Reinhard Baildon, M. D. Executive Director



Yüklə 460 b.
tarix26.02.2017
ölçüsü460 b.


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



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

  • Anaphylactoid reactions

  • Renal function

    • Proposed to monitor creatinine
  • Sepsis and host resistance

  • 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




Yüklə 460 b.

Dostları ilə paylaş:




Verilənlər bazası müəlliflik hüququ ilə müdafiə olunur ©azkurs.org 2020
rəhbərliyinə müraciət

    Ana səhifə