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Population pharmacokinetics of PM00104 (Zalypsis®) in cancer patients

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Abstract

Objective

The aim of this study was to characterize the population pharmacokinetics of PM00104 (Zalypsis®) in cancer patients.

Methods

A total of 135 patients included in four phase I clinical trials who receive intravenous PM00104 at doses ranging from 53 to 5,000 μg/m2 and administered as 1-, 3-, or 24-h infusion every 3 weeks or as 1-h infusion on days 1, 8, and 15 of a 28-day cycle, or 1-h infusion daily during 5 consecutive days every 3 weeks were included in the analysis. Pharmacokinetic data were analyzed with non-linear mixed effect model using NONMEM VI software. The effect of selected patient covariates on PM00104 pharmacokinetics was investigated. Model evaluation was performed using predictive checks and non-parametric bootstrap.

Results

An open four-compartment catenary linear model with first-order elimination was developed to best describe the data. Plasma clearance and its between-subject variability was 43.7 L/h (34%). Volume of distribution at steady state was 822 L (117%). Within the range of covariates studied, age, sex, body size variables, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, lactate dehydrogenase, creatinine clearance, albumin, total protein, hemoglobin, performance status, liver metastases, dose-limiting toxicity, and stable disease for 3 months were not statistically related to PM00104 pharmacokinetic parameters. Bootstrap and posterior predictive check evidenced the model was deemed appropriate to describe the time course of PM00104 plasma concentrations in cancer patients.

Conclusions

The integration of phase I pharmacokinetic data demonstrated PM00104 linear elimination from plasma, dose proportionality up to 5,000 μg/m2, and time-independent pharmacokinetics. No clinically relevant covariates were identified as predictors of PM00104 pharmacokinetics.

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References

  1. Leal JF, García-Hernández V, Moneo V, Domingo A, Bueren-Calabuig JA, Negri A, Gago F, Guillén-Navarro MJ, Avilés P, Cuevas C, García-Fernández LF, Galmarini CM (2009) Molecular pharmacology and antitumor activity of Zalypsis in several human cancer cell lines. Biochem Pharmacol 78:162–170

    Article  PubMed  CAS  Google Scholar 

  2. Guirouilh-Barbat J, Antony S, Pommier Y (2009) Zalypsis (PM00104) is a potent inducer of gamma-H2AX foci and reveals the importance of the C ring of trabectedin for transcription-coupled repair inhibition. Mol Cancer Ther 8:2007–2014

    Article  PubMed  CAS  Google Scholar 

  3. Ocio EM, Maiso P, Chen X, Garayoa M, Alvarez-Fernández S, San-Segundo L, Vilanova D, López-Corral L, Montero JC, Hernández-Iglesias T, de Alava E, Galmarini C, Avilés P, Cuevas C, San-Miguel JF, Pandiella A (2009) Zalypsis: a novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks. Blood 113:3781–3791

    Article  PubMed  CAS  Google Scholar 

  4. Duan Z, Choy E, Jimeno JM, Cuevas Cdel M, Mankin HJ, Hornicek FJ (2009) Diverse cross-resistance phenotype to ET-743 and PM00104 in multi-drug resistant cell lines. Cancer Chemother Pharmacol 63:1121–1129

    Article  PubMed  CAS  Google Scholar 

  5. PM00104 (Zalypsis®) investigator’s brochure version 8.1. Pharma Mar 2008

  6. Yin J, Aviles P, Lee W, Ly C, Guillen MJ, Munt S, Cuevas C, Faircloth G (2005) Development of a liquid chromatography/tandem mass spectrometry assay for the quantification of PM00104, a novel antineoplastic agent, in mouse, rat, dog, and human plasma. Rapid Commun Mass Spectrom 19:689–695

    Article  PubMed  Google Scholar 

  7. Yano Y, Beal SL, Sheiner LB (2001) Evaluating pharmacokinetic/pharmacodynamic models using the posterior predictive check. J Pharmacokinet Pharmacodyn 28:171–192

    Article  PubMed  CAS  Google Scholar 

  8. Wang DD, Zhang S (2011) Standardized visual predictive check versus visual predictive check for model evaluation. J Clin Pharmacol. doi:10.1177/0091270010390040

  9. Perez-Ruixo JJ, Zannikos P, Hirankarn S, Stuyckens K, Ludwig EA, Soto-Matos A, Lopez-Lazaro L, Owen JS (2007) Population pharmacokinetic meta-analysis of trabectedin (ET-743, Yondelis) in cancer patients. Clin Pharmacokinet 46:867–884

    Article  PubMed  CAS  Google Scholar 

  10. Nalda-Molina R, Valenzuela B, Ramon-Lopez A, Miguel-Lillo B, Soto-Matos A, Perez-Ruixo JJ (2009) Population pharmacokinetics meta-analysis of plitidepsin (Aplidin) in cancer subjects. Cancer Chemother Pharmacol 64:97–108

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Dr. Ricardo Nalda Molina for his comments and support at the beginning of this project. In addition, the authors would like to thank the patients, investigators, and their medical, nursing and laboratory staff who participated in the clinical trials included in the present study. In particular, we recognize the effort from the laboratory staff of ICON development solutions, which participated in the bioanalytical analysis of PM00104. Carlos Fernandez Teruel, Bernardo Miguel-Lillo, and Arturo Soto-Matos are employees of Pharma Mar SA, which supported this study. Consulting Projects for Research SL is consultant for Pharma Mar SA and received consultation fees for contributing to the current analysis.

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Author notes

  1. Belén Valenzuela

    Present address: Platform of Oncology, USP Hospital San Jaime, Torrevieja, Alicante, Spain

  2. Juan José Pérez-Ruixo

    Present address: Pharmacokinetics and Drug Metabolism, AMGEN, Valencia, Spain

Authors and Affiliations

  1. Consulting Projects for Research, Picayo, 3 Puzol, 46530, Valencia, Spain

    Carlos Pérez-Ruixo & Mario González-Sales

  2. Pharmaceutical Sciences Department, University Miguel Hernandez, Alicante, Spain

    Belén Valenzuela

  3. Clinical Pharmacology Department, Pharma Mar SA, Colmenar Viejo, Madrid, Spain

    Carlos Fernández Teruel, Bernardo Miguel-Lillo & Arturo Soto-Matos

  4. Pharmaceutical Sciences Department, University Miguel Hernandez, Alicante, Spain

    Juan José Pérez-Ruixo

Authors
  1. Carlos Pérez-Ruixo
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  2. Belén Valenzuela
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  3. Carlos Fernández Teruel
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  4. Mario González-Sales
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  5. Bernardo Miguel-Lillo
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  6. Arturo Soto-Matos
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  7. Juan José Pérez-Ruixo
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Corresponding author

Correspondence to Carlos Pérez-Ruixo.

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Pérez-Ruixo, C., Valenzuela, B., Fernández Teruel, C. et al. Population pharmacokinetics of PM00104 (Zalypsis®) in cancer patients. Cancer Chemother Pharmacol 69, 15–24 (2012). https://doi.org/10.1007/s00280-011-1644-6

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  • DOI: https://doi.org/10.1007/s00280-011-1644-6

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