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Antimicrobial Agents and Chemotherapy, April 2005, p. 1331-1336, Vol. 49, No. 4
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.4.1331-1336.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Pharmacokinetic and Maximum Tolerated Dose Study of Micafungin in Combination with Fluconazole versus Fluconazole Alone for Prophylaxis of Fungal Infections in Adult Patients Undergoing a Bone Marrow or Peripheral Stem Cell Transplant

J. Hiemenz,1* P. Cagnoni,2 D. Simpson,3 S. Devine,4,{dagger} N. Chao,5 J. Keirns,6 W. Lau,6 D. Facklam,6 and D. Buell6

Florida Hospital Cancer Institute, Orlando, Florida,1 University of Colorado, Denver, Colorado,2 Rush-Presbyterian-St. Luke's Medical Center,3 University of Illinois at Chicago, Chicago,4 Fujisawa Healthcare, Inc., Deerfield, Illinois,6 Duke University, Durham, North Carolina5

Received 8 September 2004/ Returned for modification 12 October 2004/ Accepted 26 December 2004

In this dose escalation study, 74 adult cancer patients undergoing bone marrow or peripheral blood stem cell transplantation received fluconazole (400 mg/day) and either normal saline (control) (12 subjects) or micafungin (12.5 to 200 mg/day) (62 subjects) for up to 4 weeks. The maximum tolerated dose (MTD) of micafungin was not reached, based on the development of Southwest Oncology Group criteria for grade 3 toxicity; drug-related toxicities were rare. Commonly occurring adverse events considered related to micafungin were headache (6.8%), arthralgia (6.8%), hypophosphatemia (4.1%), insomnia (4.1%), maculopapular rash (4.1%), and rash (4.1%). Pharmacokinetic profiles for micafungin on days 1 and 7 were similar. The mean half-life was approximately 13 h, with little variance after repeated or increasing doses. Mean maximum concentrations of the drug in serum and areas under the concentration-time curve from 0 to 24 h were approximately proportional to dose. There was no clinical or kinetic evidence of interaction between micafungin and fluconazole. Five of 12 patients (42%) in the control group and 14 of 62 (23%) in the micafungin-plus-fluconazole groups had a suspected fungal infection during treatment which resulted in empirical treatment with amphotericin B. The combination of micafungin and fluconazole was found to be safe in this high-risk patient population. The MTD of micafungin was not reached even at doses up to 200 mg/day for 4 weeks. The pharmacokinetic profile of micafungin in adult cancer patients with blood or marrow transplants is consistent with the profile in healthy volunteers, and the area under the curve is proportional to dose.

* Corresponding author. Mailing address: Medical College of Georgia, 1120 15th St., BAA 5407, Augusta, GA 30912. Phone: (706) 721-2505. Fax: (706) 721-8302. E-mail: jhiemenz{at}mcg.edu.

{dagger} Present address: Washington University, St. Louis, Mo.

Antimicrobial Agents and Chemotherapy, April 2005, p. 1331-1336, Vol. 49, No. 4
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.4.1331-1336.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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