New antifungal agents

Transcription

1 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 Conference 5 6 August 2017, Kuala Lumpur, Malaysia

2 Newer Antifungal Agents ATUL K PATEL MD, FIDSA Director Infectious Diseases clinic, Ahmedabad INDIA

3 Disclosures No Conflict of interest

4 Learning objectives Overview of newer antifungals in pipeline Newer formulation of Posaconazole Isavuconazole

5 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

6 New compounds in pipeline Compound Target Activity Stage APX001 AR 12 Glycosyl phosphatidylinositol synthesis Probably blocks fungal acetyl-coa synthetase 1 Increases host immune response by down regulating host chaperone proteins Broad-spectrum potency against pathogens, including Mucorales order, Candida spp., Aspergillus spp., Fusarium spp. and Scedosporium spp. Synergizes with approved antifungals Cryptococcus neoformans Candida albicans Mucorales order moulds Hyalohyphomycosis, including those caused by Fusarium spp. and Scedosporium spp. Phase I, Phase II Phase I Efungumab Hsp90 Candida spp. Phase II MGCD290 Hos2 Broad spectrum Synergizes with approved antifungals Nikkomycin Z Chitin synthase Coccidioidomycosis, histoplasmosis and blastomycosis Synergizes with approved antifungals Phase II Phase I Perfect JR. The antifungal pipeline: a reality check. Nat Rev Drug Discov.2017 May 12

7 Compounds with repurposed indications Compound Target Activity Existing indications Cyclosporine, Tacrolimus Rapamycin Calcineurin, mtor inhibitors Broad spectrum To be used alongside existing antifungals Rifampin RNA Polymerase Broad spectrum To be used alongside existing antifungals Sertraline Serotonin uptake Cryptococcal meningitis To be used alongside existing antifungals Tamoxifen Estrogen receptor Cryptococcal meningitis, along with existing antifungals Verapamil Calcium channel blockers Broad spectrum Post Tx immunosuppressio n Antibacterial Depression Breast Cancer Arrhythmia Perfect JR. The antifungal pipeline: a reality check. Nat Rev Drug Discov.2017 May 12 Veringa A, et al. Lancet Infect Dis Oct;16(10):1111 Rhein J, et al. Lancet Infect Dis. 2016Jul;16(7): Zhai B, et al. Antimicrob Agents Chemother Jul;56(7):

8 Currently approved new antifungal agents Newer formulations of Posaconazole & Isavuconazole

9 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:

10 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

11 Posaconazole: Absorption Suspension Posaconazole absorbed in duodenum and jejunum Absorption of Posaconazole Suspension requires dissolution of drug in to stomach The rate and extent of posaconazole dissolution 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

12 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: Ezzet F et al. Clin Pharmacokinet. 2005;44: Merck Sharp & Dohme Corp. Noxafil Package Insert. New Jersey, 2014 Durate RF et al. Abstract A Presented at the 52 nd ICAAC. San Francisco, Sept 9-12, 2012.

13 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:

14 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

15 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

16 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 Jul;49(7):825-42

17 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 MIC 90 values of 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 Jul;49(7):825-42

18 Mucorale Isavuconazole displays variable in vitro activity against the Mucorales Wide MIC ranges Rhizopus spp: 0.12 to >8 μg/ml, Absidia spp: to >8 μg/ml Mucor spp: <0.015 to >8, Rhizomucor spp: to >8 μg/ml, Cunninghamella spp: 0.12 to >8 μg/ml Which are 4- to 16-fold higher than those for posaconazole and amphotericin 4 (11%) partial response 42 days response 16 (43%) stable disease 37 received ISV 84 days 13 (35%) died 1 (3%) disease progression 3 (8%) missing information Francisco M Marty et al. Lancet Infect Diseases: 2016

19 Francisco M Marty et al. Lancet Infect Diseases: 2016

20 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 cation transporter (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 Jul;49(7):825-42

21 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

22 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 voriconazole

23 Thank You