SpringerLink
Log in

Allometric scaling of pegylated liposomal anticancer drugs

  • Published:
Journal of Pharmacokinetics and Pharmacodynamics Aims and scope Submit manuscript

Abstract

Pegylated liposomal formulations contain lipid conjugated to polyethylene glycol. The disposition of encapsulated drug is dictated by the composition of the liposome, thus altering the pharmacokinetic (PK) profile of the drug. Allometric scaling is based on a power-log relationship between body weight (W) and drug clearance (CL) among mammals and has been used to compare the disposition of nonliposomal drugs across species. The objectives of this study were to use allometric scaling to: (1) compare the disposition of pegylated liposomal drugs across speciesand determine the best scaling model and (2) predict PK parameters of pegylated liposomal drugs in humans. The PK of pegylated liposomal CKD-602 (S-CKD602), doxorubicin (Doxil®), and cisplatin (SPI-077) were compared. PK studies ofS-CKD602, Doxil®, and SPI-077 were performed at the maximum tolerated dose (MTD) in male and female mice, rats, dogs and patients with refractory solid tumors. The allometric equation used to evaluate the relationship between W and CL in each species was CL = a(W)m (a = empirical coefficient; m = allometric exponent). Substitution of physiological variables other than body weight, such as factors representative of the mononuclear phagocyte system (MPS) were evaluated. Dedrick Plots and Maximum Life-Span Potential (MLP) were used to determine scaling feasibility. Standard allometry demonstrated a relationship between clearance of S-CKD602, Doxil®, and SPI-077 and body, spleen, liver, and kidney weights, total monocyte count, and spleen and liver blood flow. However, using scaling to predict CL of these agents in humans often resulted in differences >30%. Despite a strong correlation between body weight and MPS-associated variables with CL among preclinical species, the use of the equations did not predict CL. Thus, new methods of allometric scaling and measures of MPS function need to be developed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Jain RK (1996) Delivery of molecular medicine to solid tumors. Science 271(5252):1079–1080

    Article  PubMed  CAS  Google Scholar 

  2. Zamboni WC, Houghton PJ, Hulstein JL, Kirstein M, Walsh J, Cheshire PK, Hanna SK, Danks MK, Stewart CF (1999) Relationship between tumor extracellular fluid exposure to topotecan and tumor response in human neuroblastoma xenograft and cell lines. Cancer Chemother Pharmacol 43(4):269–276

    Article  PubMed  CAS  Google Scholar 

  3. Blochl-Daum B, Muller M, Meisinger V, Eichler HG, Fassolt A, Phemaberger H (1996) Measurement of extracellular fluid carboplatin kinetics in melanoma metastases with microdialysis. Br J Cancer 73(7):920–924

    Article  PubMed  CAS  Google Scholar 

  4. Muller M, Mader RM, Steiner B, Steger GG, Jansen B, Gnant M, Helbich T, Jakesz R, Eichler HG, Blochl-Daum B (1997) 5-fluorouracil kinetics in the interstitial tumor space: clinical response in breast cancer patients. Cancer Res 57(13):2598–2601

    PubMed  CAS  Google Scholar 

  5. Drummond DC, Meyer O, Hong K, Kirpotin DB, Papahadjopoulos D (1999) Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev 51(4):691–743

    PubMed  CAS  Google Scholar 

  6. Zamboni WC (2005) Liposomal, nanoparticle, and conjugated formulations of anticancer agents. Clin Cancer Res 11(23):8230–8234

    Article  PubMed  CAS  Google Scholar 

  7. Papahadjopoulos D, Allen TM, Gabizon A, Mayhew E, Matthay K, Huang SK, Lee KD, Woodle MC, Lasic DD, Redemann C (1991) Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci USA 88(24):11460–11464

    Article  PubMed  CAS  Google Scholar 

  8. D’Emanuele A, Attwood D (2005) Dendrimer-drug interactions. Adv Drug Deliv Rev 57(15):2147–2162

    Article  PubMed  Google Scholar 

  9. Allen TM, Martin FJ (2004) Advantages of liposomal delivery systems for anthracyclines. Semin Oncol 31(6 Suppl 13):5–15

    Article  PubMed  CAS  Google Scholar 

  10. Allen TM, Stuart DD. Liposome pharmacokinetics: Classical, sterically-stabilized, cationic liposomes and immunoliposomes. In: Janoff AS (ed) Liposomes: rational design. Marcel Dekker, Inc., New York, pp 63–87

  11. Maeda H, Wu J, Sawa T, Matsumura Y, Hori K (2000) Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 65(1–2):271–284

    Article  PubMed  CAS  Google Scholar 

  12. Lee JH, Lee JM, Lim KH, Kim JK, Ahn SK, Bang YJ, Hong CI (2000) Preclinical and phase I clinical studies with CKD-602, a novel camptothecin derivative. Ann NY Acad Sci 922:324–325

    Article  PubMed  CAS  Google Scholar 

  13. Zamboni WC, Strychor S, Joseph E, Walsh DR, Zamboni BA, Parise RA, Tonda ME, Yu NY, Engbers C, Eiseman JL (2007) Plasma, tumor and tissue disposition of STEALTH liposomal CKD-602 (S-CKD602) and nonliposomal CKD-602 in mice bearing A375 human melanoma xenografts. Clin Cancer Res 13(23):7217–7223

    Article  PubMed  CAS  Google Scholar 

  14. Gabizon A, Shmeeda H, Barenholz Y (2003) Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies. Clin Pharmacokinet 42(5):419–436

    Article  PubMed  CAS  Google Scholar 

  15. Gabizon A, Isacson R, Rosengarten O, Tzemach D, Shmeeda H, Sapir R (2008) An open-label study to evaluate dose and cycle dependence of the pharmacokinetics of pegylated liposomal doxorubicin. Cancer Chemother Pharmacol 61(4):695–702

    Article  PubMed  CAS  Google Scholar 

  16. Meerum Terwogt JM, Groenewegen G, Pluim D, Maliepaard M, Tibben MM, Huisman A, ten Bokkel Huinink WW, Schot M, Welbank H, Voest EE, Beijnen JH, Schellens JM (2002) Phase I and pharmacokinetic study of SPI-77, a liposomal encapsulated dosage form of cisplatin. Cancer Chemother Pharmacol 49(3):201–210

    Article  PubMed  CAS  Google Scholar 

  17. Meerum Terwogt JM, Tibbem MM, Wellbank H, Schellens JH, Beijnen JH (2000) Validated method for the determination of platinum from a liposomal source (SPI-77) in human plasma using graphite furnace Zeeman atomic absorption spectrometry. Fresenius J Anal Chem 366(3):298–302

    Article  PubMed  CAS  Google Scholar 

  18. Mahmood I, Balian JD (1999) The pharmacokinetic principles behind scaling from preclinical results to phase I protocols. Clin Pharmacokinet 36(1):1–11

    Article  PubMed  CAS  Google Scholar 

  19. Lin JH (1995) Species similarities and differences in pharmacokinetics. Drug Metab Dispos 23(10):1008–1021

    PubMed  CAS  Google Scholar 

  20. Lindstedt L, Schaeffer PJ (2002) Use of allometry in predicting anatomical and physiological parameters of mammals. Lab Anim 36(1):1–19

    Article  PubMed  CAS  Google Scholar 

  21. Mahmood I, Balian JD (1996) Interspecies scaling: predicting clearance of drugs in humans. Xenobiotica 26(9):887–895

    Article  PubMed  CAS  Google Scholar 

  22. McNamara PG (1991) Interspecies scaling in pharmacokinetics. In: Welling PG, Tse FLS, Dighe SV (eds) Pharmaceutical bioequivalence. Marcel Dekker Inc, New York, pp 276–300

    Google Scholar 

  23. Boxenbaum H (1984) Interspecies pharmacokinetic scaling and the evolutionary-comparative paradigm. Drug Metab Rev 15(5–6):1071–1121

    Article  PubMed  CAS  Google Scholar 

  24. Sacher G (1959) Relation of lifespan to brain weight and body weight in mammals. In: Wolstenholme GEW, O’Connor M (eds) CIBA Foundation colloquia on aging. Churchill, London, pp 115–133

    Google Scholar 

  25. Boxenbaum H, Ronfeld R (1983) Interspecies pharmacokinetic scaling and the Dedrick plots. Am J Physiol 245(6):768–777

    Google Scholar 

  26. Dedrick R, Bischoff KB, Zaharko DS (1970) Interspecies correlation of plasma concentration history of methotrexate (NSC-740). Cancer Chemother Rep 54(2):95–101

    PubMed  CAS  Google Scholar 

  27. Boxenbaum H (1982) Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics. J Pharmacokinet Biopharm 10(2):201–227

    Article  PubMed  CAS  Google Scholar 

  28. Brown RP, Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP (1997) Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health 13(4):407–484

    PubMed  CAS  Google Scholar 

  29. Food and Drug Administration (2003) Draft guidance for industry and reviewers on estimating the safe starting dose in clinical trials for therapeutics in adult healthy volunteers. Fed Regist 68:2340–2341

    Google Scholar 

  30. Schneider K, Oltmanns J, Hassauer M (2004) Allometric principles for interspecies extrapolation in toxicological risk assessment—empirical investigations. Regul Toxicol Pharmacol 39(3):334–347

    Article  PubMed  CAS  Google Scholar 

  31. Sweeting JN, Siu M, McCallum GP, Miller L, Wells PG (2010) Species differences in methanol and formic acid pharmacokinetics in mice, rabbits and primates. Toxicol Appl Pharmacol 247(1):28–35

    Article  PubMed  CAS  Google Scholar 

  32. Toutain PL, Ferran A, Bousquet-Melou A (2010) Species differences in pharmacokinetics and pharmacodynamics. Handb Exp Pharmacol 199:19–48

    Article  PubMed  CAS  Google Scholar 

  33. Hunter RP (2010) Interspecies allometric scaling. Handb Exp Pharmacol 199:139–157

    Article  PubMed  CAS  Google Scholar 

  34. Dedrick RL (1973) Animal scale-up. J Pharmacokinet Biopharm 1(5):435–461

    Article  PubMed  CAS  Google Scholar 

  35. Calder WA (1984) Size, function and life history. Harvard University Press, Cambridge, Massachusetts

    Google Scholar 

  36. Yamato O, Hayashi M, Kasai E, Tajima M, Yamasaki M, Maede Y (1999) Reduced glutathione accelerates the oxidative damage produced by sodium n-propylthiosulfate, one of the causative agents of onion-induced hemolytic anemia in dogs. Biochem Biophys Acta 1427(2):175–182

    PubMed  CAS  Google Scholar 

  37. Tang H, Mayersohn M (2011) Controversies in allometric scaling for predicting human drug clearance: an historical problem and reflections on what works and what does not. Curr Top Med Chem 11(4):340–350

    Article  PubMed  CAS  Google Scholar 

  38. Quigley KA, Chelack BJ, Haines DM, Jackson ML (2001) Application of a direct flow cytometric erythrocyte immunofluorescence assay in dogs with immune-mediated hemolytic anemia and comparison to the direct antiglobulin test. J Vet Diagn Invest 13(4):297–300

    Article  PubMed  CAS  Google Scholar 

  39. Zamboni WC, Maruca LJ, Strychor S, Zamboni BA, Ramalingam S, Edwards RP, Kim J, Bang Y, Lee H, Friedland DM, Stoller RG, Belani CP, Ramanathan RK (2010) Bidirectional pharmacodynamics interaction between pegylated liposomal CKD-602 (S-CKD602) and monocytes in patients with refractory solid tumors. J Liposome Res 21(2):158–165

    Article  PubMed  Google Scholar 

  40. Duncan JR, Prusse KW, Mahaffey EA (1994) Veterinary laboratory medicine clinical pathology, 3rd edn. Iowa State Univ Press, Ames, Iowa, p 235

    Google Scholar 

  41. Treseler KM (1995) Clinical laboratory and diagnostic tests, 3rd edn. Appleton and Lange, Norwalk, Connecticut, p 117

    Google Scholar 

  42. Fischbach F (2004) A manual of laboratory diagnostic tests, 7th edn. Lippincottand Wilkins, Philadelphia, Pennsylvania, p 47

    Google Scholar 

  43. Sharp PE, LaRegina MC (1998) The laboratory rat. CRC Press, Boston, Massachussetts, pp 4–11

    Google Scholar 

  44. Zamboni WC, Strychor S, Maruca L, Ramalingam S, Zamboni BA, Wu H, Friedland DM, Edwards RP, Stroller RG, Belani CP, Ramanathan RK (2009) Pharmacokinetic study of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced malignancies. Clin Pharmacol Ther 86(5):519–526

    Article  PubMed  CAS  Google Scholar 

  45. Wu H, Infante JR, Jones SF, Burris HA, Chan E, Keedy VL, Bendell JC, Zamboni BA, Kodaira H, Ikeda S, Zamboni WC (2009) Factors affecting the pharmacokinetics (PK) and pharmacodynamics (PD) of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors. Mol Cancer Ther 8(12):C124

    Google Scholar 

  46. Li M, Al-Jamal KT, Kosarelos K, Reineke J (2010) Physiologically based pharmacokinetic modeling of nanoparticles. ACS Nano 4(11):3617–6303

    Google Scholar 

Download references

Acknowledgments

The authors would like to thank Jerry Campbelland Miyoung Yoonof the Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina for their helpful comments and suggestions during this study.

Author information

Authors and Affiliations

  1. Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Suite 1013, CB 7361, Chapel Hill, NC, 27599-7361, USA

    Whitney P. Caron, Whitney L. Davis & William C. Zamboni

  2. The Hamner Institute for Health Sciences, Research Triangle Park, Durham, NC, USA

    Harvey Clewell

  3. U.S. Department of Health, Education, and Welfare, National Institutes of Health, Public Health Service, Bethesda, MD, USA

    Robert Dedrick

  4. Molecular Therapeutics and Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Ramesh K. Ramanathan

  5. ALZA Corporation, Mountain View, CA, USA

    Ning Yu & Margaret Tonda

  6. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Jan H. Schellens & Jos H. Beijnen

  7. UNC Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA

    William C. Zamboni

  8. UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA

    William C. Zamboni

  9. UNC Center of Cancer Nanotechnology Excellence, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA

    William C. Zamboni

  10. North Carolina Medical Innovation Network, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC, USA

    William C. Zamboni

Authors
  1. Whitney P. Caron
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Harvey Clewell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert Dedrick
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ramesh K. Ramanathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Whitney L. Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ning Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Margaret Tonda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jan H. Schellens
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jos H. Beijnen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. William C. Zamboni
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William C. Zamboni.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 39 kb)

Supplementary material 2 (PPTX 412 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Caron, W.P., Clewell, H., Dedrick, R. et al. Allometric scaling of pegylated liposomal anticancer drugs. J Pharmacokinet Pharmacodyn 38, 653–669 (2011). https://doi.org/10.1007/s10928-011-9213-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10928-011-9213-5

Keywords

Search

Navigation