Population pharmacokinetic–pharmacodynamic analysis for eribulin mesilate-associated neutropenia
Article first published online: 20 AUG 2013
© 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society
British Journal of Clinical Pharmacology
Special Issue: Cancer Therapeutics Themed Section
Volume 76, Issue 3, pages 412–424, September 2013
How to Cite
van Hasselt, J. G. C., Gupta, A., Hussein, Z., Beijnen, J. H., Schellens, J. H. M. and Huitema, A. D. R. (2013), Population pharmacokinetic–pharmacodynamic analysis for eribulin mesilate-associated neutropenia. British Journal of Clinical Pharmacology, 76: 412–424. doi: 10.1111/bcp.12143
- Issue published online: 20 AUG 2013
- Article first published online: 20 AUG 2013
- Accepted manuscript online: 19 APR 2013 02:51AM EST
- Manuscript Accepted: 26 MAR 2013
- Manuscript Received: 9 JAN 2013
- eribulin mesilate;
- haematological toxicity;
Eribulin mesilate is an inhibitor of microtubule dynamics that is approved for the treatment of late-stage metastatic breast cancer. Neutropenia is one of the major dose-limiting adverse effects of eribulin. The objective of this analysis was to develop a population pharmacokinetic–pharmacodynamic model for eribulin-associated neutropenia.
A combined data set of 12 phase I, II and III studies for eribulin mesilate was analysed. The population pharmacokinetics of eribulin was described using a previously developed model. The relationship between eribulin pharmacokinetic and neutropenia was described using a semi-physiological lifespan model for haematological toxicity. Patient characteristics predictive of increased sensitivity to develop neutropenia were evaluated using a simulation framework.
Absolute neutrophil counts were available from 1579 patients. In the final covariate model, the baseline neutrophil count (ANC0) was estimated to be 4.03 × 109 neutrophils l−1 [relative standard error (RSE) 1.2%], with interindividual variability (IIV, 37.3 coefficient of variation % [CV%]). The mean transition time was estimated to be 109 h (RSE 1.8%, IIV 13.9CV%), the feedback constant (γ) was estimated to be 0.216 (RSE 1.4%, IIV 12.2CV%), and the linear drug effect coefficient (SLOPE) was estimated to be 0.0451 μg l−1 (RSE 3.2%, IIV 54CV%). Albumin, aspartate transaminase and receival of granulocyte colony-stimulating factor (G-CSF) were identified as significant covariates on SLOPE, and albumin, bilirubin, G-CSF, alkaline phosphatase and lactate dehydrogenase were identified as significant covariates on mean transition time.
The developed model can be applied to investigate optimal treatment strategies quantitatively across different patient groups with respect to neutropenia. Albumin was identified as the most clinically important covariate predictive of interindividual variability in the neutropenia time course.