Table 1.

Biomarker functions for biological drugs.

Function	Usage	Example
Demonstrate drug activity	To provide early evidence of a drug’s effect before overt clinical outcomes manifest.	In treating chronic myeloid leukemia (CML), the BCR-ABL tyrosine kinase inhibitor imatinib is used. The decline in BCR-ABL transcript levels in patients’ blood is a functional PD marker of the drug’s activity on its target [31].
Guide dosing	To ensure optimal drug dosing using the dose–response relationship.	For cholesterol-lowering drugs like statins, the low-density lipoprotein cholesterol (LDL-C) levels in the blood serve as a PD marker to guide dosing and assess efficacy [32].
Select patients	To identify patients likely to benefit from a specific treatment.	In some breast cancers, overexpression of the HER2 protein is observed. HER2 status serves as a functional PD marker to select patients who might benefit from trastuzumab, which targets HER2 [33].
Monitor resistance	To track the development of resistance to treatments.	In HIV treatment, the emergence of specific viral mutations can serve as PD markers indicating resistance to specific antiretroviral drugs [34].
Determine the drug mechanism of action	To confirm action through its intended mechanism.	In Alzheimer’s disease, the buildup of beta-amyloid plaques is considered a hallmark. Drugs designed to reduce beta-amyloid levels in the brain might use CSF (cerebrospinal fluid) levels of beta-amyloid as a PD marker to show the drug’s effect [35].
Validate target engagement	To demonstrate that a drug is successfully engaging with and modulating its target.	For multiple sclerosis drugs like fingolimod, a PD marker such as the number of circulating lymphocytes can indicate the drug’s effect on immune cell egress from lymph nodes [36].
Evaluate drug-induced toxicity	To monitor potential adverse effects of a drug.	In chemotherapy, monitoring the levels of liver enzymes like AST and ALT in the blood can serve as PD markers for drug-induced liver damage [37].
Optimize therapeutic window	To establish the range between the minimum effective dose and the onset of adverse effects.	For anticoagulant drugs like warfarin, the INR (International Normalized Ratio) serves as a PD marker to ensure the drug’s effect is within a therapeutic range, minimizing the risk of bleeding and clot formation [38].
Predict long-term drug effects	To predict longer-term therapeutic or adverse effects using early changes in PD markers.	In osteoporosis treatments, reducing bone resorption markers like CTX (C-terminal telopeptide) can predict longer-term benefits in bone mineral density and fracture risk [39].
Assess immune response	For immunotherapies, to gauge the body’s immune response to the treatment.	In cancer immunotherapy, the presence and proliferation of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment can serve as a PD marker to indicate the activation and targeting of the immune system against tumor cells [40].
Indicate drug combination efficacy	In combination therapies, to show the synergistic or additive effects of the combined drugs.	In treatments for tuberculosis, monitoring bacterial load in sputum samples can serve as a PD marker for the combined efficacy of multiple antimicrobial agents [41].
Track reversal of disease progression	To indicate whether a drug is not just halting but reversing disease progression.	In fibrotic diseases like idiopathic pulmonary fibrosis, measuring levels of collagen-derived peptides in blood or bronchoalveolar lavage fluid can act as PD markers, indicating the repair or degradation of fibrotic tissue [42].
Evaluate neural activity and plasticity	To track neural activity or connection changes in neurologic disorders and treatments.	For treatments aimed at Alzheimer’s or other neurodegenerative conditions, the levels of synaptic proteins or neuronal activity markers in CSF can indicate neural activity and synaptic plasticity [43].
Monitoring metabolic responses	To help track changes in metabolic pathways.	In diabetes management, measuring C-peptide levels alongside insulin can give insights into endogenous insulin production and pancreatic function [44].
Monitoring cellular senescence and aging	In treatments aiming to affect aging processes or cellular health, to track cellular senescence.	Measured levels of senescence-associated beta-galactosidase or p16^INK4a expression can act as PD markers for cellular aging or the efficacy of anti-aging treatments [45].
Evaluating epigenetic changes	To track changes in DNA methylation, histone modification, or other epigenetic markers.	In oncology, when treating with drugs targeting DNA methyltransferases, the global or gene-specific changes in DNA methylation levels can serve as PD markers [46].
Assessing drug-induced autophagy	For therapies inducing autophagy as a mechanism, to monitor the process.	When monitoring LC3B lipidation, a critical step in autophagosome formation can serve as a PD marker for autophagy activation [47].
Monitoring immune checkpoint inhibition	In cancer immunotherapy, target immune checkpoints to gauge the effectiveness of checkpoint inhibition.	In patients receiving PD-1 or PD-L1 inhibitors, monitored circulating tumor DNA (ctDNA) levels can serve as a PD marker to indicate response to therapy [48].