In the dynamic world of drug development, safety pharmacology continues to evolve alongside scientific innovation. For decades, pharmacokinetic-pharmacodynamic (PK/PD) modeling has been integral to designing and interpreting safety pharmacology studies thus bridging the gap between exposure and biological effect. PK/PD principles have allowed researchers to predict dose-response relationships, assess therapeutic windows, and guide early clinical decision-making. However, as therapies have become increasingly complex, particularly in the era of biologics, gene, and cell therapies, the need for a deeper, systems-level understanding has emerged.

Enter Quantitative Systems Pharmacology (QSP)—a transformative modeling approach that integrates drug mechanism of action with the intricate web of biological and pathological processes. Unlike traditional PK/PD models, which primarily quantify relationships between drug concentration and effect, QSP captures the mechanistic interplay across molecular pathways, cell types, and organ systems. This allows researchers to simulate clinical responses with greater physiological fidelity, providing insight not only into “how much” effect is produced, but also why and through what mechanisms.

The Shift from PK/PD to QSP

The adoption of QSP marks a pivotal shift in how safety pharmacology data are interpreted and applied. According to a recent review published by the U.S. Food and Drug Administration (FDA), the agency received 367 QSP submissions between 2013 and 2023, with nearly 80 submissions in 2023 alone (doi:10.1002/psp4.13208). Notably, approximately one-third of these submissions focused on drug safety, highlighting QSP’s expanding role in preclinical assessment and regulatory strategy.

Among those safety-focused QSP models:

• 48% addressed drug-induced liver injury (DILI)
• 34% simulated or mitigated cytokine release syndrome (CRS)
• 19% examined other adverse effects, including impacts on bone density and cardiovascular function

This data underscores QSP’s growing importance in de-risking new therapeutics, particularly for biologics and immune-modulating agents where safety liabilities often emerge from complex immune or metabolic pathways.

Bridging Mechanisms and Outcomes

Where PK/PD provides quantitative relationships, QSP delivers mechanistic context. In practice, a QSP model can simulate how a candidate therapy interacts with multiple targets, how these interactions cascade through biological networks, and how compensatory pathways may influence both efficacy and toxicity. This enables a more predictive assessment of safety risk.

For example, QSP has been applied to anticipate cytokine release patterns in immunotherapies, to model liver enzyme dynamics during hepatotoxicity assessment, and to evaluate the systemic consequences of receptor modulation across organ systems. The result is a more holistic view of safety, allowing preclinical data to be interpreted within the broader framework of human physiology.

The Future of Safety Pharmacology

As the field advances, integration of PK/PD and QSP approaches will likely become the new standard allowing leveraging the strengths of both frameworks. PK/PD will continue to provide quantitative precision in exposure-response relationships, while QSP offers mechanistic depth, enabling a more predictive, translational understanding of drug safety. Together, these tools not only improve scientific rigor but also enhance the ethical and operational efficiency of safety pharmacology programs. Integration of pharmacokinetic-pharmacodynamic (PKPD) principles will be a routine part of the design and interpretation of safety pharmacology studies. Watch out for this space!

Why Choose Attentive Science

At Attentive Science, we understand that every data point tells a unique story and that safety pharmacology is about connecting those stories with clarity and confidence. Our experienced scientists apply deep expertise in PK/PD principles and mechanistic modeling to deliver studies that are both scientifically robust and regulatory-ready.

By integrating cutting-edge methodologies with a personalized approach, we help our partners bridge the gap between experimental data and clinical insight ensuring that innovative therapies reach patients safely and efficiently.

We don’t just assess safety, we help predict risks, guide your study design, and deliver insights you can rely on. Contact us whenever you’re ready, we’ll be here to help navigate your safety studies.