Practical QSP application from the preclinical phase to enhance the probability of clinical success: Insights from case studies in oncology.

Quantitative Systems Pharmacology (QSP) has emerged as a promising modeling and simulation (M&S) approach in drug development, with potential to improve clinical success rates. While conventional M&S has significantly contributed to quantitative understanding in late preclinical and clinical phases, it falls short in explaining unexpected phenomena and testing hypotheses in the early research phase. QSP presents a solution to these limitations. To harness the full potential of QSP in early preclinical stages, preclinical modelers who are familiar with conventional M&S need to update their understanding of the differences between conventional M&S and QSP. This review focuses on QSP applications during the preclinical stage, citing case examples and sharing our experiences in oncology. We emphasize the critical role of QSP in increasing the probability of success for clinical proof of concept (PoC) when applied from the early preclinical stage. Enhancing the quality of both hypotheses and QSP models from early preclinical stage is of critical importance. Once a QSP model achieves credibility, it facilitates predictions of clinical responses and potential biomarkers. We propose that sequential QSP applications from preclinical stages can improve success rates of clinical PoC, and emphasize the importance of refining both hypotheses and QSP models throughout the process.

Quantitative Systems Pharmacology Approaches for Immuno-Oncology: Adding Virtual Patients to the Development Paradigm.

Drug development in oncology commonly exploits the tools of molecular biology to gain therapeutic benefit through reprograming of cellular responses. In immuno-oncology (IO) the aim is to direct the patient's own immune system to fight cancer. After remarkable successes of antibodies targeting PD1/PD-L1 and CTLA4 receptors in targeted patient populations, the focus of further development has shifted toward combination therapies. However, the current drug-development approach of exploiting a vast number of possible combination targets and dosing regimens has proven to be challenging and is arguably inefficient. In particular, the unprecedented number of clinical trials testing different combinations may no longer be sustainable by the population of available patients. Further development in IO requires a step change in selection and validation of candidate therapies to decrease development attrition rate and limit the number of clinical trials. Quantitative systems pharmacology (QSP) proposes to tackle this challenge through mechanistic modeling and simulation. Compounds' pharmacokinetics, target binding, and mechanisms of action as well as existing knowledge on the underlying tumor and immune system biology are described by quantitative, dynamic models aiming to predict clinical results for novel combinations. Here, we review the current QSP approaches, the legacy of mathematical models available to quantitative clinical pharmacologists describing interaction between tumor and immune system, and the recent development of IO QSP platform models. We argue that QSP and virtual patients can be integrated as a new tool in existing IO drug development approaches to increase the efficiency and effectiveness of the search for novel combination therapies.