A pharmacokinetic-pharmacodynamic model for the MET-TKI, savolitinib, to
explore target inhibition requirements for anti-tumour activity
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.