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Factors influencing the pharmacokinetics of prophylactic posaconazole oral suspension in patients with acute myeloid leukemia or myelodysplastic syndrome

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objectives

To estimate the pharmacokinetic (PK) properties of posaconazole in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing chemotherapy in a clinical setting.

Methods

Posaconazole concentrations in patients with AML/MDS receiving prophylactic posaconazole were determined by high-performance liquid chromatography. A population PK model with nonlinear mixed effect modeling was developed. The list of tested covariates included age, weight, height, gender, posaconazole dose, ethnicity, co-administration of antineoplastic chemotherapy, ranitidine or pantoprazole, coincident fever, diarrhea, leukocyte counts, and γ-glutamyltransterase plasma activity.

Results

A total of 643 serum concentrations of posaconazole from 84 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 56.8 L/h [95% confidence interval (CI) 52.8–60.8 L/h] and an apparent volume of distribution of 2,130 L (95% CI 1,646–2,614 L). Significant effects on apparent clearance (CL/F) were found for presence of diarrhea and for co-medication with proton-pump inhibitors (1.5- and 1.6-fold increase in CL/F, respectively), weight (33.4 L larger apparent volume of distribution per kilogram), and co-administration of chemotherapy (0.6-fold lower apparent volume of distribution).

Conclusion

We developed a prediction basis for mean posaconazole concentrations in AML/MDS patients. Patient weight, presence of diarrhea, and concomitant medication (chemotherapy and pantoprazole) showed significant effects on posaconazole exposure. Corresponding adjustments of the starting dose according to the presence of diarrhea and during the co-administration of chemotherapy or proton-pump inhibitors appear justified before therapeutic drug monitoring results are available. Further investigation of the interaction between different chemotherapeutic regimens and posaconazole is warranted.

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Transparency declaration

Carsten Müller, Farowski Fedja, Uwe Fuhr, Michael Hallek, and Victoria Kohl have no conflicts to declare.

JJV has served on the speakers’ bureau of Astellas, Gilead, Merck/Schering-Plough, and Pfizer, and received research grants from Merck/Schering-Plough and Pfizer.

Maria Vehreschild has served on the speakers’ bureau of Astellas, Gilead, Merck/Schering-Plough and Pfizer.

Oliver A Cornely is supported by the German Federal Ministry of Research and Education (BMBF grant 01KN0706), 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, Mölnlycke, Optimer, and Pfizer, and has received lecture honoraria from Astellas, Gilead, Merck/Schering, and Pfizer.

KAK is a consultant to and has received financial or material support from Merck.

Funding

No funding of any kind was received for this project.

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Authors and Affiliations

  1. Department I of Internal Medicine, University of Cologne, Cologne, Germany

    J. J. Vehreschild, F. Farowski, M. J. G. T. Vehreschild, O. A. Cornely, K.-A. Kreuzer & M. Hallek

  2. Department of Pharmacology, University of Cologne, Cologne, Germany

    C. Müller, U. Fuhr & V. Kohl

  3. Clinical Trials Center Cologne, ZKS Köln, BMBF 01KN0706, and CECAD, University of Cologne, Cologne, Germany

    O. A. Cornely

  4. Uniklinik Köln, Kerpener Straße 62, 50937, Cologne, Germany

    O. A. Cornely

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  1. J. J. Vehreschild
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Correspondence to O. A. Cornely.

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Vehreschild, J.J., Müller, C., Farowski, F. et al. Factors influencing the pharmacokinetics of prophylactic posaconazole oral suspension in patients with acute myeloid leukemia or myelodysplastic syndrome. Eur J Clin Pharmacol 68, 987–995 (2012). https://doi.org/10.1007/s00228-012-1212-y

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  • DOI: https://doi.org/10.1007/s00228-012-1212-y

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