# Presentation: 705095

## 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**

## Slide 3

## 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

**Fluconazole **

**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)

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

**Fluconazole Susceptibility (Log****10**** MIC)**

**Voriconazole Susceptibility (Log****10**** MIC)**

**2**
**1**
**0**
**-1**
**-2**
**-3**

**-1****	****0****	****1****	****2****	****3**

## 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

**Colony Count (mean log****10**** CFU/g of tissue + SE) **

**Dose (mg/kg/day)**

**Treatment group**

**	****1.25**
**	****5**
**10**
**	**** ****5**
**10**
**	**
**	**

**Source: Kirkpatrick et al, AAC, 2000**

**Tissue**

## 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***

***Jezequel et al. 1995, ICAAC**

## 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**

**Average Steady State**
**Plasma Concentration (********g/ml)**

**Twice Daily Dose (mg)**

## VoriconazoleLoading 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)**

**Time Post First Dose (hours)**

**400mg**

**400mg**

**200mg**

## 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**

**No dose **
**adjustment**

## 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**

## 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)****	****	****     ****	**

*** Studied in volunteers, other interactions predicted**

## Voriconazole Drug-drug Interactions: Dose Adjustment

**Voriconazole ****Drug-drug Interactions: Dose Adjustment**

*** Studied in volunteers**

## Voriconazole Drug-drug Interactions: Dose Adjustment

*** Studied in volunteers, other interactions predicted**

## 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**

## 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

**Pathogen**

**Voriconazole**

**Host**

**Clinical PK**
**Variability**
**Dose ranging**
**Safety: MTD**

**Susceptibility**
**Variability**
**Pre-clinical PD**

**Immune dysfunction**
**Organ dysfunction**
**Other risk factors**

## VoriconazoleDose Selection

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

## VoriconazoleDosage and Administration

**Voriconazole****Dosage and Administration**

**If patient response is inadequate, increase dose to 4 mg/kg IV or 300 mg oral**

## Slide 41

## 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

*** Median duration 73 days**
**** Median duration 12 days**

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

**Amphotericin B +/- ****OLAT**** **

**Voriconazole +/- ****OLAT**** **

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

**Number of Days of Treatment**

**Probability of Survival**

**Hazard ratio = 0.60  ( 95% CI  0.42 , 0.84)**

**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)**

## Discontinuations Due to Adverse Events and Laboratory Abnormalities 

**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

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

**1**** 12813 patient-days****	****2**** 11243 patient-days**

## 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

**Patients with Visual Disturbance**
**% frequency (n/N)**

**Time on Therapy**

**NDA Therapeutic Studies****Distribution of Time to First Visual Disturbance**

**n/N first reports/patients at risk**

## 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)**

**0**
**-100**
**-200**
**-300**
**-400**

**Baseline****	****Day 1****	****Day 8****	****Day 29****	****Day 43**
**	****	****Study Day**

**Voriconazole**

**Placebo**

**A-wave Amplitude (****V)**

**White stimulus, scotopic conditions. The a-wave measures photoreceptor activity.**

**Lines join the group mean values**

## Multiple Dose Visual Function Study (1004)

**700**
**600**
**500**
**400**
**300**
**200**

**B-wave Amplitude (****V)**

**Baseline****	****Day 1****	****Day 8****	****Day 29****	****Day 43**
**	****	****Study Day**

**Multiple Dose Visual Function Study (1004)**

**Voriconazole**

**Placebo**

**White stimulus, scotopic conditions. The b-wave measures activity of inner nuclear layer of retina.**

**Lines join the group mean values**

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

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

*** Worst of left, right eye or both **

## 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

**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**

**Subjects with ALT elevations* n/N**

**Voriconazole Dose**

***ALT upper limit of normal = 72 IU****	******IV maintenance dose following 6 mg/kg q ****	****	****12 h day 1 loading dose regimen**

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

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

**Days After Start of Dosing**

**ALT (IU)**

**Changes in alanine transaminase (ALT) over time in 6/21 volunteers with ALT abnormalities**

**ULN**
**(72 IU)**

***(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.**

## 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

**Frequency of Hepatic Failure and Death****Serious Adverse Events**

**1 additional hepatic failure leading to death occurred in the comparator arm of study 608**

## 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

**Ketoconazole**

**Voriconazole**

- Approximate human exposure range

**27.5 μM free drug **
**= 20.0 μg/ml total**

***In vitro***** Studies of Voriconazole and Ketoconazole**

**% Change**

**% Change**

**Concentration (********M)**

**Concentration (********M)**

- No effect of N-Oxide metabolite in binding or Purkinje at 50 μM

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

**All subjects from 8 single and multiple dose studies**

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

**Plasma Voriconazole Concentration (********g/ml)**

**Change in QTcF (msec)**

## Anaphylactoid Reactions

## 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**

**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**