title: Bridging the gap between in vitro and in vivo: Dose and schedule predictions for the ATR inhibitor AZD6738.
abstract: Understanding the therapeutic effect of drug dose and scheduling is critical to inform the design and implementation of clinical trials. The increasing complexity of both mono, and particularly combination therapies presents a substantial challenge in the clinical stages of drug development for oncology. Using a systems pharmacology approach, we have extended an existing PK-PD model of tumor growth with a mechanistic model of the cell cycle, enabling simulation of mono and combination treatment with the ATR inhibitor AZD6738 and ionizing radiation. Using AZD6738, we have developed multi-parametric cell based assays measuring DNA damage and cell cycle transition, providing quantitative data suitable for model calibration. Our in vitro calibrated cell cycle model is predictive of tumor growth observed in in vivo mouse xenograft studies. The model is being used for phase I clinical trial designs for AZD6738, with the aim of improving patient care through quantitative dose and scheduling prediction.
authors: AstraZeneca, Alderley Park, Macclesfield, SK10 4TG. UK.
authors: Stephen
authors: S
authors: Checkley
authors: AstraZeneca, Alderley Park, Macclesfield, SK10 4TG. UK.
authors: Linda
authors: L
authors: MacCallum
authors: AstraZeneca, Alderley Park, Macclesfield, SK10 4TG. UK.
authors: James
authors: J
authors: Yates
authors: RES Group Inc. Boston, MA. USA.
authors: Paul
authors: P
authors: Jasper
authors: RES Group Inc. Boston, MA. USA.
authors: Haobin
authors: H
authors: Luo
authors: RES Group Inc. Boston, MA. USA.
authors: John
authors: J
authors: Tolsma
authors: AstraZeneca, Alderley Park, Macclesfield, SK10 4TG. UK.
authors: Claus
authors: C
authors: Bendtsen
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011839:Radiation, Ionizing; D013312:Stress, Physiological / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D064007:Ataxia Telangiectasia Mutated Proteins