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W. Tan



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    MO07 - NSCLC - Targeted Therapies II (ID 114)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO07.04 - Clinical Implication of a Population Pharmacokinetic Analysis of XALKORI (crizotinib) in 1,182 Patients with Non-Small Cell Lung Cancer (NSCLC) and 32 Patients with Other Solid Tumors (ID 3082)

      16:15 - 17:45  |  Author(s): W. Tan

      • Abstract
      • Presentation
      • Slides

      Background
      XALKORI[Ò] (crizotinib) is a selective small-molecule inhibitor of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase (RTK) and its oncogenic variants (ie, ALK fusion events and selected ALK mutations). Crizotinib is also an inhibitor of the hepatocyte growth factor receptor (HGFR, c-Met), c-ros oncogene 1 (ROS1), and Recepteur d’Origine Nantais (RON) RTKs. Clinical studies were conducted globally to determine the maximum tolerated dose, pharmacokinetics, antitumor efficacy and safety of crizotinib in patients with ALK-positive NSCLC and other tumors sensitive to crizotinib. The major objectives of this analysis were (1) to develop a population PK model that describes crizotinib plasma PK using pooled PK data across studies in cancer patients;.and (2) to identify potential covariates which may account for the inter-individual variability in crizotinib PK.

      Methods
      Population pharmacokinetic models were developed from a dataset comprised of 8,973 pharmacokinetic samples from 1,214 cancer patients receiving crizotinib at a starting dose of 250 mg BID in Phase I, II, and III trials. The effects of pre-defined covariates pertaining to demographic characteristics, baseline renal (creatinine clearance) and hepatic function (AST, albumin, and total bilirubin) on the pharmacokinetics of crizotinib were tested in the models.

      Results
      The study population consisted of 533 males (44%) and 681 females (56%). The patients were characterized by a wide range of body weights (33 to 160 kg) and ages (19 to 83 years). There were 189 (15.6%) elderly patients (over 65 years). The majority of patients in the analysis were White (52.8%) and Asian (43.1%), followed by Black (1.8%), Hispanic (1.2%), and Other (1%). Crizotinib PK was characterized by a two-compartment model with first-order absorption and a time-dependent decrease in apparent (oral) clearance (CL/F) from baseline following multiple 250 mg BID dosing. The interindividual variability was moderate, with 40% for CL/F and 52% for the apparent central volume of distribution (V2/F), respectively. The typical PK parameters for a 65 kg non-Asian male cancer patient with baseline creatinine clearance 91.6 mL/min and total bilirubin 0.41 mg/dL were 136 L/hr, 76 L/hr, 3,520 L, and 0.73 hr-1 for the CL/F after the first dose, CL/F at steady state, V2/F, and absorption rate constant (Ka), respectively. Age, AST, albumin, smoking, or ECOG performance status were not significant covariates for crizotinib CL/F (P>0.001). Asian race, gender, body weight, creatinine clearance, and total bilirubin described a portion of the variability in CL/F, and Asian race and gender also explained some of variability in V2/F. Asian race had the greatest effect on crizotinib exposure, with a 97% probability that a typical area under the plasma drug concentration-time curve at steady state (AUCss) in an Asian patient would be >25% higher than a typical AUCss value in a Non-Asian patient. None of the other covariates investigated were found to markedly affect the systemic exposure of crizotinib.

      Conclusion
      There was moderate inter-patient variability in crizotinib disposition. No starting dose adjustments of crizotinib 250 mg BID are recommended based on age, gender, body weight, or race.

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