Voriconazole and the New Azoles

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Voriconazole and the New Azoles

• John H. Rex, M.D.
• University of Texas Medical School
• Houston, Texas

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Disclaimer

• AB Biodisk
• Baxter Healthcare
• Bristol-Myers Squibb
• Fujisawa
• Elan (The Liposome Company)
• Gilead
• Janssen Pharmaceutica

• Lilly
• Merck Research Laboratories
• Ortho-Biotech
• Pfizer Inc.
• Schering-Plough Research Institute
• Uriach Co., SA
• Versicor

3
Roadmap for This Talk

• Overview
• What we have, what we need
• Introduction to the new azoles
• One is licensed
• Voriconazole well cover its use in some detail
• About these slides
• Lots of references usedtoo many to copy. These
  slides will be available in the lecture bank of
  www.doctorfungus.org within a week.

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The New Broad-Spectrum Azoles

• Voriconazole. Now licensed
• Oral and IV forms
• Posaconazole. Phase III
• Oral only, at least at present
• Ravuconazole. Phase II. Limited public data
• Oral for sure, IV is hopeful
• Others for which we dont have time
• Albaconazole (UR-9825), CS-758, etc.

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What makes the new azoles special?

• 1. A promise of better Candida activity
• All work for C. albicans, tropicalis,
  parapsilosis
• C. glabrata (MIC90, 48h)
• Flu 32, Vori 1, Posa 2, Ravu 2
• C. krusei (MIC90, 48h)
• Flu gt 64, Vori 1, Posa 0.5, Ravu 0.5
• Neutropenic guinea pig model
• Vori reduced kidney CFU/g better than AmB or Flu
• More later on how this plays out

Ostrosky IDSA 642, 01 Pfaller AAC 461723,
02 Ghannoum J Chemother 1134, 99
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What makes the new azoles special?

• 2. Very potent anti-Aspergillus activity
• A. fumigatus (MIC90 at M38-Ps MIC-2)
• Itra 2, Vori 0.5, Posa 0.25, Ravu 1
• A. flavus
• Itra 0.5, Vori 1, Posa 0.5, Ravu 1
• These newer azoles often appear fungicidal
• Vori Sterilized valves in A. fumigatus
  endocarditis model
• Posa Also sterilizes tissue in some models
• Ravu Less data. At least equal to Itra AmB

Pfaller AAC 461032, 02 Martin AAC 4113, 97
Graybill JAC 42539, 98 Petraitiene AAC 45857
Kirkpatrick JAC 49353, 02
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What makes the new azoles special?

• 3. Other fungi More active, but they differ!
• Fusarium (Vori Posa. Limited data on Ravu)
• Vori 50 salvage rate. Licensed for this
• Posa Sterilized organs in an animal model
• Scedosporium (Vori, Posa, Ravu)
• Vori 50 salvage rate. Licensed for this.
• Posa, Ravu Not a lot of clinical data as yet
• Encouraging in vitro data (both) case reports
  (Posa)
• Zygomycetes (Posa)
• Active in vitro and in vivo. Quite encouraging.

Lozano-Chiu AAC 43589, 99 Carrillo AAC
452151, 01 Mellinghoff CID 341648, 02 Sun
AAC 462310, 02
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In Summary Form

• Vori Ravu Posa
• Candida
• Cryptococcus
• Aspergillus
• Fusarium ?
• Scedosporium
• Zygomycetes

Cryptococcus data Pfaller AAC 452862, 01
Yildiran EJCMID 19317. 00 Yamazumi AAC
442883, 00
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Voriconazole

• Now licensed. Lets look at it in some detail.

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Basic Stuff (1)

• Forms IV PO
• IV (200 mg/vial)
• Contains sulfobutylether-b-cyclodextrin
• Try to avoid if CrCl lt 50 (a few doses likely ok)
• PO (50 200 mg tablets) 96 bioavailable
• Dose
• IV 6 mg/kg q12 x 2 doses, then 4 mg/kg q12h
• PO 200 q12h if gt 40kg, 100 q12h if lt 40kg
• Can increase dose 50 if response is slow

Sabo Ann Pharmacother 341032, 00 Voriconazole
package insert, May 2002 Voriconazole FDA
Advisory Cmte, 01
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Basic Stuff (2)

• Clearance P450-based
• Mostly metabolized 2 unchanged in urine
• High inTER-subject variability, low inTRA
• Initial data little is removed by standard HD
• Special Populations
• Initial pedi data 4 mg/kg 3 mg/kg in adults
• Renal failure Use regular dose, but PO
• Hepatic failure In mild-moderate cirrhosis
  (Child-Pugh A-B), cut maintenance dose 50
• No data for severe (class C) cirrhosis

Sabo Ann Pharmacother 341032, 00 Voriconazole
package insert, May 2002 Voriconazole FDA
Advisory Cmte, 01
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Basic Stuff (3)

• What to monitor
• Blood levels Possible, but better to monitor
• Liver enzymes YES
• Rising liver enzymes suggest levels may be high
• Renal function Mentioned in PI, not sure why
• P450 drug interactions. LOTS OF THEM
• Vori increases sirolimus rifabutin dont mix
• CsA and tacrolimus are OK, but must lower dose
• Phenytoin drops vori, vori raises phenytoin
• Dosing directions in package insert read it!

Sabo Ann Pharmacother 341032, 00 Voriconazole
package insert, May 2002 Voriconazole FDA
Advisory Cmte, 01
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Adverse Events

• Hepatic
• Overall rate of 13. 2-fold more than Flu
• Visual
• Noted by 30. A sense of altered light
  perception, blurring, or photophobia
• EXHAUSTIVELY studied. No apparent consequences.
• Miscellaneous
• Photosensitivity (1)? Avoid strong sunlight.

Sabo Ann Pharmacother 341032, 00 Voriconazole
package insert, May 2002 Voriconazole FDA
Advisory Cmte, 01
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Aspergillus
Indication (US EU/UK) Treatment of invasive
aspergillosis
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Aspergillus

• Herbrecht NEJM 347408, 2002
• Randomized trial vs. amphotericin B, 277 pts
• Could switch to other licensed therapy as desired
• Vori had superior response 53 vs. 32
• Vori had superior survival 71 vs. 58
• VERY impressive and convincing
• How about vs. a lipid ampho? Unknown my
  meta-analysis suggests comparable response
• Voriconazole is now a solid first-line choice

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Time to Death Vori vs. AmB-D
100
Voriconazole
80
60
Amphotericin B
Surviving
40
P 0.02
20
0
0
14
28
42
56
70
84
Day
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Candida
Indication (EU/UK only) Treatment of
fluconazole-resistant serious invasive Candida
infections (including C. krusei)
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Vori for Esophagitis

• Ally, Clin Infect Dis 331447, 2001
• Vori 200 q12h vs. Flu 400 (day 1) then 200 qd
• Mean duration of therapy of 14-15 days
• N 256 (evaluable)
• Almost entirely C. albicans (as expected)
• Success 98 (Vori) and 95 (Flu)
• Side-effects more common with Vori
• Visual side-effect in 23 (but also in 8 for
  Flu?!)
• Stop for lab test 3.5 (Vori) vs. 1 (Flu)
• So, Vori clearly works for EC

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Vori MIC follows Flu MIC
48h NCCLS M27 MIC, 2000 bloodstream isolates
VORI MIC

• mcg/ml 0.06 0.13 0.25 0.5 1 2 4 gt 8
• 0.13 196 1 1 1 1
• 0.25 383 3 2 2 2 1 5
• 0.5 346 9 3 3 2 1 1 5
• 1 228 26 5 3 2 8
• 2 87 20 5 3 1 1 5
• 4 44 43 25 4 4 1 4
• 8 21 55 66 35 5 4 1
• 16 5 8 25 48 35 2 1
• 32 5 4 21 15 27 5 1 3
• gt 64 21 2 5 16 12 16 18 31

FLU MIC
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But, What Does This Mean?

• Blood levels are 2-5 mg/ml
• Do MICs predict response? Unknown, so ask
• Can we treat high MIC isolates?
• Ghannoum, J Chemother 1134, 1999
• Neutropenic guinea pig, C. krusei
• Vori MIC 0.5, Flu MIC 32 (M27-A, 48h)
• Effect on kidney CFU/g are encouraging
• Amphotericin B (1 mpk qod) 60 reduction
• Fluconazole (20 mpk bid) 60 reduction
• Voriconazole (5-10 mpk bid) gt 92 reduction

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Vori for Refractory Candidiasis

• A series of patients have been collected from
  several different studies
• Salvage therapy protocol
• Compassionate use protocol
• 106 enrolled
• Candidemia 21, 48 overall response
• Other invasive 34, 41 overall response
• EC 51, 61 overall response

Ostrosky, 40th IDSA Abstract 352, 2002.
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Refractory CandidiasisSuccess by Species Flu
MIC (I)

• C. albicans Invasive EC
• gt 64 1/1 (100) 6/9 (67)
• 16-32 - 1/1 (100)
• lt 8 1/3 (33) 1/1 (100)
• C. glabrata
• gt 64 3/4 (75) 1/2 (50)
• 16-32 1/1 (100) 1/1 (100)
• lt 8 0/2 (0) -

Strongest Single Datum
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Refractory CandidiasisSuccess by Species Flu
MIC (II)

• C. tropicalis Invasive EC
• gt 64 1/1 (100) 1/1 (100)
• 16-32 1/1 (100) 1/1 (100)
• lt 8 2/4 (50) 2/4 (50)
• C. krusei
• gt 64 - 1/1 (100)
• 16-32 2/2 (100) 1/1 (100)

Also very interesting
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Refractory CandidiasisSuccess by Prior Therapy

• Invasive EC
• Fluconazole 4/9 (44) 13/17 (76)
• Itraconazole 2/3 (67) 1/6 (17)
• AmB preps 8/18 (44) 5/10 (50)

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Candida Summary

• Activity clearly shown for EC
• A nicely done randomized trial
• Salvage data suggest
• Active across species with higher MICs
• Data are awaited from a candidemia study
• Vs. AmB followed by FLU, completion soon
• EU Indication (not in the US)
• Treatment of FLU-resistant serious invasive
  Candida infections (including C. krusei)

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Fusarium
Indication EU/UK Serious fungal infections
caused by Fusarium spp. US adds including F.
solani, in patients intolerant of, or refractory
to, other therapy.
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Microbiology

• Arikan JCM 373946, 1999 (M27 _at_ 24h)
• Geo Mean MIC VOR ITRA
• F. solani (18) 1.9 gt 16
• F. oxysporum (4) 0.5 0.11
• Of the common species
• F. solani tends to be the most common
• F. oxysporum moniliforme are next

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Clinical Data

• Voriconazole experience
• Primary therapy 1/2 (50)
• Salvage 5/13 (38)
• Often not fully identified
• Fusarium species 3/9 (33)
• Fusarium solani 3/6 (50)
• Reference group Boutati, Blood 90999, 97
• MDACC 13/43 (30), Literature 26/54 (48)
• At least as good as prior data

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Scedosporium
Indication EU/UK Serious fungal infections
caused by Scedosporium spp. US Serious fungal
infections caused by Scedosporium apiospermum
(asexual form of Pseudallescheria boydii), in
patients intolerant of, or refractory to, other
therapy.
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Microbiology

• A genus with a lot of names
• S. apiospermum
• Pseudallescheria (Petriellidium) boydii is
  teleomorph
• S. prolificans
• S. inflatum (obsolete), Petriella setifera is
  teleomorph
• Carrillo AAC 452151, 2001 (M-38-like)
• Geo Mean MIC VOR POS ITRA
• S. apiospermum (11) 0.06 0.08 4.5
• S. prolificans (33) 1.8 11 15

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Clinical Data

• Vori N35 (32 are salvage) Response
• S. apiospermum 16/27 (59)
• S. prolificans 2/8 (25)
• Reference groups are hard to come by
• Idigoras CID 32e158, 01, S. apiospermum
• 2/6 (33) with disseminated disease survived
• Wood CID 141027, 92, S. prolificans
• 1/5 (20) with disseminated disease survived
• Revankar CID 34467, 02, S. prolificans
• 3/30 (10) with disseminated disease survived

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Case Vignette

• 15-year-old near-drowning victim
• S. apiospermum pneumonia, then spine brain
• Lung bone still biopsy cx after 4 months itra
• Salvage therapy with voriconazole
• Received vori for 450 days
• Complete resolution
• This cases shows
• Utility for both this fungus CNS infections

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Voriconazole Summary
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Voriconazole

• Usage
• Lots of drug interactions, significant
  subject-to-subject PK variability, follow liver
  enzymes
• Microbiology
• Aspergillus
• Impressive results in a well-done trial
• Candida
• Seems OK for higher MIC isolates
• Fusarium Scedosporium
• Response rates at least equal historical data

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Thank You!