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Model-based analysis of treatment effects of paclitaxel microspheres in a microscopic peritoneal carcinomatosis model in mice

Pharmaceutical Research volume 36, Article number: 127 (2019) Cite this article

Abstract

Purpose

Paclitaxel (PTX)-loaded genipin-crosslinked gelatin microspheres (GP-MS) are a prolonged IP delivery system under development for the treatment of peritoneal minimal residual disease (pMRD). Here, we show the use of a pharmacokinetic-pharmacodynamic (PKPD) modelling approach to inform the formulation development of PTX-GP-MS in a mice pMRD model.

Methods

PTX blood concentrations and survival data were obtained in Balb/c Nu mice receiving different single IP doses (7.5 and/or 35 mg/kg) of PTX-ethanolic loaded GP-MS (PTXEtOH-GP-MS), PTX-nanosuspension loaded GP-MS (PTXnano-GP-MS), and immediate release formulation Abraxane®. A population PK model was developed to characterize the PTX blood concentration pattern and to predict PTX concentrations in peritoneum. Afterwards, PKPD relationships between the predicted peritoneal or blood concentrations and survival were explored using time-to-event modelling.

Results

A PKPD model was developed that simultaneously describes the competing effects of treatment efficacy (driven by peritoneal concentration) and toxicity (driven by blood concentration) of PTX on survival. Clear survival advantages of PTXnano-GP-MS over PTXEtOH-GP-MS and Abraxane® were found. Simulations of different doses of PTXnano-GP-MS demonstrated that drug-induced toxicity is high at doses between 20 and 35 mg/kg.

Conclusions

The model predicts that the dose range of 7.5-15 mg/kg of PTXnano-GP-MS provides an optimal balance between efficacy and safety.

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Abbreviations

AIC:

Akaike’s information criterion

BLI:

Bioluminescence imaging

CRS:

Cytoreductive surgery

DBS:

Dried blood spot

GOF:

Goodness of fit

GP-MS:

Genipin-crosslinked gelatin microspheres

IIV:

Inter-individual variability

IPC:

Intraperitoneal chemotherapy

LLOQ:

Lower limit of quantification

Nab-PTX:

Paclitaxel-loaded albumin nanoparticles

OFV:

Objective function value

pcVPCs:

Prediction-corrected visual predictive checks

PKPD:

Pharmacokinetic-pharmacodynamic

pMRD:

Peritoneal minimal residual disease

PTX:

Paclitaxel

PTX-GP-MS:

Paclitaxel-loaded genipin-crosslinked gelatin microspheres

PTXEtOH-GP-MS:

Paclitaxel-ethanolic loaded genipin-crosslinked gelatin microspheres

PTXnano-GP-MS:

Paclitaxel-ethanolic loaded genipin-crosslinked gelatin microspheres

SIR:

Sampling importance resampling

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

    Article  Google Scholar 

  2. Nosov V, Su F, Amneus M, Birrer M, Robins T, Kotlerman J, et al. Validation of serum biomarkers for detection of early-stage ovarian cancer. Am J Obstet Gynecol. 2009;200(6):639. e631–9.

    Article  Google Scholar 

  3. Tummala MK, Alagarsamy S, McGuire WP. Intraperitoneal chemotherapy: standard of care for patients with minimal residual stage III ovarian cancer? Expert Rev Anticancer Ther. 2008;8(7):1135–47.

    CAS  Article  Google Scholar 

  4. Du Bois A. Treatment of advanced ovarian cancer. Eur J Cancer. 2001;37:1–7.

    Article  Google Scholar 

  5. McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996;334(1):1–6.

    CAS  Article  Google Scholar 

  6. Ozols R. Treatment goals in ovarian cancer. Int J Gynecol Cancer. 2005;15:3–11.

    Article  Google Scholar 

  7. Berrino F, De Angelis R, Sant M, Rosso S, Lasota MB, Coebergh JW, Santaquilani M, Group EW. Survival for eight major cancers and all cancers combined for European adults diagnosed in 1995–99: results of the EUROCARE-4 study. Lancet Oncol 2007;8(9):773-783.

    Article  Google Scholar 

  8. Du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d'Investigateurs Nationaux Pour les Etudes des Cancers de l'Ovaire (GINECO). Cancer. 2009;115(6):1234–44.

    Article  Google Scholar 

  9. Chefetz I, Alvero A, Holmberg J, Lebowitz N, Craveiro V, Yang-Hartwich Y, et al. TLR2 enhances ovarian cancer stem cell self-renewal and promotes tumor repair and recurrence. Cell Cycle. 2013;12(3):511–21.

    CAS  Article  Google Scholar 

  10. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. nature. 2001;414(6859):105.

    CAS  Article  Google Scholar 

  11. Bijelic L, Jonson A, Sugarbaker P. Systematic review of cytoreductive surgery and heated intraoperative intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis in primary and recurrent ovarian cancer. Ann Oncol. 2007;18(12):1943–50.

    CAS  Article  Google Scholar 

  12. Chua TC, Robertson G, Liauw W, Farrell R, Yan TD, Morris DL. Intraoperative hyperthermic intraperitoneal chemotherapy after cytoreductive surgery in ovarian cancer peritoneal carcinomatosis: systematic review of current results. J Cancer Res Clin Oncol. 2009;135(12):1637–45.

    Article  Google Scholar 

  13. Oršolić N, Bevanda M, Kujundžić N, Plazonic A, Stajcar D, Kujundžić M. Prevention of peritoneal carcinomatosis in mice by combining hyperthermal intraperitoneal chemotherapy with the water extract from Burr parsley (Caucalis platycarpos L.). Planta Med. 2010;76(08):773–9.

    Article  Google Scholar 

  14. Bakrin N, Classe J, Pomel C, Gouy S, Chene G, Glehen O. Hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer. J Visc Surg. 2014;151(5):347–53.

    CAS  Article  Google Scholar 

  15. De Bree E, Helm CW. Hyperthermic intraperitoneal chemotherapy in ovarian cancer: rationale and clinical data. Expert Rev Anticancer Ther. 2012;12(7):895–911.

    Article  Google Scholar 

  16. Markman M, Bundy BN, Alberts DS, Fowler JM, Clark-Pearson DL, Carson LF, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol. 2001;19(4):1001–7.

    CAS  Article  Google Scholar 

  17. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354(1):34–43.

    CAS  Article  Google Scholar 

  18. Van Driel WJ, Koole SN, Sikorska K, Schagen van Leeuwen JH, Schreuder HW, Hermans RH, et al. Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N Engl J Med. 2018;378(3):230–40.

    Article  Google Scholar 

  19. Spiliotis J, Vaxevanidou A, Sergouniotis F, Lambropoulou E, Datsis A, Christopoulou A. The role of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of recurrent advanced ovarian cancer: a prospective study. J BUON. 2011;16(1):74–9.

    CAS  PubMed  Google Scholar 

  20. Markman M, Rowinsky E, Hakes T, Reichman B, Jones W, Lewis Jr JL, Rubin S, Curtin J, Barakat R, Phillips M. Phase I trial of intraperitoneal taxol: a Gynecoloic Oncology Group study. J Clin Oncol 1992;10(9):1485-1491.

    CAS  Article  Google Scholar 

  21. Tsai M, Lu Z, Wientjes MG, Au JL-S. Paclitaxel-loaded polymeric microparticles: quantitative relationships between in vitro drug release rate and in vivo pharmacodynamics. J Control Release. 2013;172(3):737–44.

    CAS  Article  Google Scholar 

  22. Vassileva V, Moriyama E, De Souza R, Grant J, Allen C, Wilson B, et al. Efficacy assessment of sustained intraperitoneal paclitaxel therapy in a murine model of ovarian cancer using bioluminescent imaging. Br J Cancer. 2008;99(12):2037.

    CAS  Article  Google Scholar 

  23. De Clercq K, Schelfhout C, Bracke M, De Wever O, Van Bockstal M, Ceelen W, et al. Genipin-crosslinked gelatin microspheres as a strategy to prevent postsurgical peritoneal adhesions: In vitro and in vivo characterization. Biomaterials. 2016;96:33–46.

    Article  Google Scholar 

  24. Xie F, De Thaye E, Vermeulen A, Van Bocxlaer J, Colin P. A dried blood spot assay for paclitaxel and its metabolites. J Pharm Biomed Anal. 2018;148:307–15.

    CAS  Article  Google Scholar 

  25. Gao Y, Shen JK, Choy E, Zhang Z, Mankin HJ, Hornicek FJ, et al. Pharmacokinetics and tolerability of NSC23925b, a novel P-glycoprotein inhibitor: preclinical study in mice and rats. Sci Rep. 2016;6:25659.

    CAS  Article  Google Scholar 

  26. Liu X-R, Wu K-C, Huang Y, Sun J-B, Ke X-Y, Wang J-C, et al. In vitro and in vivo studies on plasma-to-blood ratio of paclitaxel in human, rabbit and rat blood fractions. Biol Pharm Bull. 2008;31(6):1215–20.

    CAS  Article  Google Scholar 

  27. Owen JS, Fiedler-Kelly J. Introduction to population pharmacokinetic/pharmacodynamic analysis with nonlinear mixed effects models: John Wiley & Sons; 2014.

  28. Au JL-S, Guo P, Gao Y, Lu Z, Wientjes MG, Tsai M, et al. Multiscale tumor spatiokinetic model for intraperitoneal therapy. AAPS J. 2014;16(3):424–39.

    CAS  Article  Google Scholar 

  29. Dosne A-G, Bergstrand M, Harling K, Karlsson MO. Improving the estimation of parameter uncertainty distributions in nonlinear mixed effects models using sampling importance resampling. J Pharmacokinet Pharmacodyn. 2016;43(6):583–96.

    Article  Google Scholar 

  30. Upton R, Mould D. Basic concepts in population modeling, simulation, and Model-Based drug development: Part 3—Introduction to pharmacodynamic modeling methods. CPT Pharmacometrics Syst Pharmacol. 2014;3(1):1–16.

    Article  Google Scholar 

  31. Schettini F, Giuliano M, De Placido S, Arpino G. Nab-paclitaxel for the treatment of triple-negative breast cancer: Rationale, clinical data and future perspectives. Cancer Treat Rev. 2016;50:129–41.

    CAS  Article  Google Scholar 

  32. Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res. 2006;12(4):1317–24.

    CAS  Article  Google Scholar 

  33. Badr CE. Bioluminescence imaging: basics and practical limitations. In. Bioluminescent Imaging: Springer; 2014. p. 1-18.

    Google Scholar 

  34. Van Goor H. Consequences and complications of peritoneal adhesions. Color Dis. 2007;9:25–34.

    Article  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by a Concerted Research Action (GOA) grant (project number: 01G02916) from Ghent University. Feifan Xie acknowledges the China Scholarship Council (CSC) for his Ph.D. grant. An Vermeulen is an 80% employee of Johnson and Johnson and owns J&J stock/stock options. She is also a visiting Professor at Ghent University. All other authors declare have no conflicts of interest that are directly relevant to the contents of this manuscript. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. (Animal Ethics Committee of the Faculty of Medicine at Ghent University, permit number: ECD 17/83).

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Affiliations

  1. Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium

    Feifan Xie, Jan Van Bocxlaer, Pieter Colin & An Vermeulen

  2. Laboratory of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium

    Kaat De Clercq & Chris Vervaet

  3. University Medical Center Groningen, Department of Anesthesiology, University of Groningen, Groningen, The Netherlands

    Pieter Colin

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  1. Feifan Xie
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  2. Kaat De Clercq
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  3. Chris Vervaet
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  4. Jan Van Bocxlaer
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  5. Pieter Colin
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  6. An Vermeulen
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Correspondence to Feifan Xie.

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Xie, F., De Clercq, K., Vervaet, C. et al. Model-based analysis of treatment effects of paclitaxel microspheres in a microscopic peritoneal carcinomatosis model in mice. Pharm Res 36, 127 (2019). https://doi.org/10.1007/s11095-019-2660-1

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  • DOI: https://doi.org/10.1007/s11095-019-2660-1

Key words

  • Mouse
  • NONMEM
  • Paclitaxel
  • Peritoneal
  • PKPD