Reinhard Baildon, M.D.

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
(No Transcript)
4
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

5
Sponsor Section

• Craig Brater, MD University of Indiana
• John Camm, MD St. Georges 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

6
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

7
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)

8
Voriconazole
Fluconazole
Voriconazole
9
Voriconazole

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

10
Esophageal Candidiasis Study (305)MIC Data for
Candida Isolates
11
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)
12
Global Comparative Aspergillosis Study (307/602)
MIC Data for Aspergillus Isolates
13
VoriconazoleIn Vivo Model

• Immunocompromised guinea pigs (cyclophosphamide
  and dexamethasone)
• Dunkin Hartley guinea pigs
• gt 90 reduction in neutrophils
• Direct IV inoculation
• Efficacy measured
• Survival
• Cure
• Tissue burden

14
Neutropenic Guinea Pig ModelDisseminated
Invasive Aspergillosis
Dose (mg/kg/day)
Treatment group
1.25 5 10 5 10
Colony Count (mean log10 CFU/g of tissue SE)
Tissue
Source Kirkpatrick et al, AAC, 2000
15
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

16
Voriconazole

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

17
VoriconazoleClinical Pharmacology

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

18
Voriconazole

• Oral bioavailability of 96
• Volume of distribution of 4.6 L/kg
• Plasma protein binding 58

19
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
20
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

21
VoriconazoleNon-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

Average Steady State Plasma Concentration (?g/ml)
Twice Daily Dose (mg)
22
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)
23
Voriconazole Factors Influencing Pharmacokinetic
Variability

• CYP2C19 genotype
• Race
• Gender and age in adults
• Children (2 - lt 12 years)
• Body weight
• Hepatic impairment
• Renal impairment
• Concomitant medications

24
Voriconazole Factors Influencing Pharmacokinetic
Variability

• CYP2C19 genotype
• Race
• Gender and age in adults
• Children (2 - lt 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 - lt 12 years)
• Body weight
• Hepatic impairment
• Renal impairment
• Concomitant medications

No dose adjustment
26
Voriconazole Factors Influencing Pharmacokinetic
Variability

• CYP2C19 genotype
• Race
• Gender and age in adults
• Children (2 - lt 12 years) maintenance dose of
  4mg/kg IV q 12 h
• Body weight
• Hepatic impairment
• Renal impairment
• Concomitant medications

27
Voriconazole Factors Influencing Pharmacokinetic
Variability

• CYP2C19 genotype
• Race
• Gender and age in adults
• Children (2 - lt 12 years)
• Body weight under 40 kg halve oral maintenance
  dose
• Hepatic impairment
• Renal impairment
• Concomitant medications

28
Voriconazole Factors Influencing Pharmacokinetic
Variability

• CYP2C19 genotype
• Race
• Gender and age in adults
• Children (2 - lt 12 years)
• Body weight
• Hepatic impairment halve maintenance dose
• Renal impairment
• Concomitant medications

29
Voriconazole Factors Influencing Pharmacokinetic
Variability

• CYP2C19 genotype
• Race
• Gender and age in adults
• Children (2 - lt 12 years)
• Body weight
• Hepatic impairment
• Renal impairment use oral in patients with serum
  creatinine gt 2.5 mg/dL
• Concomitant medications

30
Voriconazole Factors Influencing Pharmacokinetic
Variability

• CYP2C19 genotype
• Race
• Gender and age in adults
• Children (2 - lt 12 years)
• Body weight
• Hepatic impairment
• Renal impairment
• Concomitant medications drug-drug interactions

31
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

32
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
33
Voriconazole Drug-drug Interactions Dose
Adjustment
Studied in volunteers
34
Voriconazole Drug-drug Interactions Dose
Adjustment
Studied in volunteers, other interactions
predicted
35
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
36
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

37
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

38
VoriconazoleFactors Affecting Dose Selection

• Clinical PK
• Variability
• Dose ranging
• Safety MTD

Voriconazole
Pathogen
Host
Susceptibility Variability Pre-clinical PD
Immune dysfunction Organ dysfunction Other risk
factors
39
VoriconazoleDose Selection

• Target maximum tolerated dose
• Aim for plasma concentrations above MIC for
  common pathogens

40
VoriconazoleDosage and Administration
If patient response is inadequate, increase dose
to 4 mg/kg IV or 300 mg oral
41
(No Transcript)
42
Voriconazole

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

43
Voriconazole Safety Database
44
VoriconazoleOverall Patient Exposure
45
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)

46
Overview of Safety Presentation

• Deaths and discontinuations
• Adverse events
• Special safety topics
• Emerging clinical, animal, published data
• Thorough investigation

47
VoriconazoleDeaths - Safety Populations
Median duration 73 days Median duration 12
days
48
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)
49
Discontinuations Due to Adverse Events and
Laboratory Abnormalities
50
Healthy Volunteers Most Frequent Voriconazole
Adverse Events
51
Global Comparative Aspergillosis Study (307/602)
Most Frequent Voriconazole Adverse Events
1 12813 patient-days 2 11243 patient-days
52
Empirical Therapy Study (603/MSG42) Most
Frequent Voriconazole Adverse Events
53
Esophageal Candidiasis Study (305) Most Frequent
Voriconazole Adverse Events
54
Voriconazole Special Safety Topics

• Visual disturbances
• Hepatic adverse events
• Skin reactions
• Other topics
• Cardiac adverse events
• Anaphylactoid reactions
• Renal function
• Sepsis
• Hallucinations

55
Voriconazole Frequency of Abnormal Vision
56
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

57
NDA Therapeutic StudiesDistribution of Time to
First Visual Disturbance
n/N first reports/patients at risk
Patients with Visual Disturbance frequency (n/N)
Time on Therapy
58
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)

59
Multiple Dose Visual Function Study (1004)
0 -100 -200 -300 -400
White stimulus, scotopic conditions. The a-wave
measures photoreceptor activity.
A-wave Amplitude (?V)
Lines join the group mean values
Baseline Day 1 Day 8 Day 29 Day 43 Study Day
Voriconazole
Placebo
60
Multiple Dose Visual Function Study (1004)
700 600 500 400 300 200
White stimulus, scotopic conditions. The b-wave
measures activity of inner nuclear layer of
retina.
B-wave Amplitude (?V)
Lines join the group mean values
Baseline Day 1 Day 8 Day 29 Day 43 Study Day
Voriconazole
Placebo
61
Multiple Dose Visual Function Study (1004) Left
Eye Visual Acuity - Change from Baseline
62
Esophageal Candidiasis Study (305)Visual Acuity
- Change from Baseline
Worst of left, right eye or both
63
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

64
Voriconazole Special Safety Topics

• Visual disturbances
• Hepatic adverse events
• Skin reactions
• Other topics
• Cardiac adverse events
• Anaphylactoid reactions
• Renal function
• Sepsis
• Hallucinations

65
Multiple Dose Escalation IV/Oral Switch Study
(230) Hepatic Function in Volunteers
Subjects with ALT elevations n/N
Voriconazole Dose
3 mg/kg IV to 200 mg oral q 12 h 0/ 14 4 mg/kg
IV to 300 mg oral q 12 h 1/ 7 5 mg/kg IV to
400 mg oral q 12 h 5/ 14
ALT upper limit of normal 72 IU IV
maintenance dose following 6 mg/kg q 12 h day 1
loading dose regimen
66
Multiple Dose Escalation IV/Oral Switch Study
(230) Hepatic Function in Volunteers
Changes in alanine transaminase (ALT) over time
in 6/21 volunteers with ALT abnormalities
ALT (IU)
ULN (72 IU)
Days After Start of Dosing
(S39) Dose of 4 mg/kg IV and 300 mg orally q 12
h, all others 5 mg/kg IV and 400 mg orally q 12 h.
67
VoriconazoleFrequency of Abnormal ALT (gt 3 x ULN)
68
VoriconazoleFrequency of Abnormal Total
Bilirubin (gt 1.5 X ULN)
69
Frequency of Hepatic Failure and DeathSerious
Adverse Events
1 additional hepatic failure leading to death
occurred in the comparator arm of study 608
70
Hepatic Failure and DeathCausal Relationship not
Excluded by Investigator or Sponsor
71
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

72
Voriconazole Special Safety Topics

• Visual disturbances
• Hepatic adverse events
• Skin reactions
• Other topics
• Cardiac adverse events
• Anaphylactoid reactions
• Renal function
• Sepsis
• Hallucinations

73
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

74
Frequency of Rash
75
Frequency of Photosensitivity Reaction
76
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

77
Voriconazole Special Safety Topics

• Visual disturbances
• Hepatic adverse events
• Skin reactions
• Other topics
• Cardiac adverse events
• Anaphylactoid reactions
• Renal function
• Sepsis
• Hallucinations

78
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

79
Voriconazole Sudden Cardiac DeathPatient 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

80
In vitro Studies of Voriconazole and Ketoconazole
Ketoconazole
Voriconazole
27.5 µM free drug 20.0 µg/ml total
Change
Change
Concentration (?M)
Concentration (?M)
Approximate human exposure range
No effect of N-Oxide metabolite in binding or
Purkinje at 50 µM
81
Phase 1 Frequency of Borderline and Abnormal QTc
(Fridericia Correction)
All subjects from 8 single and multiple dose
studies
82
Voriconazole Phase I ECG AnalysisQTc
(Fridericia) 1 hour post single dose
Change in QTcF (msec)
Plasma Voriconazole Concentration (mg/ml)
83
Anaphylactoid Reactions
84
Empirical Therapy Study (603/MSG42) Infusion
Related Reactions (MITT) - All
10,398 infusions monitored in 837 patients
Syndrome of sporadic acute infusion related
reactions due to liposomal amphotericin B Roden
et al, ICAAC, Chicago 2001
85
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

86
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

87
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