AAC Accepts, published online ahead of print on 26 October 2009

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Antimicrob. Agents Chemother. doi:10.1128/AAC.01027-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Factors Influencing Pharmacokinetics of Prophylactic Posaconazole in Patients Undergoing Allogeneic Stem Cell Transplantation

V. Kohl, C. Müller, O. A. Cornely^*, K. Abduljalil, U. Fuhr, J. J. Vehreschild, C. Scheid, M. Hallek, and M. J.G.T. Rüping

Department of Pharmacology, University of Cologne, Cologne, Germany; Department I of Internal Medicine, University of Cologne, Cologne, Germany; Clinical Trials Center Cologne, ZKS Köln, BMBF 01KN0706, University of Cologne, Cologne, Germany; Simcyp Limited, Sheffield, UK; Stem Cell Transplantation Program, Department I of Internal Medicine, University of Cologne, Cologne, Germany

^* To whom correspondence should be addressed. Email: oliver.cornely{at}ctuc.de.

Objectives: To elucidate factors influencing the pharmacokinetics of prophylactically administered posaconazole in allogeneic haematopoietic stem cell transplant (SCT) recipients.

Patients and Methods: Clinical data was obtained from all SCT recipients at the University Hospital of Cologne between May 2007 and November 2008 undergoing therapeutic drug monitoring (TDM) of serum concentrations of prophylactic posaconazole. Posaconazole concentrations were determined by high-performance liquid chromatography. We developed a population pharmacokinetic model using nonlinear mixed effect modeling (NONMEM). The list of tested covariates included age, body weight, body height, gender, posaconazole dose, race, co-administration of antineoplastic chemotherapy, day of stem cell transplantation, concomitant ranitidine, pantoprazole, cyclosporine or tacrolimus administration, coincident fever, diarrhoea and GT plasma activity.

Results: A total of 149 serum concentrations of posaconazole from 32 patients were obtained. A one-compartment model with first order absorption and elimination as the basic structural model appropriately described the data, with an apparent clearance of 75.8 L/h (95 % CI 65.2-86.4 L/h) and an apparent volume of distribution of 835 L (95 % CI 559-1111 L). Among the covariates tested, significant effects were found for age (decrease of volume of distribution by 123 L per year of age) and for presence of diarrhoea (59 % loss of bioavailability).

Conclusion: A basis for prediction of mean posaconazole concentrations in allogeneic SCT recipients with haematological malignancies is provided for a given dose. Corresponding adjustments of the starting dose according to presence of diarrhoea and to age appear justified before TDM results are available.