Pharmacokinetics of Different Dosing Strategies of Oral Posaconazole in Patients with Compromised Gastrointestinal Function and Who Are at High Risk for Invasive Fungal Infection

• Type of Material: Article
• Authors: Oliver A. Cornely, University Hospital Cologne; David Helfgott, New York Presbyterian Hospital; Amelia Langston, Emory University; Werner Heinz, University of Wurzburg; Jorg-Janne Vehreschild, University Hospital Cologne; Maria J.G.T. Vehreschild, University Hospital Cologne; Gopal Krishna, Merck & Co., Inc.; Lei Ma, Merck & Co., Inc.; Susan Huyck, Merck & Co., Inc.; Michael C. McCarthy, Merck & Co., Inc.
• Language: English
• Date: 2012-05-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2012, American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1128/AAC.05937-11
• Title of Journal or Parent Work: Antimicrobial Agents and Chemotherapy
• ISSN: 0066-4804
• Volume: 56
• Issue: 5
• Start Page: 2652
• End Page: 2658
• Grant/Funding Information: J.-J.V. is supported by the German Federal Ministry of Research and Education (BMBF grant 01KI0771) and has received research grants from or has been a speaker for Astellas, Merck, Pfizer, and Schering-Plough.; O.A.C. is supported by the German Federal Ministry of Research and Education (BMBF grant 01KN1106), has received research grants from Actelion, Astellas, Basilea, Bayer, Biocryst, Celgene, F2G, Genzyme, Gilead, Merck/Schering, Miltenyi, Optimer, Pfizer, Quintiles, and Viropharma, is a consultant to Astellas, Basilea, F2G, Gilead, Merck/Schering, Optimer, and Pfizer, and received lecture honoraria from Astellas, Gilead, Merck/Schering, and Pfizer.; This study was funded by Schering-Plough (now Merck & Co., Inc.).; D.H. has conducted clinical research for Merck & Co., Inc.; A.L. has received research support from Merck (formerly Schering-Plough) and Pfizer.; W.H. has received research grants from Astellas, Basilea, Gilead, MSD/Merck (formerly Essex/Schering-Plough), and Pfizer, is a consultant to MSD/Merck, and served on the speakers' bureau of Astellas, Bristol-Myers Squibb, Essex/Schering-Plough, Gilead, MSD/Merck, and Pfizer.
• Keywords: Life Sciences & Biomedicine; CANCER-PATIENTS; PHARMACOLOGY & PHARMACY; CHEMOTHERAPY; MICROBIOLOGY; Science & Technology; Microbiology; HEALTHY-ADULTS; EXPOSURE-RESPONSE; Pharmacology & Pharmacy; PROPHYLAXIS; PLASMA; SAFETY
• Research Categories: Health Sciences, General

Abstract

The aim of this study was to assess different dosing strategies that may result in increased posaconazole bioavailability in patients with compromised gastrointestinal function and at high risk for invasive fungal infections. Patients undergoing chemotherapy and at risk for compromised gastrointestinal function received open-label posaconazole at 200 mg three times daily (TID) on days 1 to 8. Patients were randomized to one of three open-label dosing regimens of posaconazole on days 9 to 15: 200 mg TID, 400 mg twice daily (BID), or 400 mg TID. The plasma concentrations of interest on days 8 and 15 were 500 and 700 ng/ml, respectively; day 2 plasma concentrations of 250 and 350 ng/ml were chosen as levels that might result in steady-state concentrations of > 500 and > 700 ng/ml, respectively. A total of 75 patients enrolled; 52/75 (69%) completed the study, and 49/75 were included in the pharmacokinetic analyses. Mean plasma concentrations were 230, 346, and 637 ng/ml on days 2, 3, and 8, respectively. The day 15 values were 660, 930, and 671 ng/ml for 200 mg TID, 400 mg BID, and 400 mg TID, respectively. In 12 patients with a day 8 posaconazole concentration of < 250 ng/ml, an overall benefit of the higher two doses was not apparent, suggesting that a subset of patients has low steady-state plasma concentrations. A change in dosing regimen on day 9 did not lead to higher exposures in these "poor absorbers" on day 15. Poor absorption may be enhanced with a high-fat meal, a nutritional supplement, or acidification.