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Pharmacokinetic and Pharmacodynamic Aspects of Focal and Targeted Delivery of Drugs

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Book cover Focal Controlled Drug Delivery

Part of the book series: Advances in Delivery Science and Technology ((ADST))

Abstract

In the past few decades significant progress has been made in development of drug delivery systems (DDSs) intended for targeted delivery of the drug to its site of action. Several dozens of systemically or focally administered DDSs have been approved for clinical use. However, the biofate of the drug/DDS following their administration is complex and is controllable only to a low extent. As a result, only low amounts of the drugs reach the target tissue, and the currently available DDSs are characterized by low clinical effectiveness and/or high magnitude of adverse effects. In this chapter, the major pharmacokinetic and pharmacodynamic parameters that govern the clinical effectiveness of systemically and focally administered DDSs are presented, and the ways to control the drug/DDSs disposition and to enhance the efficiency of the pharmacological responses are discussed. This chapter’s focus is on the anticancer DDSs for treatment of solid tumors and on the quantitative assessment of the analyzed factors/parameters.

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Abbreviations

DDS:

Drug delivery system

EPR:

Enhanced permeability and retention effect

PBPK model:

Physiologically based pharmacokinetic model

PD:

Pharmacodynamics

PEG:

Polyethylene glycol

PK:

Pharmacokinetics

References

  1. Maeda H (2012) Macromolecular therapeutics in cancer treatment: the EPR effect and beyond. J Control Release 164(2):138–144

    Article  CAS  PubMed  Google Scholar 

  2. Azzopardi EA, Ferguson EL, Thomas DW (2013) The enhanced permeability retention effect: a new paradigm for drug targeting in infection. J Antimicrob Chemother 68(2):257–274

    Article  CAS  PubMed  Google Scholar 

  3. Proost JH (2001) Pharmacokinetic/pharmacodynamic modelling in drug targeting. In: Molema G, Meijer DKF (eds) Drug targeting organ-specific strategies. Wiley-VCH Verlag GmbH

    Google Scholar 

  4. Bae YH, Park K (2011) Targeted drug delivery to tumors: myths, reality and possibility. J Control Release 153:198–205

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Siegel RA, MacGregor RD, Hunt CA (1991) Comparison and critique of two models for regional drug delivery. J Pharmacokinet Biopharm 19:363–373

    Article  CAS  PubMed  Google Scholar 

  6. Rowland M, Peck C, Tucker G (2011) Physiologically-based pharmacokinetics in drug development and regulatory science. Annu Rev Pharmacol Toxicol 51:45–73

    Article  CAS  PubMed  Google Scholar 

  7. Liu C, Krishnan J, Stebbing J, Xu XY (2011) Use of mathematical models to understand anticancer drug delivery and its effect on solid tumors. Pharmacogenomics 12:1337–1348

    Article  CAS  Google Scholar 

  8. Ruenraroengsak P, Cook JM, Florence AT (2010) Nanosystem drug targeting: facing up to complex realities. J Control Release 141:265–276

    Article  CAS  PubMed  Google Scholar 

  9. Moghimi SM, Hunter AC, Andresen TL (2011) Factors controlling nanoparticle pharmacokinetics: an integrated analysis and perspective. Annu Rev Pharmacol Toxicol 52:481–503

    Article  PubMed  Google Scholar 

  10. Lammers T, Kiessling F, Hennink WE, Storm G (2012) Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress. J Control Release 161:175–187

    Article  CAS  PubMed  Google Scholar 

  11. Decuzzi P, Godin B, Tanaka T, Lee SY, Chiappini C, Liu X, Ferrari M (2010) Size and shape effects in the biodistribution of intravascularly injected particles. J Control Release 141:320–327

    Article  CAS  PubMed  Google Scholar 

  12. Danhier F, Feron O, Preat V (2010) To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J Control Release 148:135–146

    Article  CAS  PubMed  Google Scholar 

  13. Barenholz Y (2012) Doxil(R)–the first FDA-approved nano-drug: lessons learned. J Control Release 160:117–134

    Article  CAS  PubMed  Google Scholar 

  14. Primeau AJ, Rendon A, Hedley D, Lilge L, Tannock IF (2005) The distribution of the anticancer drug Doxorubicin in relation to blood vessels in solid tumors. Clin Cancer Res 11:8782–8788

    Article  CAS  PubMed  Google Scholar 

  15. Minchinton AI, Tannock IF (2006) Drug penetration in solid tumours. Nat Rev Cancer 6:583–592

    Article  CAS  PubMed  Google Scholar 

  16. Florence AT (2012) “Targeting” nanoparticles: the constraints of physical laws and physical barriers. J Control Release 164(2):115–124

    Article  CAS  PubMed  Google Scholar 

  17. Li SD, Huang L (2010) Stealth nanoparticles: high density but sheddable PEG is a key for tumor targeting. J Control Release 145:178–181

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Wong C, Stylianopoulos T, Cui J, Martin J, Chauhan VP, Jiang W, Popovic Z, Jain RK, Bawendi MG, Fukumura D (2011) Multistage nanoparticle delivery system for deep penetration into tumor tissue. PNAS 108:2426–2431

    Article  CAS  PubMed  Google Scholar 

  19. Marcucci F, Corti A (2011) How to improve exposure of tumor cells to drugs – promoter drugs increase tumor uptake and penetration of effector drugs. Adv Drug Delivery Rev 64:53–68

    Article  Google Scholar 

  20. Caron WP, Song G, Kumar P, Rawal S, Zamboni WC (2012) Interpatient pharmacokinetic and pharmacodynamic variability of carrier-mediated anticancer agents. Clin Pharmacol Ther 91:802–812

    Article  CAS  PubMed  Google Scholar 

  21. Wittrup KD, Thurber GM, Schmidt MM, Rhoden JJ (2012) Practical theoretic guidance for the design of tumor-targeting agents. Methods Enzymol 503:255–268

    Article  CAS  PubMed  Google Scholar 

  22. Schmidt MM, Wittrup KD (2009) A modeling analysis of the effects of molecular size and binding affinity on tumor targeting. Mol Cancer Ther 8:2861–2871

    Article  CAS  PubMed  Google Scholar 

  23. Thurber GM, Weissleder R (2011) A systems approach for tumor pharmacokinetics. PLoS One 6:e24696

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Qin S, Seo JW, Zhang H, Qi J, Curry FR, Ferrara KW (2010) An imaging-driven model for liposomal stability and circulation. Mol Pharm 7:12–21

    Article  PubMed Central  PubMed  Google Scholar 

  25. Exner AA, Saidel GM (2008) Drug-eluting polymer implants in cancer therapy. Expert Opin Drug Deliv 5:775–788

    Article  CAS  PubMed  Google Scholar 

  26. De Souza R, Zahedi P, Allen CJ, Piquette-Miller M (2010) Polymeric drug delivery systems for localized cancer chemotherapy. Drug Deliv 17:365–375

    Article  PubMed  Google Scholar 

  27. Wadee A, Pillay V, Choonara YE, du Toit LC, Penny C, Ndesendo VM, Kumar P, Murphy CS (2011) Recent advances in the design of drug-loaded polymeric implants for the treatment of solid tumors. Expert Opin Drug Deliv 8:1323–1340

    Article  CAS  PubMed  Google Scholar 

  28. Wolinsky JB, Colson YL, Grinstaff MW (2012) Local drug delivery strategies for cancer treatment: gels, nanoparticles, polymeric films, rods, and wafers. J Control Release 159:14–26

    Article  CAS  PubMed  Google Scholar 

  29. Lin SH, Kleinberg LR (2008) Carmustine wafers: localized delivery of chemotherapeutic agents in CNS malignancies. Expert Rev Anticancer Ther 8:343–359

    Article  CAS  PubMed  Google Scholar 

  30. Elstad NL, Fowers KD (2009) OncoGel (ReGel/paclitaxel)–clinical applications for a novel paclitaxel delivery system. Adv Drug Deliv Rev 61:785–794

    Article  CAS  PubMed  Google Scholar 

  31. Fleming AB, Saltzman WM (2002) Pharmacokinetics of the carmustine implant. Clin Pharmacokinet 41:403–419

    Article  CAS  PubMed  Google Scholar 

  32. Fung LK, Shin M, Tyler B, Brem H, Saltzman WM (1996) Chemotherapeutic drugs released from polymers: distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea in the rat brain. Pharm Res 13:671–682

    Article  CAS  PubMed  Google Scholar 

  33. Weinberg BD, Ai H, Blanco E, Anderson JM, Gao J (2007) Antitumor efficacy and local distribution of doxorubicin via intratumoral delivery from polymer millirods. J Biomed Mater Res A 81:161–170

    Article  PubMed  Google Scholar 

  34. Weinberg BD, Blanco E, Gao J (2008) Polymer implants for intratumoral drug delivery and cancer therapy. J Pharm Sci 97:1681–1702

    Article  CAS  PubMed  Google Scholar 

  35. Kang YM, Kim GH, Kim JI, da Kim Y, Lee BN, Yoon SM, Kim JH, Kim MS (2011) In vivo efficacy of an intratumorally injected in situ-forming doxorubicin/poly(ethylene glycol)-b-polycaprolactone diblock copolymer. Biomaterials 32:4556–4564

    Article  CAS  PubMed  Google Scholar 

  36. Shikanov A, Shikanov S, Vaisman B, Golenser J, Domb AJ (2008) Paclitaxel tumor biodistribution and efficacy after intratumoral injection of a biodegradable extended release implant. Int J Pharm 358:114–120

    Article  CAS  PubMed  Google Scholar 

  37. Tan WH, Wang F, Lee T, Wang CH (2003) Computer simulation of the delivery of etanidazole to brain tumor from PLGA wafers: comparison between linear and double burst release systems. Biotechnol Bioeng 82:278–288

    Article  CAS  PubMed  Google Scholar 

  38. Arifin DY, Lee KY, Wang CH, Smith KA (2009) Role of convective flow in carmustine delivery to a brain tumor. Pharm Res 26:2289–2302

    Article  CAS  PubMed  Google Scholar 

  39. Arifin DY, Lee KY, Wang CH (2009) Chemotherapeutic drug transport to brain tumor. J Control Release 137:203–210

    Article  CAS  PubMed  Google Scholar 

  40. Torres AJ, Zhu C, Shuler ML, Pannullo S (2011) Paclitaxel delivery to brain tumors from hydrogels: a computational study. Biotechnol Prog 27:1478–1487

    Article  CAS  PubMed  Google Scholar 

  41. Liu Y, Paliwal S, Bankiewicz KS, Bringas JR, Heart G, Mitragotri S, Prausnitz MR (2010) Ultrasound-enhanced drug transport and distribution in the brain. AAPS PharmSciTech 11:1005–1017

    Article  PubMed Central  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, 653, Beer-Sheva, 84105, Israel

    David Stepensky

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  1. David Stepensky
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Correspondence to David Stepensky .

Editor information

Editors and Affiliations

  1. School of Pharmacy-Faculty of Medicine The Hebrew University of Jerusalem, Jerusalem, Israel

    Abraham J. Domb

  2. Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research (NIPER), Balanagar, Hyderabad, Andhra Pradesh, India

    Wahid Khan

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© 2014 Controlled Release Society

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Stepensky, D. (2014). Pharmacokinetic and Pharmacodynamic Aspects of Focal and Targeted Delivery of Drugs. In: Domb, A., Khan, W. (eds) Focal Controlled Drug Delivery. Advances in Delivery Science and Technology. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-9434-8_6

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