Author of

• 14191

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  MINI 10 - ALK and EGFR (ID 105)

  • Event: WCLC 2015
  • Type: Mini Oral
  • Track: Biology, Pathology, and Molecular Testing
  • Presentations: 1
  • Moderators:T. Yap, T. Li
  • Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f

  • 14204

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    MINI10.13 - Prediction of Human Pharmacokinetics, Efficacious Dose and BBB Penetration of a Novel EGFR Inhibitor for Treating NSCLC with CNS Metastasis (ID 3282)

    17:55 - 18:00  |  Author(s): P. Johnstroem
    • Abstract
    • Presentation
    • Slides

    Background:
    Increasing incidences of brain metastases (BM) and leptomeningeal metastases (LM) in lung cancer, especially in those patients with activating mutations of the epidermal growth factor receptor (EGFR) have been reported recently. However, there are currently no approved drugs available for the treatment of these diseases. AZD3759 is an oral EGFR TKI specifically designed to penetrate blood brain barrier (BBB) for the treatment of BM and LM.
    
    Methods:
    Efflux liability at BBB was assessed by using in vitro MDCKII-MDR1 and MDCKII-BCRP substrate assay, and central nervous system (CNS) penetration was evaluated in rats and mice and quantitatively measured by free brain to free blood ratio (K~p,uu,brain~) and CSF to free blood ratio (K~p,uu,CSF~). Brain uptake of [[11]C]-AZD3759 related radioactivity was also evaluated in two Cynomolgus monkeys by positron emission tomography (PET). Human clearance was predicted by different methods including In vitro In vivo extrapolation, liver blood flow method with fu correction and fu correction intercept method (FCIM). Human volume of distribution was projected from Oie-Tozer and PBPK methods. Human efficacious dose was predicted by achieving free brain concentration at steady state continuously covering the IC~50~ of pEGFR(Tyr1068) in PC-9(Exon19Del) cells.
    
    Results:
    AZD3759 has high passive permeability (29.5x10[-6] cm/sec) and is not a substrate of Pgp or BCRP. AZD3759 reached distribution equilibrium in rats and mice (K~puu,brain~ and K~puu,CSF~ > 0.5), suggesting good BBB penetration. The distribution of [[11]C]-AZD3759 related radioactivity to monkey brain was fast and homogenous. Estimated K~puu,brain~ in monkeys is greater than 0.5. In the animal model bearing EGFRm+ brain tumor, AZD3759 induced profound tumor regression and significantly improved animal survival. Predicted half-life in human PK is 13.3 hr and clinically observed t~1/2 ~ranges from 10 to 15 hr. Median K~puu,CSF ~value among six valuable BM patients is 1.2, suggesting good CNS penetration in human and consistent with the preclinical data. The predicted efficacious dose for AZD3759 in man is 100 mg bid. In an ongoing Phase I study, AZD3759 was well tolerated with no DLTs at 50 mg or 100 mg bid and some preliminary evidence of intracranial tumor shrinkage was observed.
    
    Conclusion:
    So far the preclinical predictions of CNS penetration of AZD3759 appear to be valid. Predicted and observed half-life of AZD3759 in human is consistent to date. Some preliminary evidence of intracranial tumor shrinkage was observed in clinical setting.
    
    

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