Biomarkers pharmacodynamic toxicity

The usual GLP 30- or 60-day repeat-dose toxicology study with a recovery group offers an opportunity to perform a more systematic investigation of the more subtle pharmacodynamic or toxicologic effects of biopharmaceuticals than those endpoints usually incorporated into such protocols. Some of these demand tissue samples, but many involve noninvasive biomarkers that can be carried forward into early phase human studies. These might include CNS assessments, inflammation and immune activation or suppression, cell proliferation or apoptosis in tissue samples, and end-organ toxicities. 

This chapter will attempt to describe the various options available to validate commercial assays used in chug development appropriately to meet the expectations and requirements of each study in which they may be used. In particular, we will examine the use of commercial kits for pharmacodynamic (PD), efficacy and toxicity (biomarkers), and pharmacokinetic (PK) assessments. The PK assessment assays will focus on those molecules that are developed as therapeutic chugs, but which are also compounds that exist endogenously in humans. These chugs are often called new biological entities (NBEs) and examples include growth hormone, insulin, and erythropoietin. 

The endpoints for phase 0 trials are pharmacokinetics, pharmacodynamics, and biomarker responses to the new drug. Phase I trials test for safety along with the pharmacokinetics and pharmacodynamics. In phase II through IV trials, common endpoints are clinical measurements of response, toxicity, time to progression or the progression-free interval, and overall survival. Several cooperative oncology groups have objective criteria to measure the severity of adverse events or serious adverse events. 

Gupta RC. (2014) Biomarkers in Toxicology. Chapter 56 Membrane Transporters and Transporter Substrates as Biomarkers for Drug Pharmacokinetics, Pharmacodynamics, and Toxicity/Adverse Events. Oxford Academic Press, pp. 947-963. 

From an aspect of PK/pharmacodynamic (PK/PD) relationships, the difference in time points to provide the maximum blood concentration of drugs and maximum efficacy or toxicity must be examined carefully. In cases where time gaps are considerable, exploration of appropriate biomarkers may be beneficial to clarify the underlying mechanisms. In such situations, it is also worth considering the irreversible inhibition of a target protein or markedly slow dissociation of the drug from the target receptors. 

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