Abstract
Background and Objective
PM00104 (Zalypsis®) is a novel marine-derived compound that has shown antineoplastic activity against a number of human tumour cell lines. Myelosuppression was found to be a PM00104 dose-limiting toxicity during phase I studies. The objective of this study was to characterize the time course of neutropenia after intravenous PM00104 administration in cancer patients.
Methods
Absolute neutrophil counts (ANCs) and pharmacokinetic data from 144 patients receiving PM00104 doses ranging from 0.053 to 5 mg/m2 were used to estimate the system-related (baseline ANC [Circ0], mean transit time [MTT], feedback on proliferation [γ] and maturation [δ]) and drug-specific (first-order elimination rate constant from effect compartment [ke0] [α and β]) parameters of a modified Friberg’s model. The concentrations in the effect compartment (Ce) were assumed to reduce the proliferation rate of the progenitor cells according to the function \( \alpha \times {\text{C}}_{\text{e}}{}^{{{\upbeta}}}.\) Model evaluation and simulations were undertaken to evaluate the effect of dose intensity, dose density and the intravenous infusion duration on severe neutropenia incidence.
Results
The typical values (between-subject variability [%]) of the Circ0, MTT, γ, δ, ke0, α and β were estimated to be 5.66 × 109 cells/L (13 %), 149 h (29 %), 0.136, 0.191, 0.00639 h−1 (32 %), 0.332 L/µg (24 %) and 1.47, respectively. Age, bodyweight, sex, serum albumin, total protein, liver metastases, number of previous chemotherapy lines and performance status were not associated with model parameters. The model evaluation evidenced an accurate prediction of the neutropenia grade 3 and/or 4 incidence. Simulations indicated that PM00104 dose and dosing interval, but not infusion duration, were the main determinants of the neutropenia severity and duration.
Conclusions
The time course of neutropenia following PM00104 was well characterized by the model developed. The model-predicted time course of the ANCs and its variability confirmed that neutropenia is reversible, of short duration and non-cumulative.
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Acknowledgments
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 the ICON DS (Manchester, UK) who participated in the bioanalytical analysis of the PM00104 samples. The views expressed in this article are the personal views of the authors reflecting their scientific knowledge of this topic and should not be understood or quoted as being made on behalf of the companies at which the authors currently work.
Conflict of interest
Carlos Fernández Teruel, Bernardo Miguel-Lillo and Arturo Soto-Matos are employees of Pharma Mar SA, which supported this study. Mario González-Sales and Carlos Pérez-Ruixo are from Consulting Projects for Research, which acts as a consultant for Pharma Mar SA, and received consultation fees for contributing to the current analysis. Belén Valenzuela and Juan Jose Pérez-Ruixo were members of the Pharmaceutical Sciences Department, University Miguel Hernández, Alicante, Spain, at the time that this project was started. Belén Valenzuela and Juan Jose Pérez-Ruixo declare no conflicts of interest.
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González-Sales, M., Valenzuela, B., Pérez-Ruixo, C. et al. Population Pharmacokinetic–Pharmacodynamic Analysis of Neutropenia in Cancer Patients Receiving PM00104 (Zalypsis®). Clin Pharmacokinet 51, 751–764 (2012). https://doi.org/10.1007/s40262-012-0011-z
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DOI: https://doi.org/10.1007/s40262-012-0011-z