Population Pharmacokinetic–Pharmacodynamic Analysis of Neutropenia in Cancer Patients Receiving PM00104 (Zalypsis ® )

摘要: PM00104 (Zalypsis®) is a novel marine-derived compound that has shown antineoplastic activity against number of human tumour cell lines. Myelosuppression was found to be dose-limiting toxicity during phase I studies. The objective this study characterize the time course neutropenia after intravenous administration in cancer patients. Absolute neutrophil counts (ANCs) and pharmacokinetic data from 144 patients receiving doses ranging 0.053 5 mg/m2 were used estimate system-related (baseline ANC [Circ0], mean transit [MTT], feedback on proliferation [γ] maturation [δ]) drug-specific (first-order elimination rate constant effect compartment [ke0] [α β]) parameters modified Friberg’s model. concentrations (Ce) assumed reduce progenitor cells according function $$ \alpha \times {\text{C}}_{\text{e}}{}^{{{\upbeta}}}.$$ Model evaluation simulations undertaken evaluate dose intensity, density infusion duration severe incidence. typical values (between-subject variability [%]) Circ0, MTT, γ, δ, ke0, α β estimated 5.66 × 109 cells/L (13 %), 149 h (29 %), 0.136, 0.191, 0.00639 h−1 (32 %), 0.332 L/µg (24 %) 1.47, respectively. Age, bodyweight, sex, serum albumin, total protein, liver metastases, previous chemotherapy lines performance status not associated with model parameters. evidenced an accurate prediction grade 3 and/or 4 Simulations indicated dosing interval, but duration, main determinants severity duration. following well characterized by developed. model-predicted ANCs its confirmed reversible, short non-cumulative.