ABSTRACT
Bispecific T-cell Engagers (TCEs) are promising anti-cancer treatments that bind to both the CD3 receptors on T cells and an antigen on the surface of tumor cells, creating an immune synapse, leading to killing of malignant tumor cells. These novel therapies have unique development challenges, with specific safety risks of cytokine release syndrome. These on-target adverse events fortunately can be mitigated and deconvoluted from efficacy via innovative dosing strategies, making clinical pharmacology key in the development of these therapies. This review assesses dose selection and the role of quantitative clinical pharmacology in the development of the first eight approved TCEs. Model informed drug development (MIDD) strategies can be used at every stage to guide TCE development. Mechanistic modeling approaches allow for (1) efficacious yet safe first-in-human dose selection as compared with in vitro minimum anticipated biological effect level (MABEL) approach; (2) rapid escalation and reducing number of patients with subtherapeutic doses through model-based adaptive design; (3) virtual testing of different step-up dosing regimens that may not be feasible to be evaluated in the clinic; and (4) selection and justification of the optimal clinical step-up and full treatment doses. As the knowledge base around TCEs continues to grow, the relevance and utilization of MIDD strategies for supporting the development and dose optimization of these molecules are expected to advance, optimizing the benefit-risk profile for cancer patients.
ABSTRACT
Gliclazide was approved as a treatment for type 2 diabetes in an era before model-based drug development, and consequently, the recommended doses were not optimised with modern methods. To investigate various dosing regimens of gliclazide, we used publicly available data to characterise the dose-response relationship using pharmacometric models. A literature search identified 21 published gliclazide pharmacokinetic (PK) studies with full profiles. These were digitised, and a PK model was developed for immediate- (IR) and modified-release (MR) formulations. Data from a gliclazide dose-ranging study of postprandial glucose were used to characterise the concentration-response relationship using the integrated glucose-insulin model. Simulations from the full model showed that the maximum effect was 44% of the patients achieving HbA1c <7%, with 11% experiencing glucose <3 mmol/L and the most sensitive patients (i.e., 5% most extreme) experiencing 35 min of hypoglycaemia. Simulations revealed that the recommended IR dose (320 mg) was appropriate with no efficacy gain with increased dose. However, the recommended dose for the MR formulation may be increased to 270 mg, with more patients achieving HbA1c goals (i.e., HbA1c <7%) without a hypoglycaemic risk higher than the resulting risk from the recommended IR dose.
