The AAPS Journal

, 13:255 | Cite as

Physiologically Based Pharmacokinetic Model of Amphotericin B Disposition in Rats Following Administration of Deoxycholate Formulation (Fungizone®): Pooled Analysis of Published Data

  • Leonid Kagan
  • Pavel Gershkovich
  • Kishor M. Wasan
  • Donald E. Mager
Research Article


The time course of tissue distribution of amphotericin B (AmB) has not been sufficiently characterized despite its therapeutic importance and an apparent disconnect between plasma pharmacokinetics and clinical outcomes. The goals of this work were to develop and evaluate a physiologically based pharmacokinetic (PBPK) model to characterize the disposition properties of AmB administered as deoxycholate formulation in healthy rats and to examine the utility of the PBPK model for interspecies scaling of AmB pharmacokinetics. AmB plasma and tissue concentration–time data, following single and multiple intravenous administration of Fungizone® to rats, from several publications were combined for construction of the model. Physiological parameters were fixed to literature values. Various structural models for single organs were evaluated, and the whole-body PBPK model included liver, spleen, kidney, lung, heart, gastrointestinal tract, plasma, and remainder compartments. The final model resulted in a good simultaneous description of both single and multiple dose data sets. Incorporation of three subcompartments for spleen and kidney tissues was required for capturing a prolonged half-life in these organs. The predictive performance of the final PBPK model was assessed by evaluating its utility in predicting pharmacokinetics of AmB in mice and humans. Clearance and permeability–surface area terms were scaled with body weight. The model demonstrated good predictions of plasma AmB concentration–time profiles for both species. This modeling framework represents an important basis that may be further utilized for characterization of formulation- and disease-related factors in AmB pharmacokinetics and pharmacodynamics.


amphotericin B interspecies scaling physiologically based pharmacokinetic model tissue distribution 



The authors would like to thank Dr. John M. Harrold for his help in developing a MATLAB code for this project.


  1. 1.
    Lemke A, Kiderlen AF, Kayser O. Amphotericin B. Appl Microbiol Biotechnol. 2005;68(2):151–62.PubMedCrossRefGoogle Scholar
  2. 2.
    Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–20.PubMedCrossRefGoogle Scholar
  3. 3.
    Gershkovich P, Wasan EK, Lin M, Sivak O, Leon CG, Clement JG, et al. Pharmacokinetics and biodistribution of amphotericin B in rats following oral administration in a novel lipid-based formulation. J Antimicrob Chemother. 2009;64(1):101–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Kayser O, Olbrich C, Yardley V, Kiderlen AF, Croft SL. Formulation of amphotericin B as nanosuspension for oral administration. Int J Pharm. 2003;254(1):73–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Delmas G, Park S, Chen ZW, Tan F, Kashiwazaki R, Zarif L, et al. Efficacy of orally delivered cochleates containing amphotericin B in a murine model of aspergillosis. Antimicrob Agents Chemother. 2002;46(8):2704–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Benson JM, Nahata MC. Pharmacokinetics of amphotericin B in children. Antimicrob Agents Chemother. 1989;33(11):1989–93.PubMedGoogle Scholar
  7. 7.
    Graybill JR. Is there a correlation between serum antifungal drug concentration and clinical outcome? J Infect. 1994;28 Suppl 1:17–24.PubMedCrossRefGoogle Scholar
  8. 8.
    Bekersky I, Fielding RM, Dressler DE, Lee JW, Buell DN, Walsh TJ. 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. 2002;46(3):834–40.PubMedCrossRefGoogle Scholar
  9. 9.
    Matsui S, Imai S, Yabuki M, Komuro S. Pharmacokinetics characterization of liposomal amphotericin B: investigation of clearance process and drug interaction potential. Arzneimittelforschung. 2009;59(9):461–70.PubMedGoogle Scholar
  10. 10.
    Hutchaleelaha A, Chow HH, Mayersohn M. Comparative pharmacokinetics and interspecies scaling of amphotericin B in several mammalian species. J Pharm Pharmacol. 1997;49(2):178–83.PubMedCrossRefGoogle Scholar
  11. 11.
    Atkinson Jr AJ, Bennett JE. Amphotericin B pharmacokinetics in humans. Antimicrob Agents Chemother. 1978;13(2):271–6.PubMedGoogle Scholar
  12. 12.
    Bekersky I, Fielding RM, Dressler DE, Lee JW, Buell DN, Walsh TJ. Pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate in humans. Antimicrob Agents Chemother. 2002;46(3):828–33.PubMedCrossRefGoogle Scholar
  13. 13.
    Fielding RM, Smith PC, Wang LH, Porter J, Guo LS. Comparative pharmacokinetics of amphotericin B after administration of a novel colloidal delivery system, ABCD, and a conventional formulation to rats. Antimicrob Agents Chemother. 1991;35(6):1208–13.PubMedGoogle Scholar
  14. 14.
    Gershkovich P, Wasan EK, Sivak O, Li R, Zhu X, Werbovetz KA, et al. Visceral leishmaniasis affects liver and spleen concentrations of amphotericin B following administration to mice. J Antimicrob Chemother. 2010;65:535–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Rowland M, Peck C, Tucker G. Physiologically-based pharmacokinetics in drug development and regulatory science. Annu Rev Pharmacol Toxicol. 2010;51:45–73.CrossRefGoogle Scholar
  16. 16.
    Angra PK, Siddig A, Nettey H, Desai N, Oettinger C, D’Souza MJ. Pharmacokinetic and biodistribution studies of amphotericin B microspheres. J Microencapsul. 2009;26(7):627–34.PubMedCrossRefGoogle Scholar
  17. 17.
    Wang LH, Fielding RM, Smith PC, Guo LS. Comparative tissue distribution and elimination of amphotericin B colloidal dispersion (Amphocil) and Fungizone after repeated dosing in rats. Pharm Res. 1995;12(2):275–83.PubMedCrossRefGoogle Scholar
  18. 18.
    Chow HH, Cai Y, Mayersohn M. Disposition kinetics of amphotericin B in rats. The influence of dose. Drug Metab Dispos. 1992;20(3):432–5.PubMedGoogle Scholar
  19. 19.
    Chow HH, Wu Y, Mayersohn M. Pharmacokinetics of amphotericin B in rats as a function of dose following constant-rate intravenous infusion. Biopharm Drug Dispos. 1995;16(6):461–73.PubMedCrossRefGoogle Scholar
  20. 20.
    Robbie G, Chiou WL. Elucidation of human amphotericin B pharmacokinetics: identification of a new potential factor affecting interspecies pharmacokinetic scaling. Pharm Res. 1998;15(10):1630–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Brown RP, Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP. Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health. 1997;13(4):407–84.PubMedGoogle Scholar
  22. 22.
    Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993;10(7):1093–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Gerlowski LE, Jain RK. Physiologically based pharmacokinetic modeling: principles and applications. J Pharm Sci. 1983;72(10):1103–27.PubMedCrossRefGoogle Scholar
  24. 24.
    Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York, NY, USA: Marcel Dekker, Inc.; 1982.Google Scholar
  25. 25.
    Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, et al. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol. 2008;24(1):67–76.PubMedCrossRefGoogle Scholar
  26. 26.
    Kawai R, Lemaire M, Steimer JL, Bruelisauer A, Niederberger W, Rowland M. Physiologically based pharmacokinetic study on a cyclosporin derivative, SDZ IMM 125. J Pharmacokinet Biopharm. 1994;22(5):327–65.PubMedCrossRefGoogle Scholar
  27. 27.
    Yamey G, Torreele E. The world’s most neglected diseases. BMJ. 2002;325(7357):176–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Mathers CD, Ezzati M, Lopez AD. Measuring the burden of neglected tropical diseases: the global burden of disease framework. PLoS Negl Trop Dis. 2007;1(2):e114.PubMedCrossRefGoogle Scholar
  29. 29.
    Christiansen KJ, Bernard EM, Gold JW, Armstrong D. Distribution and activity of amphotericin B in humans. J Infect Dis. 1985;152(5):1037–43.PubMedCrossRefGoogle Scholar
  30. 30.
    Olivier M, Tanner CE. Susceptibilities of macrophage populations to infection in vitro by Leishmania donovani. Infect Immun. 1987;55(2):467–71.PubMedGoogle Scholar
  31. 31.
    Adolph EF. Quantitative relations in the physiological constitutions of mammals. Science. 1949;109(2841):579–85.PubMedCrossRefGoogle Scholar
  32. 32.
    Wasan EK, Bartlett K, Gershkovich P, Sivak O, Banno B, Wong Z, et al. Development and characterization of oral lipid-based Amphotericin B formulations with enhanced drug solubility, stability and antifungal activity in rats infected with Aspergillus fumigatus or Candida albicans. Int J Pharm. 2009;372(1–2):76–84.PubMedCrossRefGoogle Scholar
  33. 33.
    Gupta S, Dube A, Vyas SP. Antileishmanial efficacy of amphotericin B bearing emulsomes against experimental visceral leishmaniasis. J Drug Target. 2007;15(6):437–44.PubMedCrossRefGoogle Scholar
  34. 34.
    Cortadellas O. Initial and long-term efficacy of a lipid emulsion of amphotericin B desoxycholate in the management of canine leishmaniasis. J Vet Intern Med. 2003;17(6):808–12.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2011

Authors and Affiliations

  • Leonid Kagan
    • 1
  • Pavel Gershkovich
    • 2
  • Kishor M. Wasan
    • 2
  • Donald E. Mager
    • 1
  1. 1.Department of Pharmaceutical SciencesUniversity at Buffalo, The State University of New YorkBuffaloUSA
  2. 2.Faculty of Pharmaceutical SciencesThe University of British ColumbiaVancouverCanada

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