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Antimicrobial Agents and Chemotherapy, June 2006, p. 1993-1999, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.00157-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics and Safety of Oral Posaconazole in Neutropenic Stem Cell Transplant Recipients

Paul O. Gubbins,1* Gopal Krishna,2 Angela Sansone-Parsons,2 Scott R. Penzak,3 Li Dong,4 Monika Martinho,2 and Elias J. Anaissie4

College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas,1 Schering-Plough Research Institute, Kenilworth, New Jersey,2 National Institutes of Health, Clinical Pharmacokinetics Laboratory, Clinical Center Pharmacy Department, Bethesda, Maryland,3 Myeloma Institute for Research and Therapy, Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas4

Received 6 February 2006/ Returned for modification 1 March 2006/ Accepted 1 April 2006

The pharmacokinetics of posaconazole oral suspension in neutropenic patients undergoing high-dose chemotherapy and stem cell transplantation were evaluated, and the association of plasma posaconazole exposure with the presence and severity of oral mucositis was explored in this nonrandomized, open-label, parallel-group, multiple-dose pharmacokinetic study. Thirty patients were enrolled and received one of three regimens (group I, 200 mg once daily; group II, 400 mg once daily; group III, 200 mg four times daily) for the duration of neutropenia. The mean total exposure for day 1, as shown by the area under the concentration-time curve from 0 to 24 h (AUC0-24), was 1.96 mg · h/liter in group I and was 51% higher in group II and in group III. Increases in AUC0-24 and maximum plasma concentration (Cmax) in groups II and III were dose related. The AUC0-24 and Cmax values on day 1 were similar between groups II and III. There was interpatient variability of up to 68% in the pharmacokinetic values for our study population. Steady state was attained by days 5 to 6. Average steady-state plasma posaconazole trough values were 192, 219, and 414 ng/ml in groups I, II, and III, respectively. The AUC0-24 and apparent oral clearance increased by increasing dose and dosing frequency. Mucositis appeared to reduce exposure but did not significantly affect mean total posaconazole exposure (AUC and Cmax) at steady state (P = 0.1483). Moreover, this reduction could be overcome by increasing the total dose and dosing frequency. Posaconazole was safe and well tolerated.

* Corresponding author. Mailing address: Department of Pharmacy Practice, College of Pharmacy, University of Arkansas for Medical Sciences, 4301 W. Markham #522, Little Rock, AR 72205. Phone: (501) 686-6683. Fax: (501) 296-1168. E-mail: gubbinspaulo{at}uams.edu.

Antimicrobial Agents and Chemotherapy, June 2006, p. 1993-1999, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.00157-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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