Clinical Pharmacokinetics

, Volume 58, Issue 3, pp 363–374 | Cite as

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-TeruelEmail author
  • Ignacio Gonzalez
  • Iñaki F. Trocóniz
  • Rubin Lubomirov
  • Arturo Soto
  • Salvador Fudio
Original Research Article


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.


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.


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.


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.



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


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)


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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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