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

European Journal of Clinical Pharmacology volume 63, pages 165–172 (2007)Cite this article

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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References

  1. Harvie P, Desormeaux A, Bergeron MC, Tremblay M, Beauchamp D, Poulin L, Bergeron MG (1996) Comparative pharmacokinetics, distributions in tissue, and interactions with blood proteins of conventional and sterically stabilized liposomes containing 2′,3′-dideoxyinosine. Antimicrob Agents Chemother 40:225–229

    PubMed  CAS  Google Scholar 

  2. Amantea MA, Forrest A, Northfelt DW, Mamelok R (1997) Population pharmacokinetics and pharmacodynamics of pegylated-liposomal doxorubicin in patients with AIDS-related Kaposi’s sarcoma. Clin Pharmacol Ther 61:301–311

    PubMed  Article  CAS  Google Scholar 

  3. Fielding RM, Lewis RO, Moon-McDermott L (1998) Altered tissue distribution and elimination of amikacin encapsulated in unilamellar, low-clearance liposomes (MiKasome). Pharmaceut Res 15:1775–1781

    Article  CAS  Google Scholar 

  4. Newman MS, Colbern GT, Working PK, Engbers C, Amantea MA (1999) Comparative pharmacokinetics, tissue distribution, and therapeutic effectiveness of cisplatin encapsulated in long-circulating, pegylated liposomes (SPI-077) in tumor-bearing mice. Cancer Chemother Pharmacol 43:1–7

    PubMed  Article  CAS  Google Scholar 

  5. Krishna R, Webb MS, St Onge G, Mayer LD (2001) Liposomal and nonliposomal drug pharmacokinetics after administration of liposome-encapsulated vincristine and their contribution to drug tissue distribution properties. J Pharmacol Exp Ther 298:1206–1212

    PubMed  CAS  Google Scholar 

  6. Bekersky I, Fielding RM, Dressler DE, Lee JW, Buell DN, Walsh TJ (2002) Pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate in humans. Antimicrob Agents Chemother 46:828–833

    PubMed  Article  CAS  Google Scholar 

  7. Wasan KM, Cassidy SM (1998) Role of plasma lipoproteins in modifying the biological activity of hydrophobic drugs. J Pharmaceut Sci 87:411–424

    Article  CAS  Google Scholar 

  8. Wasan KM, Ramaswamy M, Kwong M, Boulanger KD (2002) Role of plasma lipoproteins in modifying the toxic effects of water-insoluble drugs: studies with cyclosporine A. AAPS PharmSci 4:E30

    Article  Google Scholar 

  9. Wasan KM, Ng S, Cassidy SM (1997) Modifications in high-density lipoprotein lipid composition and structure alter the plasma distribution of free and liposomal annamycin. J Pharmaceut Sci 86:872–875

    Article  CAS  Google Scholar 

  10. Wasan KM, Pritchard PH, Ramaswamy M, Wong W, Donnachie EM, Brunner LJ (1997) Differences in lipoprotein lipid concentration and composition modify the plasma distribution of cyclosporine. Pharmaceut Res 14:1613–1620

    Article  CAS  Google Scholar 

  11. Cassidy SM, Strobel FW, Wasan KM (1998) Plasma lipoprotein distribution of liposomal nystatin is influenced by protein content of high-density lipoproteins. Antimicrob Agents Chemother 42:1878–1888

    PubMed  CAS  Google Scholar 

  12. Wasan KM, Ramaswamy M, McIntosh MP, Porter CJ, Charman WN (1999) Differences in the lipoprotein distribution of halofantrine are regulated by lipoprotein apolar lipid and protein concentration and lipid transfer protein I activity: in vitro studies in normolipidemic and dyslipidemic human plasmas. J Pharmaceut Sci 88:185–190

    Article  CAS  Google Scholar 

  13. Zahir H, McCaughan G, Gleeson M, Nand RA, McLachlan AJ (2004) Factors affecting variability in distribution of tacrolimus in liver transplant recipients. Br J Clin Pharmacol 57:298–309

    PubMed  Article  CAS  Google Scholar 

  14. Zahir H, McCaughan G, Gleeson M, Nand RA, McLachlan AJ (2004) Changes in the protein binding and distribution of tacrolimus in the early phase of liver transplant recipients. Ther Drug Monit 26:506–515

    PubMed  Article  CAS  Google Scholar 

  15. Wasan KM, Kennedy AL, Cassidy SM, Ramaswamy M, Holtorf L, Chou JW, Pritchard PH (1998) Pharmacokinetics, distribution in serum lipoproteins and tissues, and renal toxicities of amphotericin B and amphotericin B lipid complex in a hypercholesterolemic rabbit model: single-dose studies. Antimicrob Agents Chemother 42:3146–3152

    PubMed  CAS  Google Scholar 

  16. Rossignol DP, Wasan KM, Choo E, Yau E, Wong N, Rose J, Moran J, Lynn M (2004) Safety, pharmacokinetics, pharmacodynamics, and plasma lipoprotein distribution of eritoran (E5564) during continuous intravenous infusion into healthy volunteers. Antimicrob Agents Chemother 48:3233–3240

    PubMed  Article  CAS  Google Scholar 

  17. Wasan KM, Lopez-Berestein G (1996) Characteristics of lipid-based formulations that influence their biological behaviour in the plasma of patients. Clin Infect Dis 23:1126–1138

    PubMed  CAS  Google Scholar 

  18. Boman NL, Cullis PR, Mayer LD, Webb MS (1997) Liposomal vincristine: the central role of drug retention in defining therapeutically optimized anticancer formulations. In: Woodle MC, Storm G (eds) Long circulating liposomes: old drugs, new therapeutics. Landes Bioscience, Georgetown pp 29–49

    Google Scholar 

  19. Bakker-Woudenberg IA (2002) Long-circulating sterically stabilized liposomes as carriers of agents for treatment of infection or for imaging infectious foci. Int J Antimicrob Agents 19:299–311

    PubMed  Article  CAS  Google Scholar 

  20. Hong Y, Shaw PJ, Nath CE, Yadav SP, Stephen KR, Earl JW, McLachlan AJ (2006) Population pharmacokinetics of liposomal amphotericin B in pediatric patients with malignant diseases. Antimicrob Agents Chemother 50:935–942

    PubMed  Article  CAS  Google Scholar 

  21. Boeckmann AJ, Sheiner LB, Beal SL (1992) NONMEM users guide – part V introductory guide. NONMEM Project Group, University of California, San Francisco

  22. Chung BH, Segrest JP, Ray MJ, Brunzell JD, Hokanson JE, Krauss RM, Beaudrie K, Cone JT (1986) Single vertical spin density gradient ultracentrifugation. Methods Enzymol 128:181–209

    PubMed  CAS  Article  Google Scholar 

  23. Hong Y, Ramzan I, McLachlan AJ (2004) Disposition of amphotericin B in the isolated perfused rat liver. J Pharmaceut Pharmacol 56:35–41

    Article  CAS  Google Scholar 

  24. Alak A, Moy S, Bekersky I (1996) A high-performance liquid chromatographic assay for the determination of amphotericin B serum concentrations after the administration of AmBisome, a liposomal amphotericin B formulation. Ther Drug Monit 18:604–609

    PubMed  Article  CAS  Google Scholar 

  25. Lee JW, Petersen ME, Lin P, Dressler D, Bekersky I (2001) Quantitation of free and total amphotericin B in human biologic matrices by a liquid chromatography tandem mass spectrometric method. Ther Drug Monit 23:268–276

    PubMed  Article  CAS  Google Scholar 

  26. Hartsel SC, Baas B, Bauer E, Foree LT Jr, Kindt K, Preis H, Scott A, Kwong EH, Ramaswamy M, Wasan KM (2001) Heat-induced superaggregation of amphotericin B modifies its interaction with serum proteins and lipoproteins and stimulation of TNF-alpha. J Pharmaceut Sci 90:124–133

    Article  CAS  Google Scholar 

  27. Bekersky I, Fielding RM, Dressler DE, Lee JW, Buell DN, Walsh TJ (2002) Plasma protein binding of amphotericin B and pharmacokinetics of bound versus unbound amphotericin B after administration of intravenous liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate. Antimicrob Agents Chemother 46:834–840

    PubMed  Article  CAS  Google Scholar 

  28. Surewicz WK, Epand RM, Pownall HJ, Hui SW (1986) Human apolipoprotein A-I forms thermally stable complexes with anionic but not with zwitterionic phospholipids. J Biol Chem 261:16191–16197

    PubMed  CAS  Google Scholar 

  29. Wasan KM, Brazeau GA, Keyhani A, Hayman AC, Lopez-Berestein G (1993) Roles of liposome composition and temperature in distribution of amphotericin B in serum lipoproteins. Antimicrob Agents Chemother 37:246–250

    PubMed  CAS  Google Scholar 

  30. Sivak O, Lau B, Patankar N, Wasan KM (2004) Unidirectional inhibition of lipid transfer protein I-mediated transfer of cholesteryl esters between high-density and low-density lipoproteins by amphotericin B lipid complex. Pharmaceut Res 21:2336–2339

    Article  CAS  Google Scholar 

  31. Cullis PR, Chonn A, Semple SC (1998) Interactions of liposomes and lipid-based carrier systems with blood proteins: relation to clearance behaviour in vivo. Adv Drug Deliv Rev 32:3–17

    PubMed  Article  Google Scholar 

  32. Garrett RH, Grisham CM (1995) Transport of many lipids occurs via lipoprotein complexes. In: Garrett RH, Grisham CM (eds) Biochemistry, 2nd edn. Saunders College Publ, Philadelphia, pp 840–846

  33. Adler-Moore J, Proffitt RT (2002) AmBisome: liposomal formulation, structure, mechanism of action and pre-clinical experience. J Antimicrob Chemother 49[S1]:21–30

    PubMed  CAS  Google Scholar 

  34. Brajtburg J, Bolard J (1996) Carrier effects on biological activity of amphotericin B. Clin Microbiol Rev 9:512–531

    PubMed  CAS  Google Scholar 

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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.

Author information

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

Authors
  1. Ying Hong
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  2. Peter J. Shaw
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  7. Andrew J. McLachlan
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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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Keywords

  • Liposomal amphotericin B
  • Lipoprotein-liposome interactions
  • Paediatric patients
  • Posterior Bayesian estimates
  • Protein binding