Skip to main content
SpringerLink
Log in
Book cover

Handbook of Anticancer Pharmacokinetics and Pharmacodynamics pp 193–208Cite as

Pharmacodynamic Modeling

  • Chapter
  • First Online:

  • 3782 Accesses

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

The pharmacodynamics of anti-cancer agents, as opposed to direct acting medications, pose a unique set of challenges. These challenges include; delayed response, inadequate number of response measurements, and limited set of biomarkers for effect or toxicity. However these challenges can be overcome and more advancements have allowed for limiting the aforementioned challenges. Pharmacodynamic assessment in early stage oncology clinical requires a study design optimized not only for the determination of clinical response and toxicity, but also for optimal measure of pharmacokinetic and pharmacodynamic measures. Pharmacodynamic models, study design, and pharmacodynamic biomarkers for anti-cancer clinical trials are discussed.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   219.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   279.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   279.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Evans WE, Relling MV, Rodman JH, Crom WR (1989) Anticancer therapy as a pediatric pharmacodynamic paradigm. Dev Pharmacol Ther 13(2–4):85–95

    CAS  PubMed  Google Scholar 

  2. Gianni L, Kearns CM, Giani A, Capri G, Viganó L, Lacatelli A, Bonadonna G, Egorin MJ (1995) Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 13(1):180–90

    CAS  PubMed  Google Scholar 

  3. Figg WD, Stevens JA, Cooper MR (1994) Adaptive control with feedback of suramin using intermittent infusions. J Clin Oncol 12(7):1523–4

    CAS  PubMed  Google Scholar 

  4. Lowis SP, Price L, Pearson AD, Newell DR, Cole M (1998) A study of the feasibility and accuracy of pharmacokinetically guided etoposide dosing in children. Br J Cancer 77(12):2318–23

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Ghazal-Aswad S, Tilby MJ, Lind M, Baily N, Sinha DP, Calvert AH, Newell DR (1999) Pharmacokinetically guided dose escalation of carboplatin in epithelial ovarian cancer: effect on drug-plasma AUC and peripheral blood drug-DNA adduct levels. Ann Oncol 10(3):329–34

    Article  CAS  PubMed  Google Scholar 

  6. Bauer KS, Figg WD, Hamilton JM, Jones EC, Premkumar A, Steinberg SM, Dyer V, Linehan WM, Pluda JM, Reed E (1999) A pharmacokinetically guided Phase II study of carboxyamidotriazole in androgen-independent prostate cancer. Clin Cancer Res 5(9):2324–9

    CAS  PubMed  Google Scholar 

  7. Ratain MJ, Mick R, Janisch L, Berezin F, Schilsky RL, Vogelzang NJ, Kut M (1996) Individualized dosing of amonafide based on a pharmacodynamic model incorporating acetylator phenotype and gender. Pharmacogenetics 6(1):93–101

    Article  CAS  PubMed  Google Scholar 

  8. Burke GA, Estlin EJ, Lowis SP (1999) The role of pharmacokinetic and pharmacodynamic studies in the planning of protocols for the treatment of childhood cancer. Cancer Treat Rev 25(1):13–27

    Article  CAS  PubMed  Google Scholar 

  9. Wagner JG (1968) Kinetics of pharmacologic response I. Proposed relationships between response and drug concentration in the intact animal and man. J Theoret Biol 20:173–201

    Article  CAS  Google Scholar 

  10. Sheiner LB, Beal SL (1981) Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm 4:503–12

    Article  Google Scholar 

  11. Boxenbaum H, Fertig JB (1984) Scaling of antipyrine intrinsic clearance of unbound drug in 15 mammalian species. Eur J Drug Metab Pharmacokinet 9(2):177–83

    Article  CAS  PubMed  Google Scholar 

  12. Mahmood I (1999) Allometric issues in drug development. J Pharm Sci 88(11):1101–6

    Article  CAS  PubMed  Google Scholar 

  13. Food and Drug Administration. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. July 2005. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm078932.pdf, 07/06/05

  14. Sausville EA, Lush RD, Headlee D, Smith AC, Figg WD, Arbuck SG, Senderowicz AM, Fuse E, Tanii H, Kuwabara T, Kobayashi S (1998) Clinical pharmacology of UCN-01: initial observations and comparison to preclinical models. Cancer Chemother Pharmacol 42(Suppl):S54–9

    Article  CAS  PubMed  Google Scholar 

  15. Egorin MJ, Van Echo DA, Tipping SJ, Olman EA, Whitacre MY, Thompson BW, Aisner J (1984) Pharmacokinetics and dosage reduction of cis-diammine(1,1-cyclobutanedicarboxylato) platinum in patients with impaired renal function. Cancer Res 44(11):5432–8

    CAS  PubMed  Google Scholar 

  16. Newell DR, Siddik ZH, Gumbrell LA, Boxall FE, Gore ME, Smith IE, Calvert AH (1987) Plasma free platinum pharmacokinetics in patients treated with high dose carboplatin. Eur J Cancer Clin Oncol 23(9):1399–405

    Article  CAS  PubMed  Google Scholar 

  17. Wittes RE, Brescia F, Young CW, Magill GB, Golbey RB, Krakoff IH (1975) Combination chemotherapy with cis-diamminedichloroplatinum (II) and bleomycin in tumors of the head and neck. Oncology 32(5–6):202

    Article  CAS  PubMed  Google Scholar 

  18. Bruno R, Hille D, Riva A, Vivier N, ten Bokkel Huinnink WW, van Oosterom AT, Kaye SB, Verweij J, Fossella FV, Valero V, Rigas JR, Seidman AD, Chevallier B, Fumoleau P, Burris HA, Ravdin PM, Sheiner LB (1998) Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 16(1):187–96

    CAS  PubMed  Google Scholar 

  19. Minami H, Ohtsu T, Fujii H, Igarashi T, Itoh K, Uchiyama-Kokubu N, Aizawa T, Watanabe T, Uda Y, Tanigawara Y, Sasaki Y (2001) Phase I study of intravenous PSC-833 and doxorubicin: reversal of multidrug resistance. Jpn J Cancer Res 92(2):220–30

    Article  CAS  PubMed  Google Scholar 

  20. Ratain MJ, Schilsky RL, Choi KE, Guarnieri C, Grimmer D, Vogelzang NJ, Senekjian E, Liebner MA (1989) Adaptive control of etoposide administration: impact of interpatient pharmacodynamic variability. Clin Pharmacol Ther 45(3):226–33

    Article  CAS  PubMed  Google Scholar 

  21. Vokes EE, Mick R, Kies MS, Dolan ME, Malone D, Athanasiadis I, Haraf DJ, Kozloff M, Weichselbaum RR, Ratain MJ (1996) Pharmacodynamics of fluorouracil-based induction chemotherapy in advanced head and neck cancer. J Clin Oncol 14(5):1663–71

    CAS  PubMed  Google Scholar 

  22. Kerbusch T, de Kraker J, Keizer HJ, van Putten JW, Groen HJ, Jansen RL, Schellens JH, Beijnen JH (2001) Clinical pharmacokinetics and pharmacodynamics of ifosfamide and its metabolites. Clin Pharmacokinet 40(1):41–62

    Article  CAS  PubMed  Google Scholar 

  23. Slichenmyer WJ, Rowinsky EK, Grochow LB, Kaufmann SH, Donehower RC (1994) Camptothecin analogues: studies from the Johns Hopkins Oncology Center. Chemother Pharmacol 34(Suppl):S53–7

    Article  Google Scholar 

  24. Oliff A, Bleyer WA, Poplack DG (1979) Methotrexate-induced oral mucositis and salivary methotrexate concentrations. Cancer Chemother Pharmacol 2(3):225–6

    Article  CAS  PubMed  Google Scholar 

  25. Gianni L, Kearns CM, Giani A, Capri G, Vigano L, Lacatelli A, Bonadonna G, Egorin MJ (1995) Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 13(1):180–90

    CAS  PubMed  Google Scholar 

  26. Stewart CF, Baker SD, Heideman RL, Jones D, Crom WR, Pratt CB (1994) Clinical pharmacodynamics of continuous infusion topotecan in children: systemic exposure predicts hematologic toxicity. J Clin Oncol 12(9):1946–54

    CAS  PubMed  Google Scholar 

  27. Cianfrocca M, Cooley TP, Lee JY, Rudek MA, Scadden DT, Ratner L, Pluda JM, Figg WD, Krown SE, Dezube BJ (2002) Matrix metalloproteinase inhibitor COL-3 in the treatment of AIDS-related Kaposi’s sarcoma: a phase I AIDS malignancy consortium study. J Clin Oncol 20(1):153–9

    Article  CAS  PubMed  Google Scholar 

  28. Stopeck A, Sheldon M, Vahedian M, Cropp G, Gosalia R, Hannah A (2002) Results of a Phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies. Clin Cancer Res 8(9):2798–805

    CAS  PubMed  Google Scholar 

  29. Chow S, Patel H, Hedley DW (2001) Measurement of MAP kinase activation by flow cytometry using phospho-specific antibodies to MEK and ERK: potential for pharmacodynamic monitoring of signal transduction inhibitors. Cytometry 46(2):72–8

    Article  CAS  PubMed  Google Scholar 

  30. Lièvre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, Ychou M, Bouché O, Landi B, Louvet C, André T, Bibeau F, Diebold MD, Rougier P, Ducreux M, Tomasic G, Emile JF, Penault-Llorca F, Laurent-Puig P (2008) KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 26(3):374–9

    Article  PubMed  Google Scholar 

  31. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Jänne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, Iafrate AJ (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363(18):1693–703, Erratum in: N Engl J Med. 2011 10;364(6):588

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Baselga J, Rischin D, Ranson M, Calvert H, Raymond E, Kieback DG, Kaye SB, Gianni L, Harris A, Bjork T, Averbuch SD, Feyereislova A, Swaisland H, Rojo F, Albanell J (2002) Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 20(21):4292–302

    Article  CAS  PubMed  Google Scholar 

  33. Karp JE, Lancet JE, Kaufmann SH, End DW, Wright JJ, Bol K, Horak I, Tidwell ML, Liesveld J, Kottke TJ, Ange D, Buddharaju L, Gojo I, Highsmith WE, Belly RT, Hohl RJ, Rybak ME, Thibault A, Rosenblatt J (2001) Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood 97(11):3361–9

    Article  CAS  PubMed  Google Scholar 

  34. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA (2011) BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364(26):2507–16

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Belhocine T, Steinmetz N, Hustinx R, Bartsch P, Jerusalem G, Seidel L, Rigo P, Green A (2002) Increased uptake of the apoptosis-imaging agent (99m)Tc recombinant human Annexin V in human tumors after one course of chemotherapy as a predictor of tumor response and patient prognosis. Clin Cancer Res 8(9):2766–74

    CAS  PubMed  Google Scholar 

  36. Watson RG, McLeod HL (2011) Pharmacogenomic contribution to drug response. Cancer J 17(2):80–8

    Article  CAS  PubMed  Google Scholar 

  37. Rifai N, Gillette MA, Carr SA (2006) Protein biomarker discovery and validation: the long and uncertain path to clinical utility. Nat Biotechnol 24(8):971–83

    Article  CAS  PubMed  Google Scholar 

  38. Bjartell A, Montironi R, Berney DM, Egevad L (2011) Tumour markers in prostate cancer II: diagnostic and prognostic cellular biomarkers. Acta Oncol 50(Suppl 1):76–84

    Article  PubMed  Google Scholar 

  39. Rusling JF, Kumar CV, Gutkind JS, Patel V (2010) Measurement of biomarker proteins for point-of-care early detection and monitoring of cancer. Analyst 135(10):2496–511

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Manne U, Srivastava RG, Srivastava S (2005) Recent advances in biomarkers for cancer diagnosis and treatment. Drug Discov Today 10(14):965–76

    Article  CAS  PubMed  Google Scholar 

  41. Denlinger CS, Cohen SJ (2007) Progress in the development of prognostic and predictive markers for gastrointestinal malignancies. Curr Treat Options Oncol 8(5):339–51

    Article  PubMed  Google Scholar 

  42. Armstrong AJ, Eisenberger MA, Halabi S, Oudard S, Nanus DM, Petrylak DP, Sartor AO, Scher HI (2012) Biomarkers in the management and treatment of men with metastatic castration-resistant prostate cancer. Eur Urol 61(3):549–59

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Vickers AJ, Ulmert D, Serio AM, Björk T, Scardino PT, Eastham JA, Berglund G, Lilja H (2007) The predictive value of prostate cancer biomarkers depends on age and time to diagnosis: towards a biologically-based screening strategy. Int J Cancer 121(10):2212–7

    Article  CAS  PubMed  Google Scholar 

  44. Makawita S, Diamandis EP (2010) The bottleneck in the cancer biomarker pipeline and protein quantification through mass spectrometry-based approaches: current strategies for candidate verification. Clin Chem 56(2):212–22

    Article  CAS  PubMed  Google Scholar 

  45. Rojo F, Dalmases A, Corominas JM, Albanell J (2007) Pharmacodynamics: biological activity of targeted therapies in clinical trials. Clin Transl Oncol 9(10):634–44

    Article  CAS  PubMed  Google Scholar 

  46. Bakry R, Rainer M, Huck CW, Bonn GK (2011) Protein profiling for cancer biomarker discovery using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and infrared imaging: a review. Anal Chim Acta 690(1):26–34

    Article  CAS  PubMed  Google Scholar 

  47. Quan G, Du X, Huo T, Li X, Wei Z, Cui H, Chang X, Cheng Y, Ye X, Cheng H (2010) Targeted molecular imaging of antigen OC183B2 in ovarian cancers using MR molecular probes. Acad Radiol 17(12):1468–76

    Article  PubMed  Google Scholar 

  48. Dahabreh IJ, Linardou H, Kosmidis P, Bafaloukos D, Murray S (2011) EGFR gene copy number as a predictive biomarker for patients receiving tyrosine kinase inhibitor treatment: a systematic review and meta-analysis in non-small-cell lung cancer. Ann Oncol 22(3):545–52

    Article  CAS  PubMed  Google Scholar 

  49. Swaby RF, Cristofanilli M (2011) Circulating tumor cells in breast cancer: a tool whose time has come of age. BMC Med 9:43

    Article  PubMed Central  PubMed  Google Scholar 

  50. Paradiso A, Mangia A, Chiriatti A, Tommasi S, Zito A, Latorre A, Schittulli F, Lorusso V (2005) Biomarkers predictive for clinical efficacy of taxol-based chemotherapy in advanced breast cancer. Ann Oncol 16(Suppl 4):iv14–19

    PubMed  Google Scholar 

  51. Chakravarti A, DeSilvio M, Zhang M, Grignon D, Rosenthal S, Asbell SO, Hanks G, Sandler HM, Khor LY, Pollack A, Shipley W (2007) Radiation Therapy Oncology Group. Prognostic value of p16 in locally advanced prostate cancer: a study based on Radiation Therapy Oncology Group Protocol 9202. J Clin Oncol 25(21):3082–9

    Article  PubMed Central  PubMed  Google Scholar 

  52. Augustin H, Freibauer C, Bayer L, Lunglmayr G, Tschurlovich F, Kuber W, Pummer K (2006) Molecular markers and their prognostic impact in patients with advanced prostate cancer undergoing intermittent androgen suppression. Prostate Cancer Prostatic Dis 9(3):279–83

    Article  CAS  PubMed  Google Scholar 

  53. Yang X, Knopp MV (2011) Quantifying tumor vascular heterogeneity with dynamic contrast-enhanced magnetic resonance imaging: a review. J Biomed Biotechnol 2011:732848

    PubMed Central  PubMed  Google Scholar 

  54. Beloueche-Babari M, Chung YL, Al-Saffar NM, Falck-Miniotis M, Leach MO (2010) Metabolic assessment of the action of targeted cancer therapeutics using magnetic resonance spectroscopy. Br J Cancer 102(1):1–7

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Miller JC, Sorensen AG (2005) Imaging biomarkers predictive of disease/therapy outcome: ischemic stroke and drug development. Prog Drug Res 62:319–56

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Maryland School of Pharmacy, Pharmacy Hall, Room N 415, 20N. Pine Street, Baltimore, MD, 21201, USA

    Kenneth S. Bauer Pharm.D., Ph.D.

  2. University of Maryland School of Pharmacy, Baltimore, MD, 21201, USA

    Fatemeh Tavakkoli M.D.

Authors
  1. Kenneth S. Bauer Pharm.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fatemeh Tavakkoli M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenneth S. Bauer Pharm.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Sidney Kimmel Comprehensive Cancer Cente, Baltimore, Maryland, USA

    Michelle A. Rudek

  2. Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA

    Cindy H. Chau

  3. Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA

    William D. Figg

  4. Moffitt Cancer Center, Tampa, Florida, USA

    Howard L. McLeod

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Bauer, K.S., Tavakkoli, F. (2014). Pharmacodynamic Modeling. In: Rudek, M., Chau, C., Figg, W., McLeod, H. (eds) Handbook of Anticancer Pharmacokinetics and Pharmacodynamics. Cancer Drug Discovery and Development. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9135-4_12

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-9135-4_12

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4614-9134-7

  • Online ISBN: 978-1-4614-9135-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation