new antifungal agents - afwg · need for new antifungal agents •increase in invasive fungal...
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New antifungal agents
Dr Atul Patel, MD, FIDSA Chief Consultant and Director
Infectious Diseases Clinic
Vedanta Institute of Medical Sciences
Ahmedabad, India
Presented at MMTN Malaysia Conference5–6 August 2017, Kuala Lumpur, Malaysia
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Newer Antifungal Agents
ATUL K PATEL MD, FIDSA
Director Infectious Diseases clinic, Ahmedabad
INDIA
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Disclosures
• No Conflict of interest
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Learning objectives
• Overview of newer antifungals in pipeline
• Newer formulation of Posaconazole
• Isavuconazole
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Need for new antifungal agents
• Increase in invasive fungal infections
• Limitations associated with existing antifungal agents (toxicity, drug interactions, acquired and inherent resistance)
• High mortality associated with invasive fungal infections with current antifungal agents
• New agent with rapid fungicidal activity
• Need antifungal agents to treat certain difficult to treat fungal infections (Scedosporium, fusarium, C. auris, certain mucor species)
• Need to develop combination antifungal strategy PRESENTED AT M
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New compounds in pipelineCompound Target Activity Stage
APX001 Glycosylphosphatidylinositol synthesis
Broad-spectrum potency against pathogens, including Mucorales order, Candida spp., Aspergillus spp., Fusariumspp. and Scedosporium spp. Synergizes with approved antifungals
Phase I, Phase II
AR 12 Probably blocks fungal acetyl-CoA synthetase 1 Increases host immune response by down regulating host chaperone proteins
Cryptococcus neoformansCandida albicansMucorales order mouldsHyalohyphomycosis, including those caused by Fusarium spp. and Scedosporium spp.
Phase I
Efungumab Hsp90 Candida spp. Phase II
MGCD290 Hos2 Broad spectrum Synergizes with approved antifungals
Phase II
Nikkomycin Z Chitin synthase Coccidioidomycosis, histoplasmosis and blastomycosisSynergizes with approved antifungals
Phase I
Perfect JR. The antifungal pipeline: a reality check. Nat Rev Drug Discov.2017 May 12PRESENTED AT M
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Compounds with repurposed indicationsCompound Target Activity Existing indications
Cyclosporine, TacrolimusRapamycin
Calcineurin, mTORinhibitors
Broad spectrum To be used alongside existing antifungals
Post Tximmunosuppression
Rifampin RNA Polymerase Broad spectrum To be used alongside existing antifungals
Antibacterial
Sertraline Serotonin uptake Cryptococcal meningitis To be used alongside existing antifungals
Depression
Tamoxifen Estrogen receptor Cryptococcal meningitis, along with existing antifungals
Breast Cancer
Verapamil Calcium channel blockers
Broad spectrum Arrhythmia
Perfect JR. The antifungal pipeline: a reality check. Nat Rev Drug Discov.2017 May 12Veringa A, et al. Lancet Infect Dis. 2016 Oct;16(10):1111Rhein J, et al. Lancet Infect Dis. 2016Jul;16(7):809-18Zhai B, et al. Antimicrob Agents Chemother. 2012 Jul;56(7):3758-66
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Currently approved new antifungal agents
Newer formulations of Posaconazole & Isavuconazole
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Posaconazole
• Posaconazole is a broad-spectrum, triazole antifungal
• Spectrum of activity: Candida spp., Aspergillus spp., and most Mucorales
• Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane
• Approved for antifungal prophylaxis in neutropenic and GVHD in post HSCT
• Drawback of suspension formulation: • Requires frequent dosing (ie, 200 mg, 3 times daily) with food (preferably a high-fat meal)
to ensure adequate oral absorption
• Patients with chemotherapy-associated nausea or vomiting, mucositis or diarrhea, or GVHD: It’s absorption could be compromised resulting in to inadequate blood levels with increased risk of breakthrough fungal infection
Dolton MJ et al. Antimicrob Agents Chemother. 2012;56:5503-5510
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Newer Formulations: Posaconazole• New delayed release tablet (100mg) and injectable
formulations now approved by FDA for clinical use
• Both formulations circumvent the absorption problems of the oral suspension
• Convenient dosing of posaconazole: Once daily after a twice-daily loading dose on the first day
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Posaconazole: Absorption
• Posaconazole absorbed in duodenum and jejunum
• Absorption of Posaconazole Suspension requires dissolution of drug in to stomach
• The rate and extent of posaconazoledissolution is maximized when the drug is taken as smaller, more frequent doses with a high-fat meal• Which lowers gastric pH, prolongs
gastric residence time, and stimulates splanchnic blood and bile flow
• Rapid gastric transit, elevated pH slow down the rate and extent of dissolution & less absorbable drug reaches to duodenum and jejunum
Suspension
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Posaconazole Tablet• Tablet formulation uses pH-sensitive polymers to release posaconazole
at a controlled rate in the duodenum
• It overcomes many of the issues associated with poor gastric dissolution of the drug
• Important benefits with tablet• Patient achieves higher trough level 1400 ng/ml (loading dose of 300 mg BD on day 1
followed by 300 OD) compared to 517 ng/ml with the oral suspension(200 mg 4 times daily) (Ezzet 2005; Duarte 2012)
• Early steady state level (24 to 48 hours with tablet compared to 7 to 10 days with suspension) (Merck 2014)
• Coadministration of acid suppressing agents (antacids, H2-receptor antagonists, proton pump inhibitors) does not significantly decrease the bioavailability of the delayed-release tablet while 20% to 40% decrease in mean AUC oral suspension
• Administration with food increases absorption of tablet
Percival KM et al. Curr Fungal Infect Rep. 2014;8:139-145Ezzet F et al. Clin Pharmacokinet. 2005;44:211-220. Merck Sharp & Dohme Corp. Noxafil Package Insert. New Jersey, 2014Durate RF et al. Abstract A-1934. Presented at the 52nd ICAAC. San Francisco, Sept 9-12, 2012.
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Posaconazole tablets: Limitations
• It can’t be divided or crushed, administered through gastric feeding tubes
• Coadministration of the tablet with the prokinetic agent metoclopramide resulted in modest decreases in the Cmax(14%) and AUC (7%) of the delayed-release tablet (Kraft 2014)
Kraft WK et al. Antimicrob Agents Chemother. 2014;58:4020-4025
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IV Posaconazole
• IV preparation is solubilized in sulfobutylether β-cyclodextrin
• Achieves early steady state level
• Must be administered through Central Line (High infusion related ADR when administered through peripheral line)
• Similar safety profile
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Isavuconazole
• Isavuconazole is a second-generation triazole antifungal• Ergosterol synthesis inhibitors• Available in Oral and IV: high oral bioavailability and the
absorption is not significantly affected by food intake or gastric acidity
• Dose recommendation: • 200mg q8h (PO/IV) X 2 days followed by 200mg OD• Dose adjustment in patients with liver impairment, a 50%
dose reduction is recommended • Dose reductions are not required for patients with renal
insufficiency or dialysis
• Nursing mother shouldn’t breast feed as in animal models showed level up to 17 times plasma level
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Important PK parameters
• Prolonged half-life (>75 hours) with convenient OD dosing
• Less inter-patient variability in drug levels compared to posaconazole, itraconazole, and voriconazole (high oral bioavailability & consistent metabolism)
• Highly protein bound (>99%),
• CSF & ocular levels expected to be low (achieves sufficient brain parenchymal level to inhibit fungus)
• IV formulation does not contain the sulfobutylether β-cyclodextrin, which may accumulate in patients with renal dysfunction
• Isavuconazole is metabolized by hepatic CYP450 enzymes and excreted in the feces
• Minimal active drug is excreted in the urine like Voriconazole, posaconazole Pettit NN, Carver PL. Ann Pharmacother. 2015 Jul;49(7):825-42
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Spectrum & Indications
• Isavuconazole is approved for use in invasive aspergillosis & mucormycosis
• Potent in vitro activity against many opportunistic and invasive fungal organisms• Fungistatic against Yeasts with MIC <1 µg/ml for 99.5% of candida species including C. glabrata & C.
Krusei• Fungicidal activity against most Aspergillus spp, including some isolates resistant to itraconazole,
caspofungin, and amphotericin B• Active against C. neoformans & C. gattii (including isolates with reduced susceptibility to fluconazole),
with MIC90 values of 0.008 to 0.25 μg/mL• Noncandidal, Noncryptococcal Yeasts: Trichosporon, Rhodotorula, Geotrichum, Saccharomyces, and
Pichia spp.• Potent activity against all the dematiaceous molds evaluated, including Bipolaris spicifera, Curvularia
lunata, Alternaria alternata , and Exophiala spp• Histoplasma capsulatum, blastomyces dermatitidis, coccidiodomyces
• No activity against Scedosporium prolificans
• Exhibits poor activity against Fusarium spp
Pettit NN, Carver PL. Ann Pharmacother. 2015 Jul;49(7):825-42
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Mucorale
• Isavuconazole displays variable in vitro activity against the Mucorales
• Wide MIC ranges • Rhizopus spp: 0.12 to >8 μg/mL, • Absidia spp: 0.038 to >8 μg/mL• Mucor spp: <0.015 to >8, • Rhizomucor spp: 0.015 to >8
μg/mL, • Cunninghamella spp: 0.12 to >8
μg/mL
• Which are 4- to 16-fold higherthan those for posaconazole andamphotericin
37 received ISV 84 days
4 (11%) partial response
16 (43%) stable disease
13 (35%) died1 (3%) disease
progression3 (8%) missing
information
42 days response
Francisco M Marty et al. Lancet Infect Diseases: 2016
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Francisco M Marty et al. Lancet Infect Diseases: 2016
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Drug Interactions
• Isavuconazole is a substrate of cytochrome 450 (CYP) 3A4/5
• Inhibitor of CYP 3A4, CYP2C8, CYP2C9, CYP2C19, CYP2D6 enzymes
• Inhibitor of P-glycoprotein (P-gp), breast cancer resistant protein (BCRP), human organic cationtransporter (OCT2) transporters
• Mild inducer of CYP 2B6• Avoid concomitant CYP3A4 inducers like rifampicin or
inhibitors like lopinavir/ritonavir• Coadministration of P-gp substrate like colchicine,
digoxin, Mycophenolate requires close monitoring and TDM
Pettit NN, Carver PL. Ann Pharmacother. 2015 Jul;49(7):825-42
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Need for Therapeutic Drug monitoring• TDM is generally recommended for agents with a
• Narrow therapeutic index
• An established relationship between plasma drug concentrations and efficacy or toxicity
• Variable or unpredictable pharmacokinetics
• Posaconazole requires TDM
• Isavuconazole serum concentrations vary moderately (<20%); need for TDM is yet to determine
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Summary
• Many newer antifungal agents are in pipeline
• Agents approved for other indications are also evaluated for their antifungal activity
• Newer formulations of Posaconazole has improved bioavailability
• Isavuconazole is a broad spectrum antifungal activity
• Many advantages over other azole antifungals• High prodrug water solubility (obviating the need for cyclodextrin); • High oral bioavailability (allowing one to-one dosage conversions
from the IV formulation); • Prolonged half life: OD dosage• Predictable, linear pharmacokinetics with no relevant food effect; • Potentially fewer drug interactions than itraconazole or
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Thank You
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