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Allometric scaling of pegylated liposomal anticancer drugs

  • Whitney P. Caron
  • Harvey Clewell
  • Robert Dedrick
  • Ramesh K. Ramanathan
  • Whitney L. Davis
  • Ning Yu
  • Margaret Tonda
  • Jan H. Schellens
  • Jos H. Beijnen
  • William C. Zamboni
Article

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.

Keywords

Allometric Dedrick Plot Pegylated liposomes Anticancer drugs Preclinical Mononuclear phagocyte system (MPS) 

Notes

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.

Supplementary material

10928_2011_9213_MOESM1_ESM.docx (39 kb)
Supplementary material 1 (DOCX 39 kb)
10928_2011_9213_MOESM2_ESM.pptx (412 kb)
Supplementary material 2 (PPTX 412 kb)

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Whitney P. Caron
    • 1
  • Harvey Clewell
    • 2
  • Robert Dedrick
    • 3
  • Ramesh K. Ramanathan
    • 4
  • Whitney L. Davis
    • 1
  • Ning Yu
    • 5
  • Margaret Tonda
    • 5
  • Jan H. Schellens
    • 6
  • Jos H. Beijnen
    • 6
  • William C. Zamboni
    • 1
    • 7
    • 8
    • 9
    • 10
  1. 1.Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillUSA
  2. 2.The Hamner Institute for Health Sciences, Research Triangle ParkDurhamUSA
  3. 3.U.S. Department of Health, Education, and WelfareNational Institutes of Health, Public Health ServiceBethesdaUSA
  4. 4.Molecular Therapeutics and Drug Discovery ProgramUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  5. 5.ALZA CorporationMountain ViewUSA
  6. 6.Department of Clinical PharmacologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  7. 7.UNC Lineberger Comprehensive Cancer CenterUniversity of North Carolina (UNC) at Chapel HillChapel HillUSA
  8. 8.UNC Institute for Pharmacogenomics and Individualized TherapyUniversity of North Carolina (UNC) at Chapel HillChapel HillUSA
  9. 9.UNC Center of Cancer Nanotechnology ExcellenceUniversity of North Carolina (UNC) at Chapel HillChapel HillUSA
  10. 10.North Carolina Medical Innovation NetworkUniversity of North Carolina (UNC) at Chapel HillChapel HillUSA

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