Pharmacokinetics and Oral Bioavailability of Novel Triazole Derivative Syn2869 - a Potent New Antifungal Agent and Its Comparison with Itraconazole.

J.K. KHAN, H. MONTASERI, M. POGLOD, H.Z. BU, S. SALAMA, R.G. MICETICH, and M. DANESHTALAB

Abstract: 

Syn2869, (2R, 3R)-2-(2,4- Diflourophenyly)-3-[4-{4-[2-(4-triflouromethyloxybenzyl)-2H-1,2,4-triazole-3-one-4-yl] phenyl}piperazin-1-yl]1-(1H-1,2,4-triazole-1-yl)butan-2-ol, is a wide spectrum orally active antifungal agent that is being evaluated for treatment against Candida and Aspergillus infections, particularly in pulmonary invasive aspergillosis (RTI) model. Pharmacokinetic profiles of Syn2869 were studied in mice administering intravenously (i.v.) 20mg/kg and orally (p.o.) 50mg/kg dose using a microemulsion formulation containing cremophore. The AUC of Syn 2869 after i.v. administration was 44.9 +/- 16.7 micro g.hr/ml with clearance of 0.17 ml/min. Mean AUC after a 50mg/kg single oral dose was 61.4 +/- 2.93 micro g.hr/ml. The maximum concentration (Cmax) achieved in plasma was 3.02 +/- 0.08 for Syn2869 and 4.00 +/- 1.26 micro g/ml for Itraconazole (ITRA) after an oral dose of 50 and 30 mg/kg, respectively. The AUC for ITRA was 11.72 +/- 1.4 micro g.hr/ml. The absolute bioavailabilty calculated from area under the curve for Syn2869 and ITRA was 60% and 23%, respectively. The AUC0-a in mice lungs of Syn2869 and ITRA were 128.5 +/- 15.5 and 39.5 +/- 1.3 micro g. h/g, respectively. The higher tissue to plasma ratio of Syn2869 contributed to superior efficacy in RTI model when compared with ITRA. The AUC0-a in brain of Syn 2869 and ITRA were 21.8 +/- 1.1 and 4.9 +/- 0.25 micro g. h/g, respectively. The Cmax, AUC and half life of Syn2869 in rabbit after a single oral dose of 50 mg/kg were 1.30 +/- 0.29 micro g/ml, 10.59 +/- 2.78 micro g.hr/ml and 5.73 +/- 2.77 hrs, respectively. Results indicate that Syn2869 could be developed as an antifungal agent for the treatment of fungal infections especially invasive aspergillosis.
1998

abstract No: 

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Full conference title: 

38th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 38th