antifungal agent from merck research laboratories
Post on 01-Jan-2016
24 Views
Preview:
DESCRIPTION
TRANSCRIPT
Download from www.cancidas.ae
Antifungal Agent from Merck Research LaboratoriesAntifungal Agent from Merck Research Laboratories
CaspofunginCaspofungin
Discovery and Development of a Novel, PotentDiscovery and Development of a Novel, Potent
Download from www.cancidas.ae
Mortality Rates of Candida and Aspergillus InfectionsMortality Rates of Candida and Aspergillus Infections
*In transplant recipients.Edmond MB Clin Infect Dis 1999;29:239–244; Paterson DL Medicine 1999;78(2):123–138.
Aspergillus up to 90%*Candida 40%
Mortality
Download from www.cancidas.ae
Current Options in Antifungal TherapyCurrent Options in Antifungal TherapyDisadvantagesDrug Advantages
Fungizone™Fungizone™ Active against Candida, AspergillusActive against Candida, Aspergillus
NephrotoxicityPotential for toxicityNephrotoxicityPotential for toxicity
Lipid formulationLipid formulation Active against Candida, Aspergillus, CryptococcusNephrotoxicity is lower than with conventional amphotericin B
Active against Candida, Aspergillus, CryptococcusNephrotoxicity is lower than with conventional amphotericin B
FluconazoleFluconazole Active against Candida, CryptococcusActive against Candida, Cryptococcus
Ineffective against AspergillusPotential resistance developmentIneffective against AspergillusPotential resistance development
ItraconazoleItraconazole Active against Candida, Aspergillus, CryptococcusActive against Candida, Aspergillus, Cryptococcus
Potent inhibitor of cytochrome P450 3A4 system – may cause serious cardiovascular events in combination with certain drugs, contraindicated in severe renal dysfunction. Idiosyncratic hepatitis and hepatotoxicity, resistance observed
Potent inhibitor of cytochrome P450 3A4 system – may cause serious cardiovascular events in combination with certain drugs, contraindicated in severe renal dysfunction. Idiosyncratic hepatitis and hepatotoxicity, resistance observed
FlucytosineFlucytosine Selective toxicitySelective toxicity Weak activity against Candida, CryptococcusRapid resistance developmentWeak activity against Candida, CryptococcusRapid resistance development
Amphotericin BAmphotericin B
AzolesAzoles
Nucleoside analogNucleoside analog
Andriole VT J Antimicrob Chemother 1999;44:151–162; Groll AH Adv Pharmacol 1998;44:343-500; Onishi J Antimicrob Agents Chemother 2000;44:368–377; Stone EA Clin Ther 2002;24(3):351-377; Sporanox™ (Itraconazole) Injection Prescribing Information; Fluconazole Prescribing Information.
NephrotoxicityPotential for toxicityRates of acute infusion-related reactions do not differ substantially from those observed with conventional amphotericin B
NephrotoxicityPotential for toxicityRates of acute infusion-related reactions do not differ substantially from those observed with conventional amphotericin B
Download from www.cancidas.ae
Antifungal Screening: History of the EchinocandinsAntifungal Screening: History of the Echinocandins
Limited antifungal spectrum, low water solubility, poor oral bioavailability, hemolytic
Potent in vitro and in vivo activityagainst Candida with low toxicity
Identified by severalpharmaceutical companies
Cyclic hexapeptides, N-acylated with afatty acid side chain
Isolated in 1974, from Aspergillus species
Groll AH Adv Pharmacol 1998;44:343–500; Bartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001; Onishi J Antimicrob Agents Chemother 2000;44(2):368–377; Tkacz JS Emerging Targets in Antibacterial and Antifungal Chemotherapy 1992:495–523; Debono M Annu Rev Microbiol 1994;48:471–497; Bartizal K Antimicrob Agents Chemother 1997;41(11):2326–2332.
Download from www.cancidas.ae
Screening for Natural ProductsScreening for Natural Products
Identify a Therapeutic Target
Develop Assays that Look for Biological Activity Against Target
Test Fungal, Bacterial, Plant, or Other Extracts for Desired Biological Activity
Purify and Identify Lead Compound(s)
Produce Quantities for Clinical Trials
Medicinal Chemistryto Optimize Compound
Characteristics
Additionalin vitro Testing
In vivoTesting
Download from www.cancidas.ae
Discovery of Antifungal ActivityDiscovery of Antifungal Activity
In vitro activity against Candida was observedin a fermentation extract of Glarea lozoyensis In vitro activity against Candida was observedin a fermentation extract of Glarea lozoyensis
Bartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001.
Download from www.cancidas.ae
A Novel Glucan Synthesis Inhibitor(L-688786)A Novel Glucan Synthesis Inhibitor(L-688786)
OHOH
NN
HNHN
OHOHHNHNOO
HOHO
CH3CH3
OHOH
OO
NHNH
HOHO
NN
HOHOH2NH2N
OO
HOHO
OHOH
OO
OO
OO
OO
HOHO
OO
HNHN
HNHN
Groll AH Adv Pharmacol 1998;44:343–500.
Download from www.cancidas.ae
Chemical ModificationsChemical Modifications
• Water soluble
• Improved potency
• Expanded spectrum
• Favorablepharmacokinetics
• Water soluble
• Improved potency
• Expanded spectrum
• Favorablepharmacokinetics
Synthesizing Caspofungin (L-743872) from L-688786Synthesizing Caspofungin (L-743872) from L-688786
HOHO
HOHO
H3NH3N
glutamineglutamine
HOHO
HOHO
OO HNHN
HNHN
NHNH
OO
OO
OO
OONN
HNHN
HOHOOO
HOHO OHOHOO
OHOH
CH3CH3
OHOH
NHNHH3NH3N
HNHN
hemiaminalhemiaminal
H2NOCH2NOC
NN
• 2 CH3COOH• 2 CH3COOH
Bartizal K Antimicrob Agents Chemother 1997;41(11):2326–2332; Groll AH Adv Pharmacol 1998;44:343–500; Powles MA Antimicrob Agents Chemother 1998;42(8):1985–1989; Debono M Annu Rev Microbiol 1994;48:471–497; Stone EA Clin Ther 2002;24(3):351–377.
Download from www.cancidas.ae
Compound NomenclatureCompound Nomenclature
Inhibitor Class: glucan synthesis inhibitor
Generic Class: lipopeptide
Structural Class: echinocandin
Semisynthetic derivative of: L-688786 (Pneumocandin BO)
Produced by: Glarea lozoyensis
Merck L#: L-743872
Merck MK#: MK-0991
Generic Name: caspofungin acetate
Trade Name: CANCIDAS™
Inhibitor Class: glucan synthesis inhibitor
Generic Class: lipopeptide
Structural Class: echinocandin
Semisynthetic derivative of: L-688786 (Pneumocandin BO)
Produced by: Glarea lozoyensis
Merck L#: L-743872
Merck MK#: MK-0991
Generic Name: caspofungin acetate
Trade Name: CANCIDAS™
Georgopapadakou NH Exp Opin Invest Drugs 2001;10(2):269–280; Bartizal K Antimicrob Agents Chemother 1997;41(11):2326–2332; Data on file, MSD.CANCIDAS (caspofungin acetate) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Download from www.cancidas.ae
(1,3)-D-glucan: Integral Part of Fungal Cell Wall (1,3)-D-glucan: Integral Part of Fungal Cell Wall
• Fungal specific, not found in mammalian cells
• Important cell wall component of many fungal species:
– Candida species mostly -1,3 & -1,6 (~40–60%)
– Aspergillus species (hyphae mostly -1,3)
– Pneumocystis carinii (cyst form)
• C. neoformans mostly -1,3 and -1,3 (~30–50%)
• Fungal specific, not found in mammalian cells
• Important cell wall component of many fungal species:
– Candida species mostly -1,3 & -1,6 (~40–60%)
– Aspergillus species (hyphae mostly -1,3)
– Pneumocystis carinii (cyst form)
• C. neoformans mostly -1,3 and -1,3 (~30–50%)
Data on file, MSD; Debono M Annu Rev Microbiol 1994;48:471–497; Tkacz JS Emerging Targets in Antibacterial and Antifungal Chemotherapy 1992:495–523; Maertens J Current Medicinal Chemistry–Anti-Infective Agents 2002;1(1); Bartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001.
Download from www.cancidas.ae
Phospholipid bilayerof the fungal cell
membrane
Fungalcell wall
(1,3)-glucan
(1,6)-glucan
(1,3)-glucan synthase Ergosterol
Fungal Cell WallFungal Cell Wall
Kartsonis NA. Presented at the 12th European Congress of Clinical Microbiology and Infectious Diseases. April 24–27, 2002.
Download from www.cancidas.ae
Glucan Synthesis and Its InhibitionGlucan Synthesis and Its Inhibition
Download from www.cancidas.ae
Caspofungin: Preclinical In Vitro DataCaspofungin: Preclinical In Vitro Data
Download from www.cancidas.ae
Caspofungin In Vitro Spectrum of ActivityCaspofungin In Vitro Spectrum of Activity
Candida species Histoplasma capsulatum Cryptococcus neoformans
Aspergillus species Coccidiodes imitis Fusarium species
Saccharomyces cerevisiae Paracoccidiodes species Trichosporon species
Alternaria species Blastomyces dermatitidis Rhizopus species
Curvularia species Sporothrix schenckii Trichophyton species
Fonseca pedrosoi Phiolophora species Scedosporium species
Pneumocystis carinii** Epidermophyton species Pseudallescheria boydii
Candida species Histoplasma capsulatum Cryptococcus neoformans
Aspergillus species Coccidiodes imitis Fusarium species
Saccharomyces cerevisiae Paracoccidiodes species Trichosporon species
Alternaria species Blastomyces dermatitidis Rhizopus species
Curvularia species Sporothrix schenckii Trichophyton species
Fonseca pedrosoi Phiolophora species Scedosporium species
Pneumocystis carinii** Epidermophyton species Pseudallescheria boydii
Potent(0.03–2.0 g/mL)
Potent(0.03–2.0 g/mL)
Minimum Inhibitory Concentrations* (g/mL)Minimum Inhibitory Concentrations* (g/mL)
*Data derived from MRL, National Fungus Testing Laboratory and National Mycology Reference Laboratory**Based on in vivo dataBartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001.
Intermediate(2.0–16.0 g/mL)
Intermediate(2.0–16.0 g/mL)
Weak(16.0–>64.0 g/mL)
Weak(16.0–>64.0 g/mL)
Download from www.cancidas.ae
Glucan Synthesis Inhibition vs. MIC ValueGlucan Synthesis Inhibition vs. MIC Value
Candida albicans (MY1028) 0.6 0.125
Aspergillus fumigatus (MF4839) 9.6 0.125
Candida albicans (MY1028) 0.6 0.125
Aspergillus fumigatus (MF4839) 9.6 0.125
Glucan SynthesisIC50 (nM)
Glucan SynthesisIC50 (nM)
Mean MICµg/mL ± SE Mean MIC
µg/mL ± SE
Data on file, MSD.
Download from www.cancidas.ae
In Vitro SusceptibilityIn Vitro Susceptibility
C. albicans 0.12 0.25 0.50
Candida spp. (non-albicans) 0.50 0.50 16.0
Aspergillus spp. 0.38 0.43 >64.0
Cryptococcus neoformans 16.0 0.50 0.50
C. albicans 0.12 0.25 0.50
Candida spp. (non-albicans) 0.50 0.50 16.0
Aspergillus spp. 0.38 0.43 >64.0
Cryptococcus neoformans 16.0 0.50 0.50
CaspofunginCaspofungin AmBAmB FluconazoleFluconazole
MIC90 (g/mL)MIC90 (g/mL)
Minimum Inhibitory ConcentrationsMinimum Inhibitory Concentrations
AmB = Amphotericin B Bartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001.
Download from www.cancidas.ae
Fluconazole-Susceptible and -Resistant Candida albicansFluconazole-Susceptible and -Resistant Candida albicans
0.05–0.8 0.400.01–0.8 0.200.04–>40 0.640.08–10 2.5
0.1–0.8 0.400.02–0.4 0.200.08–1.25 0.6420–80 80
0.05–0.8 0.400.01–0.8 0.200.04–>40 0.640.08–10 2.5
0.1–0.8 0.400.02–0.4 0.200.08–1.25 0.6420–80 80
RangeRange MIC90MIC90
MIC (g/mL)MIC (g/mL)
CaspofunginAmphotericin BFlucytosineFluconazole
CaspofunginAmphotericin BFlucytosineFluconazole
CaspofunginAmphotericin BFlucytosineFluconazole
CaspofunginAmphotericin BFlucytosineFluconazole
C. albicans (40)Susceptible
C. albicans (10)Resistant
C. albicans (40)Susceptible
C. albicans (10)Resistant
Vazquez JA Antimicrob Agents Chemother 1997;41(7):1612–1614.
Antifungal Agent
Antifungal Agent
Organism(no. of isolates)
Organism(no. of isolates)
Download from www.cancidas.ae
Drug Combination StudiesDrug Combination Studies
Candida albicans
Cryptococcus neoformans
Aspergillus fumigatus
Candida albicans
Cryptococcus neoformans
Aspergillus fumigatus
FIC* (μg/ml)MK-0991 Plus Amphotericin B
FIC* (μg/ml)MK-0991 Plus Amphotericin B
0.82
0.50
0.45
0.82
0.50
0.45
*≤0.5 = Synergistic ≤4.0 = Additive-to-indifferent ≥4.0 = AntagonisticBartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001.
Fungus(n=2)
Fungus(n=2)
Download from www.cancidas.ae
Caspofungin: Genetics Show Target Is Essential in CandidaCaspofungin: Genetics Show Target Is Essential in Candida
URA3URA3
Step 1
Or
Select for FOA resistance
URA3URA3
URA3URA3 FKS1FKS1FKS1FKS1FKS1FKS1
Download from www.cancidas.ae
Genetics Prove Caspofungin Target Is Essential in CandidaGenetics Prove Caspofungin Target Is Essential in Candida
URA3URA3
URA3URA3
If CaFKS1 is not
essential:
If CaFKS1 is essential:
No functionalFKS1 remains
Always retaina functionalcopy of FKS1
Result: Candida (1,3)-D-glucan synthase is essentialResult: Candida (1,3)-D-glucan synthase is essential
Step 2
URA3URA3 FKS1FKS1FKS1FKS1FKS1FKS1
Download from www.cancidas.ae
Colony Forming Unit QuantitationColony Forming Unit Quantitation
10 Colony Forming Units
4 Colony Forming Units
1 Colony Forming Unit
1 Colony Forming Unit
Candida spp. and Other Yeasts Aspergillus spp.
Download from www.cancidas.ae
Evaluation of Caspofungin Effect Against Aspergillus spp. In Vitro Using Vital Dyes Evaluation of Caspofungin Effect Against Aspergillus spp. In Vitro Using Vital Dyes
Alive Fluorescent Non-fluorescent
Dead Non-fluorescent Fluorescent
Alive Fluorescent Non-fluorescent
Dead Non-fluorescent Fluorescent
Status of CellStatus of CellViable Stain
(CFDA)Viable Stain
(CFDA)Non-viable Stain
(DiBAC4[3])Non-viable Stain
(DiBAC4[3])
Data on file, MSD.
Download from www.cancidas.ae
Viable Stain — Caspofungin Halts Growth of Aspergillus fumigatusViable Stain — Caspofungin Halts Growth of Aspergillus fumigatus
Amphotericin B0.15 µg/mL
Caspofungin0.30 µg/mL
Itraconazole2.5 µg/mLControl
Data on file, MSD; Bowman JC Antimicrob Agents Chemother 2002;46(9):3001–3012.
Download from www.cancidas.ae
Non-viable Stain — Cellular Lysis in Aspergillus fumigatus ConfirmedNon-viable Stain — Cellular Lysis in Aspergillus fumigatus Confirmed
Amphotericin B0.15 µg/mL
Caspofungin0.30 µg/mL
Itraconazole2.5 µg/mLControl
Data on file, MSD; Bowman JC Antimicrob Agents Chemother 2002;46(9):3001–3012.
Download from www.cancidas.ae
Effects of Caspofungin on Aspergillus fumigatusEffects of Caspofungin on Aspergillus fumigatus
Bowman JC Antimicrob Agents Chemother 2002;46(9):3001–3012.
Download from www.cancidas.ae
Caspofungin: Preclinical In Vivo DataCaspofungin: Preclinical In Vivo Data
Download from www.cancidas.ae
In Vivo Efficacy of Caspofungin & Amphotericin B Against Candida Species in MiceIn Vivo Efficacy of Caspofungin & Amphotericin B Against Candida Species in Mice
Candida albicans 0.02 0.03
Candida glabrata 0.06 0.17
Candida lusitaniae 0.16 0.11
Candida tropicalis 0.05 0.24
Candida albicans 0.02 0.03
Candida glabrata 0.06 0.17
Candida lusitaniae 0.16 0.11
Candida tropicalis 0.05 0.24
CaspofunginCaspofungin
ED (Effective Dose)90
(mg/kg/dose)ED (Effective Dose)90
(mg/kg/dose)
IsolateIsolate
Data on file, MSD; Bartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001; Abruzzo GK Antimicrob Agents Chemother 1997;41(11):2333–2338.
Amphotericin BAmphotericin B
Download from www.cancidas.ae
Caspofungin, AmB* or FCZ** in DBA/2 Mice vs. Disseminated Renal Candidiasis after Delayed TreatmentCaspofungin, AmB* or FCZ** in DBA/2 Mice vs. Disseminated Renal Candidiasis after Delayed Treatment
Days After ChallengeDays After ChallengeChallenge I.V.Challenge I.V.
20
33
44
55
66
77
88
22 44 66 88 1010 1212 1414 1616 1818
Log
CF
U C
. alb
ican
s/g
kid
ney
sL
og C
FU
C. a
lbic
ans/
g k
idn
eys
DoseI.V. q.d. x 4
Fluconazole @ 10 mg/kg0% SterilizationVehicle Control
AmB* @ 0.5 mg/kg40% SterilizationCaspofungin @ 0.38mg/kg60% Sterilization
*AmB = Amphotericin B**FCZ = FluconazoleBartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001.
Download from www.cancidas.ae
Caspofungin vs. AmB in Chronic Pancytopenic Mouse Model of Disseminated Aspergillosis
Dosing
Per
cen
t S
urv
ival
Per
cen
t S
urv
ival
2020
4040
6060
8080
100100
00 55 1010 1515 2020 2525
Days PostinfectionDays Postinfection
Day +28Day +28Day –3Day –3Immunosuppression with CyclophosphamideImmunosuppression with Cyclophosphamide
1 mg/kg
0.25 mg/kg
1 mg/kg
0.25 mg/kg
Sham-Rx
Caspofungin
AmB
Data on file, MSD.
Download from www.cancidas.ae
Disseminated Candidiasis in Chronically Pancytopenic Mice: Survival
Dosing
Per
cen
t S
urv
ival
Per
cen
t S
urv
ival
00
2020
3030
4040
5050
6060
7070
8080
9090
100100
00 44 88 1212 1616 2020 2424
1 mg/kg
0.25 mg/kg
Days After ChallengeDays After Challenge
1 mg/kg
0.25 mg/kg
Sham-Rx
Day +28Day +28Day –3Day –3Immunosuppression with CyclophosphamideImmunosuppression with Cyclophosphamide
Caspofungin
AmB
1010
2828
80 mg/kg
20 mg/kg
Fluconazole
Data on file, MSD.
Download from www.cancidas.ae
Disseminated Candidiasis in Chronically Pancytopenic Mice: Tissue Burden and SterilizationDisseminated Candidiasis in Chronically Pancytopenic Mice: Tissue Burden and Sterilization
Caspofungin 1 mg/kg 4.84 100 0.25 mg/kg 3.13 40
Amphotericin B 1 mg/kg 3.52 80 0.25 mg/kg 2.49 50
Fluconazole 80 mg/kg -0.92 205
20 mg/kg +0.75 01
Caspofungin 1 mg/kg 4.84 100 0.25 mg/kg 3.13 40
Amphotericin B 1 mg/kg 3.52 80 0.25 mg/kg 2.49 50
Fluconazole 80 mg/kg -0.92 205
20 mg/kg +0.75 01
Log10 CFU Reduction
Log10 CFU Reduction
% Kidney Tissue Sterilization
% Kidney Tissue Sterilization
Kidney Burden Reduction fromControl at Day 28*
Kidney Burden Reduction fromControl at Day 28*
* Mice were challenged IV with C. albicans MY1055 at 5.6 104 CFU/mouse and 1.22 105 CFU/mouse. Kidneys aseptically collected at Days 14 and 28 after challenge. Mean log10 CFU/g at time points after challenge for paired kidneys. Ten mice per group unless indicated by superscript number.Data on file, MSD.
Download from www.cancidas.ae
P. carinii Cyst Clearance in Mice with CaspofunginP. carinii Cyst Clearance in Mice with Caspofungin
Control
TMP-SMZ*
MK-0991
90% Reduction
99% Reduction
77
66
55
44
3300 22 44 66 88 1010 1212 1414 1616
Log
10 M
ean
Num
ber
of
Cys
ts/L
ung
Log
10 M
ean
Num
ber
of
Cys
ts/L
ung
Days of TreatmentDays of Treatment
*TMP-SMZ = Trimethoprim-sulfamethoxazole.Powles MA Antimicrob Agents Chemother 1998;42(8):1985–1989.
Download from www.cancidas.ae
Preclinical Microbiology SummaryPreclinical Microbiology Summary
• Spectrum of activity includes Candida albicans,non-albicans Candida spp., and Aspergillus spp.
• Caspofungin is fungicidal for Candida spp. based on in vitro and in vivo studies
• Caspofungin demonstrates clear activity againstAspergillus spp.
– In vitro• Kills cells with active cell wall synthesis• Effects are consistent with the mechanism of action
– In vivo, there is a sustained activity in severely immunosuppressed mice with disseminated aspergillosis
• Spectrum of activity includes Candida albicans,non-albicans Candida spp., and Aspergillus spp.
• Caspofungin is fungicidal for Candida spp. based on in vitro and in vivo studies
• Caspofungin demonstrates clear activity againstAspergillus spp.
– In vitro• Kills cells with active cell wall synthesis• Effects are consistent with the mechanism of action
– In vivo, there is a sustained activity in severely immunosuppressed mice with disseminated aspergillosis
Data on file, MSD; Maertens J Current Medicinal Chemistry–Anti-Infective Agents 2002;1(1); Bowman JC Antimicrob Agents Chemother 2002;46(9):3001–3012.
Download from www.cancidas.ae
Additional In Vivo StudiesAdditional In Vivo Studies
• Reduction of infections in CD4+ deficient micewith chronic oropharyngeal and gastrointestinal mucosal candidiasis
• Effective prophylactic and therapeutic treatment of immunocompromised rats with pulmonary aspergillosis
• Limited role in the treatment of Histoplasma capsulatum
• No activity against Cryptococcus neoformans
• Reduction of infections in CD4+ deficient micewith chronic oropharyngeal and gastrointestinal mucosal candidiasis
• Effective prophylactic and therapeutic treatment of immunocompromised rats with pulmonary aspergillosis
• Limited role in the treatment of Histoplasma capsulatum
• No activity against Cryptococcus neoformans
Flattery AM Antimicrob Agents Chemother 1996:40(7):1604–1609; Data on file, MSD; Stone EA Clin Ther 2002;24(3):351–377.
Download from www.cancidas.ae
Comparative Pharmacokinetics:Caspofungin Single IV DoseComparative Pharmacokinetics:Caspofungin Single IV Dose
100100
1010
11
0.10.100 44 88 1212 1616 2020 2424
Mea
n P
lasm
a C
once
ntra
tion
(
g/m
l)M
ean
Pla
sma
Con
cent
rati
on
(g/
ml)
Time (Hours)Time (Hours)
C. albicans MIC90
Candida spp., A. fumigatus MIC90
0.5 mg/kg
0.75 mg/kg
1 mg/kg
Mouse 7.6Rat 6.1Rhesus 5.0Chimpanzee 5.2Human 10.0
Species T1/2 hrs
Bartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001.
Download from www.cancidas.ae
Merck Antifungal Caspofungin (MK-0991)Preclinical SummaryMerck Antifungal Caspofungin (MK-0991)Preclinical Summary• Water soluble (1,3)-D-glucan synthesis inhibitor:
– 0.6 nM–Candida– 9.6 nM–Aspergillus
• Relevant spectrum: – Candida & Aspergillus
• Fungicidal against C. albicans• Low resistance induction potential• Effective vs. FCZ*, AmB**, 5FC***
resistors • No antagonism
– In combination with AmB** or FCZ*• Excellent animal efficacy:
– Candida, Aspergillus• Pharmacokinetics supports
once-daily dosing
• Water soluble (1,3)-D-glucan synthesis inhibitor:
– 0.6 nM–Candida– 9.6 nM–Aspergillus
• Relevant spectrum: – Candida & Aspergillus
• Fungicidal against C. albicans• Low resistance induction potential• Effective vs. FCZ*, AmB**, 5FC***
resistors • No antagonism
– In combination with AmB** or FCZ*• Excellent animal efficacy:
– Candida, Aspergillus• Pharmacokinetics supports
once-daily dosing
OHOH
NN
NHNH
HNHN
OHOHHNHNOO
NHNH
CH3CH3
OHOH
OO
HNHN
NHNH
HOHO
NN
HOHO
HOHOOO
HOHO
OHOH
OO
OO
OO
OO
H2NH2N
H2NH2N
·2CH3CO2H·2CH3CO2H
CH3CH3CH3
CH3
H3CH3C
*FCZ = fluconazole **AmB = amphotericin B***5FC = flucytosineData on file, MSD; Franzot SP Antimicrob Agents Chemother 1997;41(2):331–336; Bartizal K Antimicrob Agents Chemother 1997;41(11):2326–2332.
top related