Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia

• Published in: Cancer chemotherapy and pharmacology Vol. 74; no. 3; pp. 593 - 602
• Main Authors: Kaefer, Aksana, Yang, Jianning, Noertersheuser, Peter, Mensing, Sven, Humerickhouse, Rod, Awni, Walid, Xiong, Hao
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2014; Springer; Springer Nature B.V
• Subjects: Aniline Compounds - adverse effects; Aniline Compounds - pharmacokinetics; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Biological and medical sciences; Bone Marrow - drug effects; Cancer Research; Hematologic and hematopoietic diseases; Humans; Medical sciences; Medicine; Medicine & Public Health; Models, Theoretical; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Platelet Count; Platelet diseases and coagulopathies; Sulfonamides - adverse effects; Sulfonamides - pharmacokinetics; Thrombocytopenia - chemically induced; Thrombocytopenia; Platelet; ABT-263; Pharmacodynamic model; Navitoclax; Pharmacokinetic; Pharmacodynamics; Hemopathy; Biological activity; Metaanalysis; Models; Mechanism of action; Pharmacokinetics
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-014-2530-9

Objective Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor and promotes apoptosis. Thrombocytopenia is a primary dose-limiting toxicity of navitoclax which exhibited a distinct time profile in circulating platelets from that caused by traditional chemotherapies. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the pharmacokinetic of navitoclax as well as the time course of the platelet counts in cancer patients receiving navitoclax. Methods Data from 256 patients who received oral navitoclax (dose range 10–475 mg) as a 14/21-day schedule or a continuous once daily (QD) schedule were used to construct the model using NONMEM. The PK model was a two-compartmental model with a lag-time and a transit compartment in absorption. The PD model was a semi-physiological model that comprised a progenitor cell compartment, three transition compartments representing the maturation chain in the bone marrow and a peripheral blood compartment. Compared with the previously published models, the model established in this analysis applied a different feedback mechanism and introduced a new concept of progenitor cell “pool”, which describes a large pool of platelet progenitor cells at the beginning of navitoclax treatment. Results The PD model was able to describe a slight downward trend of platelet counts over the long-term navitoclax treatment as observed in around 8 % of the patients and the initial drop in platelets seen in our Phase 1/2a studies. Conclusions We have developed a new semi-physiological platelet model for describing fast drop of platelets after initial navitoclax administration and long-term decline of platelets after continuous administration of navitoclax.