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

• Published in: Clinical pharmacokinetics Vol. 51; no. 11; pp. 751 - 764
• Main Authors: González-Sales, Mario, Valenzuela, Belén, Pérez-Ruixo, Carlos, Fernández Teruel, Carlos, Miguel-Lillo, Bernardo, Soto-Matos, Arturo, Pérez-Ruixo, Juan Jose
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing AG 01.11.2012; Adis International; Springer Nature B.V
• Subjects: Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Biological and medical sciences; Dose-Response Relationship, Immunologic; General pharmacology; Hematologic and hematopoietic diseases; Humans; Internal Medicine; Leukocyte Count; Medical sciences; Medicine; Medicine & Public Health; Models, Biological; Neoplasms - blood; Neoplasms - drug therapy; Neutropenia - blood; Neutropenia - chemically induced; Original Research Article; Other diseases. Hematologic involvement in other diseases; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacotherapy; Tetrahydroisoquinolines - administration & dosage; Tetrahydroisoquinolines - pharmacokinetics; Mean Transit Time; Severe Neutropenia; Trabectedin; Pharmacodynamic Model; Effect Compartment; Human; Population pharmacokinetics; Pharmacodynamics; Leukopenia; Hemopathy; Malignant tumor; Biological activity; Cancer; Neutropenia
• ISSN: 0312-5963; 1179-1926; 1179-1926
• DOI: 10.1007/s40262-012-0011-z

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/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 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.