Advertisement

Pharmaceutical Research

, Volume 30, Issue 11, pp 2795–2807 | Cite as

Model-Based Approach to Describe G-CSF Effects in Carboplatin-Treated Cancer Patients

  • Mélanie L. Pastor
  • Céline M. Laffont
  • Laurence Gladieff
  • Antonin Schmitt
  • Etienne Chatelut
  • Didier Concordet
Research Paper

ABSTRACT

Purpose

Granulocyte colony-stimulating factor (G-CSF) is often used in cancer patients receiving cytotoxic drugs to prevent or reduce high grade neutropenia. We propose a pharmacokinetic/pharmacodynamic model to describe myelotoxicity in both G-CSF treated and non-treated patients that shall increase our understanding of G-CSF effects.

Methods

The model was built from absolute neutrophil counts (ANC) obtained in 375 carboplatin-treated patients, 47 of whom received G-CSF. It includes some prior information on G-CSF taken from the literature. Simulations were performed to understand differences in G-CSF effects and explore the impact of G-CSF formulation.

Results

Our model well described the data in all patients. Model simulations showed that G-CSF was not as beneficial as expected in some patients. Furthermore, a longer and stronger effect was observed for the pegylated formulation in comparison with the daily standard formulation even if the latter was given for 11 consecutive days.

Conclusions

The proposed model allows a mechanistic interpretation of G-CSF effects on ANC and raises the question of a systematic beneficial effect of G-CSF treatment. Other studies are needed to confirm these findings and help identifying patients for whom G-CSF is beneficial.

KEY WORDS

chemotherapy G-CSF myelotoxicity neutropenia pharmacokinetic/pharmacodynamic (PK/PD) modeling 

ABBREVIATIONS

Abs1

Absorption compartment for filgrastim/lenograstim

Abs2

Absorption compartment for pegfilgrastim

ANC

Absolute neutrophil count

Base

Baseline level of absolute neutrophil count

Ccarbo

Ultrafiltrable circulating (plasma) concentration of carboplatin

Cu

Free circulating concentration controlling G-CSF effects on bone marrow, calculated as the sum of non-pegylated and pegylated G-CSF free circulating (serum) concentrations

Circ

Circulating mature neutrophil count (=ANC)

Emax1

Maximal effect of non-pegylated or pegylated G-CSF on proliferation

Emax2

Maximal effect of non-pegylated or pegylated G-CSF on maturation

EC501

Value of Cu eliciting 50% of the maximal effect on proliferation

EC502

Value of Cu eliciting 50% of the maximal effect on maturation

F1(F2)

Absolute bioavailability of filgrastim/lenograstim(pegfilgrastim) after subcutaneous administration (which, in the model, is taking into account via the apparent volume of distribution)

G-CSF

Granulocyte colony-stimulating factor

k

Transit rate constant between compartments of granulopoiesis (function of Cu) \( \left(k={k}_{tr}\times \left(1+\frac{E_{\max }2\times {C}_u}{E{C}_{50}2+{C}_u}\right)\right) \)

ka1(2)

Absorption rate constant for filgrastim/lenograstim(pegfilgrastim)

kcirc

Rate constant of elimination of neutrophils from the systemic blood circulation

KD

Dissociation constant of RC complex ( = k off /k on )

kel1

Rate constant for the linear, non-specific elimination of endogenous G-CSF and filgrastim/lenograstim

kel2

Rate constant for the linear, non-specific elimination of pegfilgrastim

kGCSF

Rate constant of endogenous G-CSF production

kint

Rate constant for non-pegylated or pegylated G-CSF elimination after binding to receptors and internalization

kprol

Proliferation rate constant

ktr

“Virtual” transit rate constant when Cu = 0 (cf. k)

MTT

Mean transit time for maturing precursors in bone marrow \( \left( MTT=4/{k}_{tr}\times \left(1+\frac{E_{\max }2\times {C}_u}{E{C}_{50}2+{C}_u}\right)\right) \)

PK

Pharmacokinetic(s)

PK/PD

Pharmacokinetic(s)/pharmacodynamic(s)

Prol

Stem cell and progenitor cell count (i.e. proliferative cells) in bone marrow

R

Concentration in G-CSF receptors present on circulating neutrophils

RC

Concentration in bound G-CSF complex (pegylated and non-pegylated G-CSF)

Rmax

Maximal amount of receptors involved in nonlinear, specific clearance of pegylated and on-pegylated G-CSF (=R + RC)

RSE

Relative standard error

Slope

Sensitivity to carboplatin myelotoxicity

Transit1,2,3

Maturating granulocyte precursor count in transit compartments 1, 2 and 3, respectively

VDa1(2)

Apparent volume of distribution of G-CSF (pegylated G-CSF) after subcutaneous administration of filgrastim/lenograstim (pegfilgrastim) (VD1(2)/F1(2))

ξ

Proportionality constant for the amount of G-CSF receptors per cell

Supplementary material

11095_2013_1099_MOESM1_ESM.doc (22 kb)
ESM 1 (DOC 22.5 KB)
11095_2013_1099_MOESM2_ESM.doc (146 kb)
ESM 2 (DOC 145 KB)

REFERENCES

  1. 1.
    Cameron D. Management of chemotherapy-associated febrile neutropenia. Br J Cancer. 2009;101 suppl 1:S18–22.PubMedCrossRefGoogle Scholar
  2. 2.
    Segal BH, Freifeld AG, Baden LR, Brown AE, Casper C, Dubberke E, et al. Prevention and treatment of cancer-related infections. J Natl Compr Cancer Netw. 2008;6:122–74.Google Scholar
  3. 3.
    Kelly S, Wheatley D. Prevention of febrile neutropenia: use of granulocyte colony-stimulating factors. Br J Cancer. 2009;101 suppl 1:S6–S10.PubMedCrossRefGoogle Scholar
  4. 4.
    Aapro M, Crawford J, Kamioner D. Prophylaxis of chemotherapy-induced febrile neutropenia with granulocyte colony-stimulating factors: where are we now? Support Care Cancer. 2010;18:529–41.PubMedCrossRefGoogle Scholar
  5. 5.
    Cooper KL, Madan J, Whyte S, Stevenson MD, Akehurst RL. Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis. BMC Cancer. 2011;11:404.PubMedCrossRefGoogle Scholar
  6. 6.
    Lord BI, Bronchud MH, Owens S, Chang J, Howell A, Souza L, et al. The kinetics of human granulopoiesis following treatment with granulocyte colony-stimulating factor in vivo. Proc Natl Acad Sci U S A. 1989;86:9499–503.PubMedCrossRefGoogle Scholar
  7. 7.
    Price TH, Chatta GS, Dale DC. Effect of recombinant granulocyte colony-stimulating factor on neutrophil kinetics in normal young and elderly humans. Blood. 1996;88:335–40.PubMedGoogle Scholar
  8. 8.
    Aapro MS, Bohlius J, Cameron DA, Dal Lago L, Donnelly JP, Kearney N, et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 2011;47:8–32.PubMedCrossRefGoogle Scholar
  9. 9.
    Crawford J, Caserta C, Roila F. Hematopoietic growth factors: ESMO recommendations for the applications. Ann Oncol. 2009;20 Suppl 4:162–5.PubMedGoogle Scholar
  10. 10.
    Tan H, Tomic K, Hurley D, Daniel G, Barron R, Malin J. Comparative effectiveness of colony-stimulating factors for febrile neutropenia: a retrospective study. Curr Med Res Opin. 2011;27:79–86.PubMedCrossRefGoogle Scholar
  11. 11.
    Weycker D, Malin J, Barron R, Edelsberg J, Kartashov A, Oster G. Comparative effectiveness of filgrastim, pegfilgrastim, and sargramostim as prophylaxis against hospitalization for neutropenic complications in patients with cancer receiving chemotherapy. Am J Clin Oncol. 2012;35:267–74.PubMedCrossRefGoogle Scholar
  12. 12.
    Yang BB, Lum PK, Hayashi MM, Roskos LK. Polyethylene glycol modification of filgrastim results in decreased renal clearance of the protein in rats. J Pharm Sci. 2004;93:1367–73.PubMedCrossRefGoogle Scholar
  13. 13.
    Yang BB, Kido A. Pharmacokinetics and pharmacodynamics of pegfilgrastim. Clin Pharmacokinet. 2011;50:295–306.PubMedCrossRefGoogle Scholar
  14. 14.
    Friberg LE, Karlsson MO. Mechanistic models for myelosuppression. Investig New Drugs. 2003;21:183–94.CrossRefGoogle Scholar
  15. 15.
    Shochat E, Rom-Kedar V, Segel LA. G-CSF control of neutrophils dynamics in the blood. Bull Math Biol. 2007;69:2299–338.PubMedCrossRefGoogle Scholar
  16. 16.
    Testart-Paillet D, Girard P, You B, Freyer G, Pobel C, Tranchand B. Contribution of modelling chemotherapy-induced hematological toxicity for clinical practice. Crit Rev Oncol Hematol. 2007;63:1–11.PubMedCrossRefGoogle Scholar
  17. 17.
    Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol. 2002;20:4713–21.PubMedCrossRefGoogle Scholar
  18. 18.
    Quartino AL, Friberg LE, Karlsson MO. A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model. Investig New Drugs. 2012;30:833–45.CrossRefGoogle Scholar
  19. 19.
    Sandstrom M, Lindman H, Nygren P, Johansson M, Bergh J, Karlsson MO. Population analysis of the pharmacokinetics and the haematological toxicity of the fluorouracil-epirubicin-cyclophosphamide regimen in breast cancer patients. Cancer Chemother Pharmacol. 2006;58:143–56.PubMedCrossRefGoogle Scholar
  20. 20.
    Ramon-Lopez A, Nalda-Molina R, Valenzuela B, Perez-Ruixo JJ. Semi-mechanistic model for neutropenia after high dose of chemotherapy in breast cancer patients. Pharm Res. 2009;26:1952–62.PubMedCrossRefGoogle Scholar
  21. 21.
    Zandvliet AS, Schellens JH, Copalu W, Beijnen JH, Huitema AD. Covariate-based dose individualization of the cytotoxic drug indisulam to reduce the risk of severe myelosuppression. J Pharmacokinet Pharmacodyn. 2009;36:39–62.PubMedCrossRefGoogle Scholar
  22. 22.
    Sugiura M, Yamamoto K, Sawada Y, Iga T. Pharmacokinetic/pharmacodynamic analysis of neutrophil proliferation induced by recombinant granulocyte colony-stimulating factor (rhG-CSF): comparison between intravenous and subcutaneous administration. Biol Pharm Bull. 1997;20:684–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Hayashi N, Kinoshita H, Yukawa E, Higuchi S. Pharmacokinetic and pharmacodynamic analysis of subcutaneous recombinant human granulocyte colony stimulating factor (lenograstim) administration. J Clin Pharmacol. 1999;39:583–92.PubMedCrossRefGoogle Scholar
  24. 24.
    Wang B, Ludden TM, Cheung EN, Schwab GG, Roskos LK. Population pharmacokinetic-pharmacodynamic modeling of filgrastim (r-metHuG-CSF) in healthy volunteers. J Pharmacokinet Pharmacodyn. 2001;28:321–42.PubMedCrossRefGoogle Scholar
  25. 25.
    Engel C, Scholz M, Loeffler M. A computational model of human granulopoiesis to simulate the hematotoxic effects of multicycle polychemotherapy. Blood. 2004;104:2323–31.PubMedCrossRefGoogle Scholar
  26. 26.
    Sugiura M, Ohno Y, Yamada Y, Suzuki H, Iga T. Pharmacokinetic/pharmacodynamic analysis of neutrophil proliferation induced by rhG-CSF in patients receiving antineoplastic drugs. Yakugaku Zasshi. 2004;124:599–604.PubMedCrossRefGoogle Scholar
  27. 27.
    Scholz M, Engel C, Loeffler M. Modelling human granulopoiesis under poly-chemotherapy with G-CSF support. J Math Biol. 2005;50:397–439.PubMedCrossRefGoogle Scholar
  28. 28.
    Vainstein V, Ginosar Y, Shoham M, Ranmar DO, Ianovski A, Agur Z. The complex effect of granulocyte colony-stimulating factor on human granulopoiesis analyzed by a new physiologically-based mathematical model. J Theor Biol. 2005;234:311–27.PubMedCrossRefGoogle Scholar
  29. 29.
    Roskos LK, Lum P, Lockbaum P, Schwab G, Yang BB. Pharmacokinetic/pharmacodynamic modeling of pegfilgrastim in healthy subjects. J Clin Pharmacol. 2006;46:747–57.PubMedCrossRefGoogle Scholar
  30. 30.
    Shochat E, Rom-Kedar V. Novel strategies for granulocyte colony-stimulating factor treatment of severe prolonged neutropenia suggested by mathematical modeling. Clin Cancer Res. 2008;14:6354–63.PubMedCrossRefGoogle Scholar
  31. 31.
    Foley C, Mackey MC. Mathematical model for G-CSF administration after chemotherapy. J Theor Biol. 2009;257:27–44.PubMedCrossRefGoogle Scholar
  32. 32.
    Krzyzanski W, Wiczling P, Lowe P, Pigeolet E, Fink M, Berghout A, et al. Population modeling of filgrastim PK-PD in healthy adults following intravenous and subcutaneous administrations. J Clin Pharmacol. 2010;50:101S–12S.PubMedCrossRefGoogle Scholar
  33. 33.
    Scholz M, Schirm S, Wetzler M, Engel C, Loeffler M. Pharmacokinetic and -dynamic modelling of G-CSF derivatives in humans. Theor Biol Med Model. 2012;9:32.PubMedCrossRefGoogle Scholar
  34. 34.
    Schmitt A, Gladieff L, Laffont CM, Evrard A, Boyer JC, Lansiaux A, et al. Factors for hematopoietic toxicity of carboplatin: refining the targeting of carboplatin systemic exposure. J Clin Oncol. 2010;28:4568–74.PubMedCrossRefGoogle Scholar
  35. 35.
    Schmitt A, Gladieff L, Lansiaux A, Bobin-Dubigeon C, Etienne-Grimaldi MC, Boisdron-Celle M, et al. A universal formula based on cystatin C to perform individual dosing of carboplatin in normal weight, underweight, and obese patients. Clin Cancer Res. 2009;15:3633–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Molineux G. The design and development of pegfilgrastim (PEG-rmetHuG-CSF, Neulasta). Curr Pharm Des. 2004;10:1235–44.PubMedCrossRefGoogle Scholar
  37. 37.
    Aapro MS, Cameron DA, Pettengell R, Bohlius J, Crawford J, Ellis M, et al. EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. Eur J Cancer. 2006;42:2433–53.PubMedCrossRefGoogle Scholar
  38. 38.
    Brendel K, Comets E, Laffont C, Laveille C, Mentre F. Metrics for external model evaluation with an application to the population pharmacokinetics of gliclazide. Pharm Res. 2006;23:2036–49.PubMedCrossRefGoogle Scholar
  39. 39.
    Layton JE, Hockman H, Sheridan WP, Morstyn G. Evidence for a novel in vivo control mechanism of granulopoiesis: mature cell-related control of a regulatory growth factor. Blood. 1989;74:1303–7.PubMedGoogle Scholar
  40. 40.
    Takatani H, Soda H, Fukuda M, Watanabe M, Kinoshita A, Nakamura T, et al. Levels of recombinant human granulocyte colony-stimulating factor in serum are inversely correlated with circulating neutrophil counts. Antimicrob Agents Chemother. 1996;40:988–91.PubMedGoogle Scholar
  41. 41.
    Quartino LQ, Karlsson MO, Lindman H, and Friberg LE. An integrated G-CSF-myelosuppression model characterizing the target mediated disposition of endogenous G-CSF in breast cancer patients following chemotherapy. PAGE 20 (Athens) abstr 2255, 2011.Google Scholar
  42. 42.
    Avalos BR, Gasson JC, Hedvat C, Quan SG, Baldwin GC, Weisbart RH, et al. Human granulocyte colony-stimulating factor: biologic activities and receptor characterization on hematopoietic cells and small cell lung cancer cell lines. Blood. 1990;75:851–7.PubMedGoogle Scholar
  43. 43.
    Hanazono Y, Hosoi T, Kuwaki T, Matsuki S, Miyazono K, Miyagawa K, et al. Structural analysis of the receptors for granulocyte colony-stimulating factor on neutrophils. Exp Hematol. 1990;18:1097–103.PubMedGoogle Scholar
  44. 44.
    Avalos BR. Molecular analysis of the granulocyte colony-stimulating factor receptor. Blood. 1996;88:761–77.PubMedGoogle Scholar
  45. 45.
    Yang BB, Kido A, Salfi M, Swan S, Sullivan JT. Pharmacokinetics and pharmacodynamics of pegfilgrastim in subjects with various degrees of renal function. J Clin Pharmacol. 2008;48:1025–31.PubMedCrossRefGoogle Scholar
  46. 46.
    Todd RC, Lippard SJ. Inhibition of transcription by platinum antitumor compounds. Metallomics. 2009;1:280–91.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Mélanie L. Pastor
    • 1
    • 2
  • Céline M. Laffont
    • 2
  • Laurence Gladieff
    • 3
  • Antonin Schmitt
    • 4
  • Etienne Chatelut
    • 3
  • Didier Concordet
    • 2
  1. 1.Unité de Médecine, Urgences Soins IntensifsUniversité de Toulouse, INP, Ecole Nationale Vétérinaire de ToulouseToulouseFrance
  2. 2.INRA/ENVT, UMR1331, ToxalimToulouseFrance
  3. 3.Institut Claudius-RegaudUniversité de ToulouseToulouseFrance
  4. 4.UFR Sciences Pharmaceutiques et BiologiquesUniversité de BourgogneDijonFrance

Personalised recommendations