PHARMACOKINETICS AND DISPOSITION Plasma protein distribution and its impact on pharmacokinetics of liposomal amphotericin B in paediatric patients with malignant diseases Ying Hong & Peter J. Shaw & Bruce N. Tattam & Christa E. Nath & John W. Earl & Katherine R. Stephen & Andrew J. McLachlan Received: 4 August 2006 / Accepted: 17 November 2006 / Published online: 19 December 2006 # Springer-Verlag 2006 Abstract Objective This study investigates the association of liposo- mal 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 demon- strated 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 distribu- tion 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 pharmaco- kinetic profile of L-AmB. Keywords Liposomal amphotericin B . Lipoprotein-liposome interactions . Paediatric patients . Posterior Bayesian estimates . Protein binding Introduction Encapsulation in liposomes is a strategy that has been shown to improve the therapeutic index of a number of drugs, including 2′,3′-dideoxyinosine [1], doxorubicin [2], amikacin [3], cisplatin [4], vincristine [5] and amphotericin B[6], by modifying the pharmacokinetics of these drugs. A phase IV study comparing the disposition of liposomal amphotericin B (AmBisome; L-AmB) and amphotericin B deoxycholate (Fungizone; D-AmB) in healthy human volunteers has demonstrated that encapsulation of AmB into these unilamellar vesicles resulted in higher plasma concentrations and a lower volume of distribution, and greatly reduced renal and biliary clearances [6]. Therefore, it is hypothesised that the improved therapeutic properties Eur J Clin Pharmacol (2007) 63:165–172 DOI 10.1007/s00228-006-0240-x Y. Hong : B. N. Tattam : A. J. McLachlan (*) Faculty of Pharmacy, University of Sydney, Pharmacy Building (A15), Sydney, NSW 2006, Australia e-mail: andrewm@pharm.usyd.edu.au P. J. Shaw : K. R. Stephen Department of Oncology, The Children’ s Hospital Westmead, Sydney, NSW, Australia C. E. Nath : J. W. Earl Department of Biochemistry, The Children’ s Hospital Westmead, Sydney, NSW, Australia A. J. McLachlan Centre for Education and Research on Ageing, Concord Hospital, Sydney, NSW, Australia Y. Hong Department of Pharmaceutical Sciences, University at Buffalo – State University of New York (SUNY), 517 Hochstetter Hall, Buffalo, NY 14260-1200, USA