Skip to main content

Advertisement

SpringerLink
Log in

A Mechanism-Based PK/PD Model for Hematological Toxicities Induced by Antibody-Drug Conjugates

  • Research Article
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

Antibody-drug conjugates (ADCs) are complex drug platforms composed of monoclonal antibodies (mAbs) conjugated to potent cytotoxic drugs (payloads) via chemical linkers, enabling selective payload delivery to neoplastic cells, resulting in improved efficacy and reduced toxicity. Brentuximab vedotin (Adcetris®, SGN-35) and adotrastuzumab emtansine (Kadcyla®, T-DM1) are the two FDA-approved and commercially available ADCs, and both drugs exhibit ADC-related thrombocytopenia and neutropenia. A pharmacokinetic/pharmacodynamic (PK/PD) model for ADCs was developed to identify the analyte from each ADC that is most associated with the observed hematopoietic toxicities and to determine the role of the apparent in vivo payload release rate on the severity of thrombocytopenia and neutropenia. Murine xenograft experiments and data from literature were combined, and the PK of both ADCs and their analytes were described with two-compartment models, with linear elimination and first-order payload release rate constants (k rel). ADC-associated hematotoxicities were captured with a previously published PD model for myelosuppression driven by various analytes. ADC half-lives were about 5 days, and k rel values were 0.46 (T-DM1) and 0.12 h−1 (SGN-35). The lifespans of platelets following T-DM1 and neutrophils following SGN-35 were 3.73 and 4.72 days. Comparison of alternate model structures suggested that mechanisms of myelosuppression are payload-driven for SGN-35 and ADC pinocytosis-dependent for T-DM1. Model simulations suggested that a 4-fold increase (T-DM1) and 70% decrease (SGN-35) in k rel would improve hematotoxicity to grade 1. The proposed model successfully captured the PK and associated myelosuppression of both ADCs and might serve as a general PK/PD platform for assessing hematological toxicities to ADCs.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Thomas A, Teicher BA, Hassan R. Antibody-drug conjugates for cancer therapy. Lancet Oncol 2016;17(6):e254–62

    Article  CAS  PubMed  Google Scholar 

  2. Younes A, Yasothan U, Kirkpatrick P. Brentuximab vedotin. Nature Rev. 2012a;11(1):19–20

    CAS  Google Scholar 

  3. Corrigan PA, Cicci TA, Auten JJ, Lowe DK. Ado-trastuzumab emtansine: a HER2-positive targeted antibody-drug conjugate. Ann Pharmacother. 2014;48(11):1484–93

    Article  CAS  PubMed  Google Scholar 

  4. Arakawa T, Kurosawa Y, Storms M, Maruyama T, Okumura CJ, Maluf NK. Biophysical characterization of a model antibody drug conjugate. Drug Discov Ther. 2016;10(4):211–7

    Article  PubMed  Google Scholar 

  5. Tolcher AW, Ochoa L, Hammond LA, Patnaik A, Edwards T, Takimoto C, et al. Cantuzumab mertansine, a maytansinoid immunoconjugate directed to the CanAg antigen: a phase I, pharmacokinetic, and biologic correlative study. J Clin Oncol. 2003;21(2):211–22

    Article  CAS  PubMed  Google Scholar 

  6. Sievers EL, Senter PD. Antibody-drug conjugates in cancer therapy. Annu Rev Med. 2013;64:15–29

    Article  CAS  PubMed  Google Scholar 

  7. Erickson HK, Park PU, Widdison WC, Kovtun YV, Garrett LM, Hoffman K, et al. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res. 2006;66(8):4426–33

    Article  CAS  PubMed  Google Scholar 

  8. Francisco JA, Cerveny CG, Meyer DL, Mixan BJ, Klussman K, Chace DF, et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003;102(4):1458–65

    Article  CAS  PubMed  Google Scholar 

  9. Jain N, Smith SW, Ghone S, Tomczuk B. Current ADC linker chemistry. Pharm Res. 2015;32(11):3526–40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. McCombs JR, Owen SC. Antibody drug conjugates: design and selection of linker, payload and conjugation chemistry. AAPS J. 2015;17(2):339–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bender BC, Schaedeli-Stark F, Koch R, Joshi A, Chu YW, Rugo H, et al. A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer. Cancer Chemother Pharmacol. 2012;70(4):591–601

    Article  CAS  PubMed  Google Scholar 

  12. Krop IE, Beeram M, Modi S, Jones SF, Holden SN, Yu W, et al. Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol. 2010;28(16):2698–704

    Article  CAS  PubMed  Google Scholar 

  13. Burris HA 3rd, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limentani S, et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol. 2011a;29(4):398–405

    Article  CAS  PubMed  Google Scholar 

  14. Fanale MA, Forero-Torres A, Rosenblatt JD, Advani RH, Franklin AR, Kennedy DA, et al. A phase I weekly dosing study of brentuximab vedotin in patients with relapsed/refractory CD30-positive hematologic malignancies. Clin Cancer Res. 2012;18(1):248–55

    Article  CAS  PubMed  Google Scholar 

  15. Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190–6

    Article  CAS  PubMed  Google Scholar 

  16. Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363(19):1812–21

    Article  CAS  PubMed  Google Scholar 

  17. Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012b;30(18):2183–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Uppal H, Doudement E, Mahapatra K, Darbonne WC, Bumbaca D, Shen BQ, et al. Potential mechanisms for thrombocytopenia development with trastuzumab emtansine (T-DM1). Clin Cancer Res. 2015;21(1):123–33

    Article  CAS  PubMed  Google Scholar 

  19. Thon JN, Devine MT, Jurak Begonja A, Tibbitts J, Italiano JE Jr. High-content live-cell imaging assay used to establish mechanism of trastuzumab emtansine (T-DM1)—mediated inhibition of platelet production. Blood. 2012;120(10):1975–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zeuner A, Signore M, Martinetti D, Bartucci M, Peschle C, De Maria R. Chemotherapy-induced thrombocytopenia derives from the selective death of megakaryocyte progenitors and can be rescued by stem cell factor. Cancer Res. 2007;67(10):4767–73

    Article  CAS  PubMed  Google Scholar 

  21. Donaghy H. Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. MAbs. 2016;8(4):659–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shibuya K, Akahori H, Takahashi K, Tahara E, Kato T, Miyazaki H. Multilineage hematopoietic recovery by a single injection of pegylated recombinant human megakaryocyte growth and development factor in myelosuppressed mice. Blood. 1998;91(1):37–45

    CAS  PubMed  Google Scholar 

  23. Watters JW, Kloss EF, Link DC, Graubert TA, McLeod HL. A mouse-based strategy for cyclophosphamide pharmacogenomic discovery. J Appl Physiol. 2003;95(4):1352–60

    Article  CAS  PubMed  Google Scholar 

  24. Kopp HG, Avecilla ST, Hooper AT, Shmelkov SV, Ramos CA, Zhang F, et al. Tie2 activation contributes to hemangiogenic regeneration after myelosuppression. Blood. 2005;106(2):505–13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sanderson RJ, Hering MA, James SF, Sun MM, Doronina SO, Siadak AW, et al. In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate. Clin Cancer Res. 2005;11(2 Pt 1):843–52

    CAS  PubMed  Google Scholar 

  26. LoRusso PM, Weiss D, Guardino E, Girish S, Sliwkowski MX. Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. Clin Cancer Res. 2011;17(20):6437–47

    Article  CAS  PubMed  Google Scholar 

  27. Teicher BA, Doroshow JH. The promise of antibody-drug conjugates. N Engl J Med. 2012;367(19):1847–8

    Article  CAS  PubMed  Google Scholar 

  28. Hamblett KJ, Senter PD, Chace DF, Sun MM, Lenox J, Cerveny CG, et al. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res. 2004;10(20):7063–70

    Article  CAS  PubMed  Google Scholar 

  29. Jumbe NL, Xin Y, Leipold DD, Crocker L, Dugger D, Mai E, et al. Modeling the efficacy of trastuzumab-DM1, an antibody drug conjugate, in mice. J Pharmacokinet Pharmacodyn. 2010;37(3):221–42

    Article  CAS  PubMed  Google Scholar 

  30. Erickson HK, Lewis Phillips GD, Leipold DD, Provenzano CA, Mai E, Johnson HA, et al. The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates. Mol Cancer Ther. 2012;11(5):1133–42

    Article  CAS  PubMed  Google Scholar 

  31. Erickson HK, Lambert JM. ADME of antibody-maytansinoid conjugates. AAPS J. 2012;14(4):799–805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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(24):4713–21

    Article  PubMed  Google Scholar 

  33. Shah DK, Haddish-Berhane N, Betts A. Bench to bedside translation of antibody drug conjugates using a multiscale mechanistic PK/PD model: a case study with brentuximab-vedotin. J Pharmacokinet Pharmacodyn. 2012;39(6):643–59

    Article  PubMed  Google Scholar 

  34. Okeley NM, Miyamoto JB, Zhang X, Sanderson RJ, Benjamin DR, Sievers EL, et al. Intracellular activation of SGN-35, a potent anti-CD30 antibody-drug conjugate. Clin Cancer Res. 2010;16(3):888–97

    Article  CAS  PubMed  Google Scholar 

  35. Kim MT, Chen Y, Marhoul J, Jacobson F. Statistical modeling of the drug load distribution on trastuzumab emtansine (Kadcyla), a lysine-linked antibody drug conjugate. Bioconjug Chem. 2014;25(7):1223–32

    Article  CAS  PubMed  Google Scholar 

  36. Graham GJ, Wright EG. Haemopoietic stem cells: their heterogeneity and regulation. Int J Exp Pathol. 1997;78(4):197–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011;13(2):143–51

    Article  PubMed  PubMed Central  Google Scholar 

  38. Singh AP, Maass KF, Betts AM, Wittrup KD, Kulkarni C, King LE, et al. Evolution of antibody-drug conjugate tumor disposition model to predict preclinical tumor pharmacokinetics of trastuzumab-emtansine (T-DM1). AAPS J. 2016;18(4):861–75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chudasama VL, Schaedeli Stark F, Harrold JM, Tibbitts J, Girish SR, Gupta M, et al. Semi-mechanistic population pharmacokinetic model of multivalent trastuzumab emtansine in patients with metastatic breast cancer. Clin Pharmacol Ther. 2012;92(4):520–7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Manning KL, Novinger S, Sullivan PS, McDonald TP. Successful determination of platelet lifespan in C3H mice by in vivo biotinylation. Lab Anim Sci. 1996;46(5):545–8

    CAS  PubMed  Google Scholar 

  41. Pillay J, den Braber I, Vrisekoop N, Kwast LM, de Boer RJ, Borghans JA, et al. In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days. Blood. 2010;116(4):625–7

    Article  CAS  PubMed  Google Scholar 

  42. Sekhon SS, Roy V. Thrombocytopenia in adults: a practical approach to evaluation and management. South Med J. 2006;99(5):491–8 quiz 9-500, 33

    Article  PubMed  Google Scholar 

  43. Dinan MA, Hirsch BR, Lyman GH. Management of chemotherapy-induced neutropenia: measuring quality, cost, and value. J Natl Compr Cancer Netw. 2015;13(1):e1–7

    Article  Google Scholar 

  44. Chari RV. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41(1):98–107

    Article  CAS  PubMed  Google Scholar 

  45. Bender B, Leipold DD, Xu K, Shen BQ, Tibbitts J, Friberg LE. A mechanistic pharmacokinetic model elucidating the disposition of trastuzumab emtansine (T-DM1), an antibody-drug conjugate (ADC) for treatment of metastatic breast cancer. AAPS J. 2014;16(5):994–1008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Barreto JN, McCullough KB, Ice LL, Smith JA. Antineoplastic agents and the associated myelosuppressive effects: a review. J Pharm Pract. 2014;27(5):440–6

    Article  PubMed  Google Scholar 

  47. Rothe A, Sasse S, Goergen H, Eichenauer DA, Lohri A, Jager U, et al. Brentuximab vedotin for relapsed or refractory CD30+ hematologic malignancies: the German Hodgkin Study Group experience. Blood. 2012;120(7):1470–2

    Article  CAS  PubMed  Google Scholar 

  48. Curtis BR. Drug-induced immune neutropenia/agranulocytosis. Immunohematology. 2014;30(2):95–101

    PubMed  Google Scholar 

  49. van den Bemt PM, Meyboom RH, Egberts AC. Drug-induced immune thrombocytopenia. Drug Saf. 2004;27(15):1243–52

    Article  PubMed  Google Scholar 

  50. Perry MC, McKinney MF. Chemotherapeutic agents: trastuzumab (herceptin). In: Perry MC, editor. The chemotherapy source book. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2008. p. 629

    Google Scholar 

  51. Blum RH, Kahlert T. Maytansine: a phase I study of an ansa macrolide with antitumor activity. Cancer Treat Rep. 1978;62(3):435–8

    CAS  PubMed  Google Scholar 

  52. Blum RH, Wittenberg BK, Canellos GP, Mayer RJ, Skarin AT, Henderson IC, et al. A therapeutic trial of maytansine. Cancer Clin Trials. 1978;1(2):113–7

    CAS  PubMed  Google Scholar 

  53. Rodon J, Garrison M, Hammond LA, de Bono J, Smith L, Forero L, et al. Cantuzumab mertansine in a three-times a week schedule: a phase I and pharmacokinetic study. Cancer Chemother Pharmacol. 2008;62(5):911–9

    Article  CAS  PubMed  Google Scholar 

  54. Galsky MD, Eisenberger M, Moore-Cooper S, Kelly WK, Slovin SF, DeLaCruz A, et al. Phase I trial of the prostate-specific membrane antigen-directed immunoconjugate MLN2704 in patients with progressive metastatic castration-resistant prostate cancer. J Clin Oncol. 2008;26(13):2147–54

    Article  CAS  PubMed  Google Scholar 

  55. Burris HA 3rd, Tibbitts J, Holden SN, Sliwkowski MX, Lewis Phillips GD. Trastuzumab emtansine (T-DM1): a novel agent for targeting HER2+ breast cancer. Clin Breast Cancer. 2011b;11(5):275–82

    Article  CAS  PubMed  Google Scholar 

  56. Press MF, Cordon-Cardo C, Slamon DJ. Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene. 1990;5(7):953–62

    CAS  PubMed  Google Scholar 

  57. Zhang CY, Booth JW. Divergent intracellular sorting of Fc{gamma}RIIA and Fc{gamma}RIIB2. J Biol Chem. 2010;285(44):34250–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nieswandt B, Bergmeier W, Schulte V, Rackebrandt K, Gessner JE, Zirngibl H. Expression and function of the mouse collagen receptor glycoprotein VI is strictly dependent on its association with the FcRgamma chain. J Biol Chem. 2000;275(31):23998–4002

    Article  CAS  PubMed  Google Scholar 

  59. Poole A, Gibbins JM, Turner M, van Vugt MJ, van de Winkel JG, Saito T, et al. The Fc receptor gamma-chain and the tyrosine kinase Syk are essential for activation of mouse platelets by collagen. EMBO J. 1997;16(9):2333–41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lyon RP, Setter JR, Bovee TD, Doronina SO, Hunter JH, Anderson ME, et al. Self-hydrolyzing maleimides improve the stability and pharmacological properties of antibody-drug conjugates. Nat Biotechnol. 2014;32(10):1059–62

    Article  CAS  PubMed  Google Scholar 

  61. Junutula JR, Raab H, Clark S, Bhakta S, Leipold DD, Weir S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26(8):925–32

    Article  CAS  PubMed  Google Scholar 

  62. Cunningham D, Parajuli KR, Zhang C, Wang G, Mei J, Zhang Q, et al. Monomethyl auristatin E phosphate inhibits human prostate cancer growth. Prostate. 2016;76(15):1420–30

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr. Robert Straubinger for his helpful advice on the design of the experiments, Dr. Wojciech Krzyzanski for the use of the hematology analyzer, and Dr. Gerald Fetterly for his help in acquiring the ADCs from RPCI. This work was supported by funding from the UB Center for Protein Therapeutics.

Author information

Authors and Affiliations

  1. Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, 6550 Sanger Road, Room 469, Orlando, Florida, 32827, USA

    Sihem Ait-Oudhia

  2. Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, 14214, USA

    Weiyan Zhang & Donald E. Mager

Authors
  1. Sihem Ait-Oudhia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weiyan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Donald E. Mager
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Ait-Oudhia participated in the research design and performed the data analysis; Ait-Oudhia and Zhang conducted the experiments; and Ait-Oudhia and Mager wrote the manuscript.

Corresponding author

Correspondence to Sihem Ait-Oudhia.

Electronic Supplementary Material

ESM 1

(DOCX 412 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ait-Oudhia, S., Zhang, W. & Mager, D.E. A Mechanism-Based PK/PD Model for Hematological Toxicities Induced by Antibody-Drug Conjugates. AAPS J 19, 1436–1448 (2017). https://doi.org/10.1208/s12248-017-0113-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12248-017-0113-5

KEY WORDS

Search

Navigation