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Antimicrobial Agents and Chemotherapy, May 2005, p. 2084-2092, Vol. 49, No. 5
0066-4804/05/$08.00+0 doi:10.1128/AAC.49.5.2084-2092.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
Efficacy, Plasma Pharmacokinetics, and Safety of Icofungipen, an Inhibitor of Candida Isoleucyl-tRNA Synthetase, in Treatment of Experimental Disseminated Candidiasis in Persistently Neutropenic Rabbits
Ruta Petraitiene,1,2 Vidmantas Petraitis,1,2 Amy M. Kelaher,1 Alia A. Sarafandi,1 Diana Mickiene,1 Andreas H. Groll,1,3 Tin Sein,1 John Bacher,4 and Thomas J. Walsh1*Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda,1 SAIC-Frederick, Inc., Frederick,2 Surgery Service, Veterinary Resources Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland,3 Department of Pediatric Hematology/Oncology, University Children's Hospital, Muenster, Germany4
Received 29 July 2004/ Returned for modification 10 September 2004/ Accepted 9 December 2004
Icofungipen (formerly PLD-118) is a synthetic derivative of the naturally occurring ß-amino acid cispentacin that blocks isoleucyl-tRNA synthetase, resulting in the inhibition of protein synthesis and growth of fungal cells. We investigated the efficacy, plasma pharmacokinetics, and safety of icofungipen in escalating dosages for the treatment of experimental subacute disseminated candidiasis in persistently neutropenic rabbits. Icofungipen was administered for 10 days starting 24 h after the intravenous inoculation of 103 Candida albicans blastoconidia. Study groups consisted of rabbits treated with icofungipen at 4 (ICO-4), 10 (ICO-10), and 25 (ICO-25) mg/kg of body weight/day in two divided dosages, rabbits treated with fluconazole at 10 mg/kg/day, rabbits treated with amphotericin B at 1 mg/kg/day, and untreated controls. Levels of icofungipen in plasma were derivatized by phthaldialdehyde and quantified by high-performance liquid chromatography with fluorescence detection. Rabbits treated with ICO-10 (P < 0.01) and ICO-25 (P < 0.001) showed significant dosage-dependent tissue clearance of C. albicans from the liver, spleen, kidney, brain, vitreous, vena cava, and lung in comparison to untreated controls. ICO-25 cleared C. albicans from all tissues and had activity comparable to that of amphotericin B versus untreated controls (P < 0.001). Pharmacokinetics of icofungipen in plasma approximated a dose-dependent relationship of the maximum concentration of drug in serum and the area under the concentration-time curve. There was no significant elevation of the levels of hepatic transaminases, alkaline phosphatase, bilirubin, urea nitrogen, or creatinine in icofungipen-treated rabbits. Icofungipen followed dose-dependent pharmacokinetics and was effective in the treatment of experimental disseminated candidiasis, including central nervous system infection, in persistently neutropenic rabbits.
* Corresponding author. Mailing address: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Building 10, CRC, Rm. 1W-5740, 10 Center Drive, MSC 1100, Bethesda, MD 20892-1100. Phone: (301) 402-0023. Fax: (301) 480-2308. E-mail: walsht{at}mail.nih.gov.
Antimicrobial Agents and Chemotherapy, May 2005, p. 2084-2092, Vol. 49, No. 5
0066-4804/05/$08.00+0 doi:10.1128/AAC.49.5.2084-2092.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
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