety Population)

Discontinuations Due to Adverse Events and Laboratory Abnormalities

Healthy Volunteers Most Frequent Voriconazole Adverse Events

Global Comparative Aspergillosis Study (307/602) Most Frequent Voriconazole Adverse Events

Empirical Therapy Study (603/MSG42) Most Frequent Voriconazole Adverse Events

Esophageal Candidiasis Study (305) Most Frequent Voriconazole Adverse Events

Voriconazole Special Safety Topics

• Visual disturbances

• Hepatic adverse events

• Skin reactions

• Other topics

• Cardiac adverse events
• Anaphylactoid reactions
• Renal function
• Sepsis
• Hallucinations

Voriconazole Frequency of Abnormal Vision

Descriptions of Visual Disturbances

• Enhanced perception of light

• “Brightness of lights”, “brightness of vision”, “feeling of strong brightness”, “objects appear bright”

• Blurred vision

• “Smoke in eyes”, “fuzzy vision”, “hazy eyesight”, “vision blurring”

• Photophobia

• “Severe dazzling”, “light sensitivity”, “flash in eyes with dazzling”

• Color vision changes

• “Yellow fog”, “colors more vivid”, “difficult to distinguish blue and green”

NDA Therapeutic Studies Distribution of Time to First Visual Disturbance

Multiple Dose Visual Function Study (1004)

• Double-blind, randomized, placebo-controlled, parallel group study (N = 18/group), treatment duration 28.5 days

• Oral voriconazole
• Usual loading dose regimen, followed by 300 mg q 12 h

• ERG at screening and on Days 1, 8, 29 and 43

• Tests on Days 3, 7, 28 and 42

• Farnsworth-Munsell 100 Hue test
• Humphrey Visual field test
• Slit lamp test
• Visual acuity test
• External eye examinations
• Funduscopy (indirect and direct)

Multiple Dose Visual Function Study (1004)

Multiple Dose Visual Function Study (1004)

Multiple Dose Visual Function Study (1004) Left Eye Visual Acuity - Change from Baseline

Esophageal Candidiasis Study (305) Visual Acuity - Change from Baseline*

Visual Disturbances: Conclusions

• Most frequent adverse drug reaction

• Site of action: Retina determined by electroretinography (ERG)

• Decreased amplitude of ERG waveform in human and dog

• No structural alterations in retina or visual pathways in 6 and 12 month dog studies

• Occur early in course of therapy and dosing

• Functional changes reversible after discontinuation

Voriconazole Special Safety Topics

• Visual disturbances

• Hepatic adverse events

• Skin reactions

• Other topics

• Cardiac adverse events
• Anaphylactoid reactions
• Renal function
• Sepsis
• Hallucinations

Multiple Dose Escalation IV/Oral Switch Study (230) Hepatic Function in Volunteers

Multiple Dose Escalation IV/Oral Switch Study (230) Hepatic Function in Volunteers

Voriconazole Frequency of Abnormal ALT (> 3 x ULN)

Voriconazole Frequency of Abnormal Total Bilirubin (> 1.5 X ULN)

Frequency of Hepatic Failure and Death Serious Adverse Events

Hepatic Failure and Death Causal Relationship not Excluded by Investigator or Sponsor

Hepatic Conclusions

• Enzyme elevations reversible after dose withdrawal

• Comparative studies hepatic adverse effects

• Similar frequency for voriconazole and amphotericin B formulations
• Greater frequency for voriconazole than for fluconazole

• Monitoring of hepatic function is recommended

Voriconazole Special Safety Topics

• Visual disturbances

• Hepatic adverse events

• Skin reactions

• Other topics

• Cardiac adverse events
• Anaphylactoid reactions
• Renal function
• Sepsis
• Hallucinations

Descriptions of Skin Adverse Events

• Rash

• “rash on trunk and arms”, “facial erythema”, “exanthema”, “generalized erythema”, “head, neck and shoulder erythema”, “neck redness”, “dermatitis”, “allergic skin reaction”

• Photosensitivity Reaction

• “photosensitivity skin reaction”, “photosensitization of face”, “photosensitivity rash”, “skin rash in sun exposed regions”, “sunburn”

Frequency of Rash

Frequency of Photosensitivity Reaction

Skin Conclusions

• In comparative studies, skin adverse effects occurred with a similar frequency in voriconazole, amphotericin B- and fluconazole-treated patients

• Photosensitivity potential cannot be excluded

Voriconazole Special Safety Topics

• Visual disturbances

• Hepatic adverse events

• Skin reactions

• Other topics

• Cardiac adverse events
• Anaphylactoid reactions
• Renal function
• Sepsis
• Hallucinations

Other Safety Issues

• Cardiac adverse events

• One cardiac death
• Thorough in vitro, Phase 1 and clinical investigations

• Anaphylactoid reactions

• Renal function

• Proposed to monitor creatinine

• Sepsis and host resistance

• No association identified

• Hallucinations

• Role for voriconazole not excluded
• No impact on therapy

Voriconazole Sudden Cardiac Death Patient 603/1485

• 52 year old white female, acute myeloid leukemia

• Previous idarubicin therapy, dilated left ventricle, history of benign ventricular arrhythmias

• Hypokalemia (3.1 mmol/L; normal = 3.5 - 5.1)

• Hypophosphatemia (0.49 mmol/L; normal = 1.13 - 1.60)

• KCl infusion plus 30 mEq bolus administered prior to voriconazole, phosphorous not replaced

• Seizure and cardiac arrest after voriconazole infusion

• Death attributed to ventricular fibrillation, medullary hypoplasia, myeloid leukemia by investigator

• Sponsor could not exclude contribution of voriconazole

In vitro Studies of Voriconazole and Ketoconazole

Phase 1: Frequency of Borderline and Abnormal QTc (Fridericia Correction)

Voriconazole Phase I ECG Analysis QTc (Fridericia) 1 hour post single dose

Anaphylactoid Reactions

Empirical Therapy Study (603/MSG42) Infusion Related Reactions (MITT) - All*

Other Safety Issues

• Cardiac adverse events

• One cardiac death
• Thorough in vitro, Phase 1 and clinical investigations

• Anaphylactoid reactions

• Renal function

• Proposed to monitor creatinine

• Sepsis and host resistance

• No association identified

• Hallucinations

• Role for voriconazole not excluded
• No impact on therapy

Safety Conclusions

• Visual disturbances

• Site of action is the retina
• No structural alterations in retina or visual pathways in 6 and 12 month dog studies
• Functional changes reversible after discontinuation

• Hepatic adverse events

• Enzyme elevations reversible after dose reduction/withdrawal
• In comparative studies frequency similar to that seen in amphotericin B-treated patients, greater frequency than in fluconazole-treated patients
• Monitoring of hepatic function is recommended

• Skin reactions

• In comparative studies, skin adverse effects occurred with a similar frequency as for comparators
• Photosensitivity potential cannot be excluded

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