title: Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia.
abstract: 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.
authors: Department of Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1N. Waukegan Road, North Chicago, IL, 60064, USA, aksana.kaefer@abbvie.com.
authors: Aksana
authors: A
authors: Kaefer
authors: Jianning
authors: J
authors: Yang
authors: Peter
authors: P
authors: Noertersheuser
authors: Sven
authors: S
authors: Mensing
authors: Rod
authors: R
authors: Humerickhouse
authors: Walid
authors: W
authors: Awni
authors: Hao
authors: H
authors: Xiong
mesh_terms: D000814:Aniline Compounds / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics; D001853:Bone Marrow / Q000187:drug effects; D006801:Humans; D008962:Models, Theoretical; D010976:Platelet Count; D013449:Sulfonamides / Q000009:adverse effects* / Q000493:pharmacokinetics*; D013921:Thrombocytopenia / Q000139:chemically induced*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D013449:Sulfonamides; C528561:navitoclax