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A pharmacokinetic-pharmacodynamic model for the MET-TKI, savolitinib, to explore target inhibition requirements for anti-tumour activity
  • +11
  • Rhys Jones,
  • Mike Grondine,
  • Alexandra Borodovsky,
  • Maryann San Martin,
  • Michelle DuPont,
  • Celina D'Cruz,
  • Alwin Schuller,
  • Ryan Henry,
  • Evan Barry,
  • Lillian Castriotta,
  • Rana Anjum,
  • Klas Petersson,
  • Tarjinder Sahota,
  • Ghada Ahmed
Rhys Jones
AstraZeneca PLC

Corresponding Author:[email protected]

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Mike Grondine
AstraZeneca
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Alexandra Borodovsky
AstraZeneca
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Maryann San Martin
AstraZeneca
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Michelle DuPont
AstraZeneca
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Celina D'Cruz
AstraZeneca
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Alwin Schuller
AstraZeneca
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Ryan Henry
AstraZeneca
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Evan Barry
AstraZeneca
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Lillian Castriotta
AstraZeneca
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Rana Anjum
AstraZeneca
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Klas Petersson
qPharmetra LLC
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Tarjinder Sahota
AstraZeneca
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Ghada Ahmed
AstraZeneca
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Abstract

Background and purpose: Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, potent, and highly selective MET receptor tyrosine kinase inhibitor. This series of studies aimed to develop a pharmacokinetic-pharmacodynamic (PK/PD) model to link inhibition of MET phosphorylation (pMET) by savolitinib with anti-tumour activity. Experimental approach: Cell line-derived xenograft (CDX) experiments using human lung cancer (EBC-1) and gastric cancer (MKN-45) cells were conducted in athymic nude mice using a variety of doses and schedules of savolitinib. Tumour pMET changes and growth inhibition were calculated after 28 days. Population PK/PD techniques were used to construct a PK/PD model for savolitinib. Key results: Savolitinib showed dose- and schedule-dependent anti-tumour activity in the CDX models, with more frequent, lower dosing schedules (e.g. twice daily) being more effective than intermittent, higher dosing schedules (e.g. 4 days on/3 days off or 2 days on/5 days off). There was a clear exposure–response relationship, with maximal suppression of pMET of >90%. Data from additional CDX and patient-derived xenograft (PDX) models overlapped, allowing the calculation of a single EC50 of 0.38 ng/mL. Tumour growth modelling demonstrated that prolonged, high levels of pMET inhibition (>90%) were required for tumour stasis and regression in the models. Conclusion and implications: High and durable levels of MET inhibition by savolitinib are needed for optimal monotherapy anti-tumour activity in preclinical models. The modelling framework developed here can be used to translate tumour growth inhibition from the mouse to human, and thus guide choice of clinical dose and schedule.
24 Feb 2020Submitted to British Journal of Pharmacology
25 Feb 2020Submission Checks Completed
25 Feb 2020Assigned to Editor
09 Mar 2020Reviewer(s) Assigned
04 May 2020Editorial Decision: Revise Minor
04 Aug 20201st Revision Received
08 Aug 2020Assigned to Editor
08 Aug 2020Submission Checks Completed
17 Aug 2020Reviewer(s) Assigned
26 Aug 2020Review(s) Completed, Editorial Evaluation Pending
02 Sep 2020Editorial Decision: Revise Minor
05 Oct 20202nd Revision Received
05 Oct 2020Submission Checks Completed
05 Oct 2020Assigned to Editor
07 Oct 2020Review(s) Completed, Editorial Evaluation Pending
20 Oct 2020Editorial Decision: Accept