An Introduction to the Use of Pharmacodynamic Biomarkers in Drug Development
In the realm of drug development, precision and efficacy are paramount.
Enter pharmacodynamic (PD) biomarkers, the unsung heroes that offer a deeper understanding of how drugs affect the body.
This article delves into the basics, applications, and technologies of PD biomarkers in drug development including a case study where PD biomarkers were important.
Basics of Pharmacodynamic Biomarkers
Pharmacodynamics explores how drugs exert their effects on biological systems. Unlike pharmacokinetic (PK) biomarkers, which measure the drug's journey through the body, pharmacodynamic biomarkers assess the drug's biological impact. They can be indicators of a drug’s activity and efficacy, such as receptor occupancy or enzyme inhibition, providing invaluable insight into the drug's mechanism of action.
PK markers - time courses of drug concentrations in the body. Understanding of the absorption. distribution, metabolism, and excretion of a drug.
PD markers - the biochemical and physiological effects of drugs on the body. Understanding the mechanism of action of drugs.
PK and PD markers can be analyzed in tandem (PK/PD modeling) to determine the relationship between drug-induced pharmacological effects and drug concentration in the body.
Applications in Drug Development
Preclinically, these biomarkers facilitate the assessment of drug efficacy and safety, guiding dose selection for initial human trials. PD biomarkers can determine the mode of action of the drug as well as providing proof of concept studies. These data are included in the IND application to the FDA.
Clinically, they serve to optimize dosing and monitor therapeutic response, significantly impacting clinical trial outcomes. In human studies, you can use these markers to determine:
Whether the drug hit the intended target, AKA a target engagement biomarker
Whether hitting the target results in the downstream effect - AKA a downstream biomarker
These insights can be studied alongside the efficacy measurements on the trial to see if there is a relationship between dose and response to the drug. It can also help determine when you are starting to hit efficacious doses in a dose escalation study.
An example of both target engagement and downstream biomarker relationships can be illustrated by the studies performed by Genentech during the development of their KRAS G12C inhibitor GDC-6036 (divarasib).
Divarasib suppresses downstream MAPK signaling by alkylation of KRAS G12C, thereby locking KRAS in its inactive GDP-bound state.
In preclinical models, researchers used the level of KRAS G12C alkylation, measured by mass spectrometry, to show that divarasib does in fact alkylate KRAS G12C. Target engagement biomarker ✅
In addition, they used DUSP6 mRNA, a marker of MAPK pathway activity, as a downstream marker for the study, to illustrate that divarasib is suppressing the MAPK pathway. Downstream biomarker ✅
Through this, they could show that divarasib shows dose-dependent target inhibition (KRAS G12C alkylation) and MAPK pathway inhibition, which correlate with high antitumor potency in the MIA PaCa-2 pancreatic xenograft model.
MAPK pathway inhibition, measured by DUSP6, correlates with KRAS G12C alkylation. Tran et al Anal. Chem. 2023, 95, 11, 4834–4839.
Therefore, when they took this agent into clinical trials they collected tumor tissue in some of the patients to assess this.
Patients with lesions safely accessible to biopsy underwent a fresh pre-treatment tumor biopsy (or provided a recent archival tumor tissue sample that was collected prior to completion of the last anti-cancer therapy) and an on- treatment tumor biopsy after approximately 1-2 weeks of divarasib daily dosing. Unfortunately, the results of this are not public.
In addition, they measured KRAS G12C in the circulating tumor DNA of patients’ plasma which showed clearance of the mutant tumor DNA, suggesting the drug is eliminating cells containing KRAS G12C.
Desai et al 2024 Nature Medicine volume 30, pages 271–278 (2024)
What PD biomarker plots may you see in drug development?
PD biomarkers are usually plotted in one of two ways:
PD biomarker vs Time plots have a line per dose and show how the biomarker changes over time. This enables determination of the biomarker’s dynamic range across relevant doses. It can also be helpful in identifying when to collect samples for your biomarker studies in the clinic, and what effect size you would expect to see at those timepoints.
Temporal and dose response data. FDA
2. PD biomarker vs dose. In a dose escalation trial, you may have the first cohort showing no PD biomarker response, because the dose is too low. Then as the dose increases with more patients on the trial, you start to see a biomarker response. The doses where the PD biomarker dynamically changes are the sensitive doses, the lowest of which is the minimal active dose. When you reach doses where the biomarker starts to plateau, there is no increase in activity for each increase in dose, and, for targeted agents, it is usually not worth increasing the dose much above that.
Dose response relationship of a PD biomarker. FDA
Conclusion
The role of pharmacodynamic biomarkers in bridging laboratory research and clinical success cannot be overstated.
The journey of drug development is complex, but with the aid of pharmacodynamic biomarkers, it is becoming increasingly precise and impactful.
If you’d like to research pharmacodynamic biomarkers further, here are a few tools and seminars:
The importance of PK/PD in drug discovery
