CX-072 is an anti-PD-L1 (programmed death ligand 1) Probody therapeutic (Pb-Tx) designed to be preferentially activated by proteases in the tumor microenvironment and not in healthy tissue. Here, we report the model-informed drug development of CX-072. A quantitative systems pharmacology (QSP) model that captured known mechanisms of Pb-Tx activation, biodistribution, elimination, and target engagement was used to inform clinical translation. The QSP model predicted that a trough level of masked CX-072 (intact CX-072) of 13-99 nM would correspond to a targeted, 95% receptor occupancy in the tumor. The QSP model predictions appeared consistent with preliminary human single-dose pharmacokinetic (PK) data following CX-072 0.03-30.0 mg/kg as monotherapy: CX-072 circulated predominantly as intact CX-072 with minimal evidence of target-mediated drug disposition. A preliminary population PK (POPPK) analysis based upon 130 subjects receiving 0.03-30.0 mg/kg as monotherapy included a provision for a putative time-dependent and dose-dependent antidrug antibody (ADA) effect on clearance (CL) with a mixture model. Preliminary POPPK estimates for intact CX-072 time-invariant CL and volume of distribution were 0.306 L/day and 4.84 L, respectively. Exposure-response analyses did not identify statistically significant relationships with best change from baseline sum of measurements and either adverse events of grade ≥ 3 or of special interest. Simulations suggested that > 95% of patients receiving CX-072 10 mg/kg every two weeks would exceed the targeted trough level regardless of ADA, and that dose adjustment by body weight was not necessary, supporting a fixed 800 mg dose for evaluation in phase II.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1002/cpt.1985 | DOI Listing |
Handb Exp Pharmacol
December 2024
Rosa & Co, LLC, San Carlos, CA, USA.
Quantitative systems pharmacology (QSP) is a modeling approach employed in drug research and development that combines mechanistic representations of biological processes with drug pharmacology to deepen biological understanding and predict the responses to novel drugs or protocols. QSP has evolved from and is related to other modeling approaches, but has a number of unique attributes and applications. Here, we clarify the definition of QSP and its key features, trace its evolution, briefly compare it to other approaches, and explain why and how it can be used to reduce risk and improve efficiency in drug research and development.
View Article and Find Full Text PDFCPT Pharmacometrics Syst Pharmacol
December 2024
Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.
Type 2 diabetes mellitus (T2DM), characterized by insulin resistance, is closely associated with Alzheimer's disease (AD). Cerebrovascular dysfunction is manifested in both T2DM and AD, and is often considered as a pathological link between the two diseases. Insulin signaling regulates critical functions of the blood-brain barrier (BBB), and endothelial insulin resistance could lead to BBB dysfunction, aggravating AD pathology.
View Article and Find Full Text PDFHandb Exp Pharmacol
December 2024
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Despite an increasing number of clinical trials, cancer is one of the leading causes of death worldwide in the past decade. Among all complex diseases, clinical trials in oncology have among the lowest success rates, in part due to the high intra- and inter-tumoral heterogeneity. There are more than a thousand cancer drugs and treatment combinations being investigated in ongoing clinical trials for various cancer subtypes, germline mutations, metastasis, etc.
View Article and Find Full Text PDFJ Pharmacokinet Pharmacodyn
December 2024
PK Sciences, Translational Medicine, Novartis Biomedical Research, Cambridge, MA, USA.
Antibody drug conjugates (ADC) are a promising class of oncology therapeutics consisting of an antibody conjugated to a payload via a linker. DYP688 is a novel ADC comprising of a signaling protein inhibitor payload (FR900359) that undergoes unique on-antibody inactivation in plasma, resulting in complex pharmacology. To assess the impact of FR inactivation on DYP688 pharmacology and clinical developability, we performed translational modeling of preclinical PK and tumor growth inhibition (TGI) data, accompanied by mechanistic Krogh cylinder tumor modeling.
View Article and Find Full Text PDFHandb Exp Pharmacol
December 2024
Pharmacokinetics, Dynamics, Metabolism - Translational Medicine, Research & Development, Sanofi-US, Bridgewater, NJ, USA.
Quantitative Systems Pharmacology (QSP) models offer a promising approach to extrapolate drug efficacy across different patient populations, particularly in rare diseases. Unlike conventional empirical models, QSP models can provide a mechanistic understanding of disease progression and therapeutic response by incorporating current disease knowledge into the descriptions of biomarkers and clinical endpoints. This allows for a holistic representation of the disease and drug response.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!