A pharmacokinetic–pharmacodynamic model for the MET tyrosine kinase inhibitor, savolitinib, to explore target inhibition requirements for anti‐tumour activity

Abstract

Background and Purpose: Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, potent, and highly MET receptor TK 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 dose frequency-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 calculation of a single EC 50 of 0.38 ngÁml −1 . 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 persistent levels of MET inhibition by savolitinib were 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.

Differences in Sustained Cellular Effects of MET inhibitors Are Driven by Prolonged Target Engagement and Lysosomal Retention

“…around the need for prolonged, high levels of MET inhibition for clinical activity and identified once-and twicedaily dosing, respectively, as optimal (Jones et al, 2020;Xiong et al, 2021). In the present study, we confirm that persistent target inhibition results in a stronger, phenotypic viability effect as our washout effects on pMET and viability correlate well (Fig.…”

“…In clinical settings, MET inhibitors can be differentiated by pharmacokinetic characteristics such as volume of distribution and half-life, which not only influence drug dosage (Jones et al, 2020;Xiong et al, 2021), but also potentially modulate primary pharmacology and the risk:benefit ratio of therapeutic agents. In particular, volume of distribution is largely driven by specific and unspecific binding of the therapeutic agent to intracellular proteins and membranes, and to a lesser extent by the stability of the drug-target complex and lysosomal retention on a subcellular level (Hamid and Krise, 2016;Schmitt et al, 2021).…”

Pharmacokinetic/Pharmacodynamic Analysis of Savolitinib plus Osimertinib in an EGFR Mutation–Positive, MET-Amplified Non–Small Cell Lung Cancer Model

“…Mouse population PK models for savolitinib and osimertinib previously developed were used as a starting point in these analyses ( 34, 35 ). A direct response maximum effect (E max ) model linking savolitinib plasma concentration to inhibition of pMET and TGI had been evaluated previously ( 34 ).…”

“…Savolitinib has demonstrated antitumor effects in combination with gefitinib in a phase Ib study (NCT02511106) in patients with EGFRm, MET-amplified NSCLC, and in combination with osimertinib in the phase Ib TATTON study (NCT02143466) in patients with MET-amplified, EGFRm, advanced NSCLC, who had disease progression on a previous EGFR-TKI ( 11–13 ). A recent study of savolitinib in PDX and cell line–derived xenograft models suggests that high and durable levels of MET inhibition are needed for optimal monotherapy in preclinical models ( 34 ).…”

Landscape of Savolitinib Development for the Treatment of Non-Small Cell Lung Cancer with MET Alteration—A Narrative Review

“…Early on, in vitro studies have established inhibitory effect of savolitinib on growth of gastric cells lines, while in vivo studies observed anti-tumor activity in human xenograft tumor models of MET -amplified gastric cancer and PRCC [ 33 , 34 , 35 ]. Another study by Jones and colleagues related to pharmacokinetic-pharmacodynamic (PK-PD) model observed inhibition of phosphorylated-MET by savolitinib at an effective concentration (EC)50 of 0.35 ng/mL and EC90 of 3.2 ng/mL in a cell line-derived xenograft (CDX) mice model using human lung cancer (EBC-1) and gastric cancer (MKN-45) cells [ 36 ]. Furthermore, PK studies in healthy male Chinese volunteers administered with single oral savolitinib doses of 200, 400 and 600 mg following an overnight fast or a high-fat and high-calorie breakfast prior to dosing showed no clinically relevant impact on PK and bioavailability of savolitinib [ 37 ].…”