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Plasma protein distribution and its impact on pharmacokinetics of liposomal amphotericin B in paediatric patients with malignant diseases

  • Pharmacokinetics and Disposition
  • Published:
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Abstract

Objective

This study investigates the association of liposomal amphotericin B (L-AmB) with plasma proteins and its impact on the pharmacokinetics of L-AmB in paediatric patients with malignant diseases.

Methods

Paediatric oncology patients (n = 39) who received multiple-doses of L-AmB were recruited into this study. The association of the drug with plasma lipoprotein was investigated using single vertical spin density gradient ultracentrifugation and quantitated with a validated HPLC assay. The unbound amphotericin B (AmB) in the plasma was separated by ultrafiltration and determined with a validated LC/MS/MS assay.

Results

The ex vivo lipoprotein distribution of L-AmB found that 68.3 ± 11.8% of the drug was associated with the high density lipoprotein (HDL) fraction, which demonstrated a significant inverse correlation with posterior Bayesian estimates of L-AmB clearance (r = −0.690, p < 0.01). The average of unbound fraction of AmB in plasma of patients administered with L-AmB was 0.005, but its relationship with L-AmB clearance did not reach a statistical significance.

Conclusion

L-AmB displays different lipoprotein distribution profile from that of the conventional AmB formulation, with L-AmB preferentially associated with HDL in plasma. The inverse correlation of L-AmB clearance to its HDL distribution contributes to the difference in the pharmacokinetic profile of L-AmB.

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Acknowledgements

Y.H. is supported by a University of Sydney International Postgraduate Research Scholarships. C.E.N is supported by the Leukaemia Research & Support Fund at the Children’s Hospital at Westmead.

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Authors and Affiliations

  1. Faculty of Pharmacy, University of Sydney, Pharmacy Building (A15), Sydney, NSW, 2006, Australia

    Ying Hong, Bruce N. Tattam & Andrew J. McLachlan

  2. Department of Oncology, The Children’s Hospital Westmead, Sydney, NSW, Australia

    Peter J. Shaw & Katherine R. Stephen

  3. Department of Biochemistry, The Children’s Hospital Westmead, Sydney, NSW, Australia

    Christa E. Nath & John W. Earl

  4. Centre for Education and Research on Ageing, Concord Hospital, Sydney, NSW, Australia

    Andrew J. McLachlan

  5. Department of Pharmaceutical Sciences, University at Buffalo – State University of New York (SUNY), 517 Hochstetter Hall, Buffalo, NY, 14260-1200, USA

    Ying Hong

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  1. Ying Hong
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Correspondence to Andrew J. McLachlan.

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Hong, Y., Shaw, P.J., Tattam, B.N. et al. Plasma protein distribution and its impact on pharmacokinetics of liposomal amphotericin B in paediatric patients with malignant diseases. Eur J Clin Pharmacol 63, 165–172 (2007). https://doi.org/10.1007/s00228-006-0240-x

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  • DOI: https://doi.org/10.1007/s00228-006-0240-x

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