The Pharmacokinetic–Pharmacodynamic (PKPD) Relationships of AZD3229, a Novel and Selective Inhibitor of KIT, in a Range of Mouse Xenograft Models of GIST

Abstract

Pre-clinical animal models in translational research are fundamental to the understanding of disease and drug pharmacology but are often limited in their utility to robustly define an efficacious dose in the clinic. A reverse translational strategy using known clinical information from the bedside to bench can play a crucial role in improving this situation. In this work we evaluate the translational pharmacokinetic-pharmacodynamic (PKPD) assumptions for the KIT/PDGFRα inhibitor AZD3229 by using drug exposure and known clinical activity of standard of care (SoC) agents across the population of KIT driven gastro intestinal stromal tumor (GIST) patients to correlate against in vitro potency data for a spectrum of primary and secondary KIT mutations. AZD3229 has potential as a best in class treatment for GIST patients with mutations in KIT and PDGFRα and this compound may overcome the limitations experienced with existing treatment options in the clinic which are limited by off-target effects leading to drug holidays and dose reductions leading to lack of optimum efficacy.

Systemic Therapy for Gastrointestinal Stromal Tumor: Current Standards and Emerging Challenges

“…AZD3229 is a new selectively KIT/PDGFRA inhibitor, specifically targeting a spectrum of primary and drug-resistant KIT/ PDGFRA mutations observed in GIST [ 66 •]. The superior inhibitory efficacy on primary and activation-loop mutations has been demonstrated in in-vitro and the PDX model [ 66 •, 67 ], which needs further clinical trial to confirm its role in the treatment of advanced GIST. Recently, PLX9486, a type I inhibitor selectively blocking the active conformation of KIT, presented its efficacy combined with type II inhibitor such as sunitinib or pexidartinib in a phase Ib/IIa trial [ 68 ].…”

Pharmacokinetics under the COVID‐19 storm

“…In this study, we utilized in vitro IC 50 rather than in vivo EC 50 due to the scarcity of this data. Nevertheless, when unbound in vivo EC 50 data become available, one can easily update the exposure profiles with the relevant target inhibition values and explore In vitro in vivo extrapolation, as shown in Pilla Reddy et al 97 in vitro IC 50 values were generated for antiviral drugs using serum‐free media in most instances, and thus we can assume in vitro IC 50 are basically unbound values; however, in vivo lung tissue and plasma profiles should be corrected for lung tissue protein binding and plasma protein binding, respectively, to obtain K P,uu , under the assumption that the unbound drug is pharmacologically active 59 …”

Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors

“…6C). The predicted efficacious exposure in humans was based on AZD3229 efficacy in several GIST and PDX models and PK/PD modeling of doses leading to >90% of KIT phosphorylation inhibition over the dosing interval, which resulted in maximum tumor growth inhibition in efficacy studies (35). On the basis of this information, the predicted efficacious human Cmax range for AZD3229 was between 0.004 and 0.139 M for different models.…”

“…We demonstrate that the dose of AZD3229 in these models that results in robust antitumor activity (20 mg/kg) also leads to >90% of inhibition of KIT phosphorylation. On the basis of these data along with extensive PK/PD modeling of the efficacy data in several PDX models (35) and the PK properties of AZD3229 ( 21), the predicted human dose of AZD3229 is anchored at 34 mg BID, resulting in an unbound Cmax of 139 nM (35), which would provide adequate exposure to provide coverage for all the mutations tested in vivo and represented in the Ba/F3 cell panel. Figure 7 lists the GI 90 values measured across the Ba/F3 KIT/PDGFR cell panel for AZD3229 and the SoC/investigational drugs.…”