Population pharmacokinetic-pharmacodynamic analysis of neutropenia in cancer patients receiving PM00104 (Zalypsis(®)).
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/m(2) were used to estimate the system-related (baseline ANC [Circ(0)], mean transit time [MTT], feedback on proliferation [γ] and maturation [δ]) and drug-specific (first-order elimination rate constant from effect compartment [k(e0)] [α and β]) parameters of a modified Friberg's model. The concentrations in the effect compartment (C(e)) were assumed to reduce the proliferation rate of the progenitor cells according to the function [Formula: see text] 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 Circ(0), MTT, γ, δ, k(e0), α and β were estimated to be 5.66 × 10(9) 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.
Consulting Projects for Research, Picayo, 3 Puzol, 46530, Valencia, Spain.
Mario
M
González-Sales
Belén
B
Valenzuela
Carlos
C
Pérez-Ruixo
Carlos
C
Fernández Teruel
Bernardo
B
Miguel-Lillo
Arturo
A
Soto-Matos
Juan Jose
JJ
Pérez-Ruixo
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007958:Leukocyte Count; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy; D009503:Neutropenia / Q000097:blood / Q000139:chemically induced*; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage* / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; C500383:PM 00104; D044005:Tetrahydroisoquinolines