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Population-Pharmacokinetic and Covariate Analysis of Lurbinectedin (PM01183), a New RNA Polymerase II Inhibitor, in Pooled Phase I/II Trials in Patients with Cancer

  • Carlos Fernandez-Teruel
  • Ignacio Gonzalez
  • Iñaki F. Trocóniz
  • Rubin Lubomirov
  • Arturo Soto
  • Salvador Fudio
Original Research Article

Abstract

Background and Objectives

Lurbinectedin is an inhibitor of RNA polymerase II currently under clinical development for intravenous administration as a single agent and in combination with other anti-tumor agents for the treatment of several tumor types. The objective of this work was to develop a population-pharmacokinetic model in this patient setting and to elucidate the main predictors to guide the late stages of development.

Methods

Data from 443 patients with solid and hematologic malignancies treated in six phase I and three phase II trials with lurbinectedin as a single agent or combined with other agents were included in the analysis. The potential influence of demographic, co-treatment, and laboratory characteristics on lurbinectedin pharmacokinetics was evaluated.

Results

The final population-pharmacokinetic model was an open three-compartment model with linear distribution and linear elimination from the central compartment. Population estimates for total plasma clearance, and apparent volume at steady state were 11.2 L/h and 438 L, respectively. Inter-individual variability was moderate for all parameters, ranging from 20.9 to 51.2%. High α-1-acid glycoprotein and C-reactive protein, and low albumin reduced clearance by 28, 20, and 20%, respectively. Co-administration of cytochrome P450 3A inhibitors reduced clearance by 30%. Combinations with other anti-tumor agents did not modify the pharmacokinetics of lurbinectedin significantly.

Conclusion

The population-pharmacokinetic model indicated neither a dose nor time dependency, and no clinically meaningful pharmacokinetic differences were found when co-administered with other anticancer agents. A chronic inflammation pattern characterized by decreased albumin and increased C-reactive protein and α-1-acid glycoprotein levels led to high lurbinectedin exposure. Co-administration of cytochrome P450 3A inhibitors increased lurbinectedin exposure.

Notes

Acknowledgements

The authors thank the patients, their families, and the clinical research teams for their time and trust, and for making these clinical trials and associated research possible.

Compliance with Ethical Standards

Funding

All analyses were funded by PharmaMar, S.A.

Conflict of interest

Carlos Fernandez-Teruel, Ignacio Gonzalez, Rubin Lubomirov, Arturo Soto, and Salvador Fudio are employees and shareholders of PharmaMar S.A. Iñaki F. Trocóniz received a consulting honorarium from PharmaMar S.A.

Supplementary material

40262_2018_701_MOESM1_ESM.docx (342 kb)
Supplementary material 1 (DOCX 341 kb)

References

  1. 1.
    Leal JF, Martinez-Diez M, Garcia-Hernandez V, Moneo V, Domingo A, Bueren-Calabuig JA, et al. PM01183, a new DNA minor groove covalent binder with potent in vitro and in vivo anti-tumour activity. Br J Pharmacol. 2010;161(5):1099–110.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Santamaria Nunez G, Robles CM, Giraudon C, Martinez-Leal JF, Compe E, Coin F, et al. Lurbinectedin specifically triggers the degradation of phosphorylated RNA polymerase II and the formation of DNA breaks in cancer cells. Mol Cancer Ther. 2016;15(10):2399–412.CrossRefPubMedGoogle Scholar
  3. 3.
    Carter NJ, Keam SJ. Trabectedin: a review of its use in soft tissue sarcoma and ovarian cancer. Drugs. 2010;70(3):355–76.CrossRefPubMedGoogle Scholar
  4. 4.
    Elez ME, Tabernero J, Geary D, Macarulla T, Kang SP, Kahatt C, et al. First-in-human phase I study of lurbinectedin (PM01183) in patients with advanced solid tumors. Clin Cancer Res. 2014;20(8):2205–14.CrossRefPubMedGoogle Scholar
  5. 5.
    Calvo E, Moreno V, Flynn M, Holgado E, Olmedo ME, Lopez Criado MP, et al. Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study. Ann Oncol. 2017;28(10):2559–66.CrossRefPubMedGoogle Scholar
  6. 6.
    Paz-Ares L, Forster M, Boni V, Szyldergemajn S, Corral J, Turnbull S, et al. Phase I clinical and pharmacokinetic study of PM01183 (a tetrahydroisoquinoline, lurbinectedin) in combination with gemcitabine in patients with advanced solid tumors. Investig New Drugs. 2017;35(2):198–206.CrossRefGoogle Scholar
  7. 7.
    Sauri T, Awada A, Calvo E, Moreno V, Szyldergemajn S, Elez E, et al. Lurbinectedin (PM01183) administered once (C1) every 3 weeks (q3w) in combination with capecitabine (XEL) in patients (pts) with metastatic breast (MBC), colorectal (CRC) or pancreatic (PaC) cancer. Eur J Cancer. 2016;27(Suppl. 6):392P.Google Scholar
  8. 8.
    European Medicines Agency. Yondelis® (trabectedin): summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000773/WC500045832.pdf. Accessed 22 Jun 2018.
  9. 9.
    US Food and Drug Administration. Yondelis® (trabctedin): prescription information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207953s000lbl.pdf. Accessed 22 Jun 2018.
  10. 10.
    PharmaMar. Clinical trial of lurbinectedin (PM01183)/doxorubicin (DOX) versus cyclophosphamide (CTX), doxorubicin (DOX) and vincristine (VCR) (CAV) or topotecan as treatment in patients with small-cell lung cancer. 2019. https://ClinicalTrials.gov/show/NCT02566993. Accessed Mar 2018.
  11. 11.
    PharmaMar. Clinical trial of lurbinectedin (PM01183) in selected advanced solid tumors. 2019. https://ClinicalTrials.gov/show/NCT02454972. Accessed 23 Jul 2018.
  12. 12.
    PharmaMar. Clinical trial of lurbinectedin (PM01183) in platinum resistant ovarian cancer patients. 2018. https://ClinicalTrials.gov/show/NCT02421588. Accessed 23 Jul 2018.
  13. 13.
    Erba E, Romano M, Gobbi M, Zucchetti M, Ferrari M, Matteo C, et al. Ascites interferes with the activity of lurbinectedin and trabectedin: potential role of their binding to alpha 1-acid glycoprotein. Biochem Pharmacol. 2017;144:52–62.CrossRefPubMedGoogle Scholar
  14. 14.
    Brandon EF, Sparidans RW, Guijt KJ, Lowenthal S, Meijerman I, Beijnen JH, et al. In vitro characterization of the human biotransformation and CYP reaction phenotype of ET-743 (Yondelis, trabectidin), a novel marine anti-cancer drug. Investig New Drugs. 2006;24(1):3–14.CrossRefGoogle Scholar
  15. 15.
    Lindbom L, Pihlgren P, Jonsson EN. PsN-Toolkit: a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed. 2005;79(3):241–57.CrossRefPubMedGoogle Scholar
  16. 16.
    Jonsson EN, Karlsson MO. Xpose: an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. J Biomech. 1998;58(1):51–64.Google Scholar
  17. 17.
    Wickham H. ggplot2: elegant graphics for data analysis. New York: Springer; 2009.CrossRefGoogle Scholar
  18. 18.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Bergstrand M, Karlsson MO. Handling data below the limit of quantification in mixed effect models. AAPS J. 2009;11(2):371–80.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Jimeno A, Sharma MR, Szyldergemajn S, Gore L, Geary D, Diamond JR, et al. Phase I study of lurbinectedin, a synthetic tetrahydroisoquinoline that inhibits activated transcription, induces DNA single- and double-strand breaks, on a weekly × 2 every-3-week schedule. Investig New Drugs. 2017;35(4):471–7.CrossRefGoogle Scholar
  21. 21.
    Poveda A, Del Campo JM, Ray-Coquard I, Alexandre J, Provansal M, Guerra Alia EM, et al. Phase II randomized study of PM01183 versus topotecan in patients with platinum-resistant/refractory advanced ovarian cancer. Ann Oncol. 2017;28(6):1280–7.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Peters AM, Glass DM. Use of body surface area for assessing extracellular fluid volume and glomerular filtration rate in obesity. Am J Nephrol. 2010;31(3):209–13.CrossRefPubMedGoogle Scholar
  23. 23.
    Fernandez-Teruel C, Del Campo JM, Berton-Rigaud D, Ray-Coquard I, Alexandre J, Provansal M, et al. Lurbinectedin (PM01183) efficacy in platinum-resistant/refractory ovarian cancer (PRROC) patients correlates with drug exposure using pharmacokinetic/pharmacodynamic (PK/PD) modelling. In: 19th international meeting of the European Society of Gynaecological (ESGO), Nice, France, 24–27 October. Int J Gynecol Cancer. 2015;25(2_suppl);433.Google Scholar
  24. 24.
    Nicholson JP, Wolmarans MR, Park GR. The role of albumin in critical illness. Br J Anaesth. 2000;85(4):599–610.CrossRefPubMedGoogle Scholar
  25. 25.
    Morgan ET, Goralski KB, Piquette-Miller M, Renton KW, Robertson GR, Chaluvadi MR, et al. Regulation of drug-metabolizing enzymes and transporters in infection, inflammation, and cancer. Drug Metab Dispos. 2008;36(2):205–16.CrossRefPubMedGoogle Scholar
  26. 26.
    Kenmotsu H, Imamura CK, Ono A, Omori S, Nakashima K, Wakuda K, et al. The effects of advanced age and serum alpha1-acid glycoprotein on docetaxel unbound exposure and dose-limiting toxicity in cancer patients. Br J Clin Pharmacol. 2017;83(11):2416–25.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Coutant DE, Kulanthaivel P, Turner PK, Bell RL, Baldwin J, Wijayawardana SR, et al. Understanding disease-drug interactions in cancer patients: implications for dosing within the therapeutic window. Clin Pharmacol Ther. 2015;98(1):76–86.CrossRefPubMedGoogle Scholar
  28. 28.
    Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther. 2002;71(3):115–21.CrossRefPubMedGoogle Scholar
  29. 29.
    PharmaMar. Clinical study of PM01183 in patients with acute leukemia or relapsed/refractory myelodysplastic syndrome. https://ClinicalTrials.gov/show/NCT01314599. Accessed 2 Mar 2018.
  30. 30.
    Patel H, Egorin MJ, Remick SC, Mulkerin D, Takimoto CHM, Doroshow JH, et al. Comparison of Child-Pugh (CP) criteria and NCI Organ Dysfunction Working Ggroup (NCI-ODWG) criteria for hepatic dysfunction (HD): implications for chemotherapy dosing. Am J Clin Oncol. 2004;22(14_Suppl):6051.CrossRefGoogle Scholar
  31. 31.
    Benton CB, Pavon JRD, Maiti A, Daver NG, Ravandi F, Jain N, Alvarado Y, Jabbour E, Pierce S, Kwari M, Santos MA, Martinez S, Siguero M, Tefferi A, Cortes JE, Kantarjian HM, Pardanani AD, Garcia-Manero G. Phase I study of lurbinectedin (PM11083) in patients with advanced AML and MDS. J Clin Oncol. 2017;35(15_suppl):e18521.  https://doi.org/10.1200/JCO.2017.35.15_suppl.e18521.Google Scholar
  32. 32.
    Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Clinical PharmacologyPharmaMar, S.A.MadridSpain
  2. 2.Pharmacometrics and Systems Pharmacology, School of Pharmacy and NutritionUniversity of NavarraPamplonaSpain
  3. 3.IdiSNA, Navarra Institute for Health ResearchPamplonaSpain

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