Pharmacodynamics biomarkers

In this emerging era of molecular-targeted therapies, biomarkers are becoming more useful and perhaps even necessary for the success of new drugs. In this context, the two classes of biomarkers that are most relevant are pharmacodynamic biomarkers, which are used to confirm drug activity and mechanism of action, and predictive biomarkers, which are used to predict clinical response to targeted therapies. 

Step 3. Combination of individual PK (exposure) variables from virtual subjects with subject-specific covariate data together with the real data set (including the pharmacodynamics-biomarker response data) to create a PK/PD knowledge creation data set. 

Sometimes it is not possible to measure the direct effect of the drug. Endpoints or surrogate biomarkers are used to monitor the pharmacodynamics and pharmacokinetics of the drug. These markers may be changes in blood pressure, cholesterol level, concentrations of certain enzymes, proteins, blood glucose levels, and similar factors (see Table 6.2 for serum tumor markers and Appendix 7 for general biomarkers). 

As an example, Hsieh et al. identified toxicodynamic biomarkers in monkey semm that demonstrated a quantitative relationship with drug exposure (Cr iax, AUC) and related pathological events [148], The biomarkers were used for a more precise calculation of the no observed adverse effect level (NOAEL). The safety of three different dosing schedules was predicted using pharmacokinetic pharmacodynamic (PKPD) modeling and biomarker analysis. 

Danhof M, Alvan G, Dahl SG, Kuhlmann J, Paintaud G. Mechanism-based pharmacokinetic-pharmacodynamic modelling - a new classification of biomarkers. Pharm Res 2005 22 1432-7. 

In this chapter a number of approaches will be discussed that have been developed to address the challenges in macromolecule drag assays that impact upon selectivity, accuracy, and precision. The most commonly used methods for pro-tein/peptide drags - IA and LC-MS/MS - are discussed in detail, with case studies to illustrate the process, issues, assay approaches, and method limitations. Other less common methods and emerging technologies will be briefly mentioned. Biologic therapeutics that are not pure and/or not well characterized pose extra challenges which are beyond the scope of this chapter. Neither will biomarker assays used to support pharmacodynamic (PD) studies be covered in this chapter. 

A pharmacodynamic (PD) model describing the relationship between the observed concentration/exposure measure (e.g. the area under the plasma concentration-time profile AUC) and the observed drug effects on biomarkers, efficacy or safety measurements (or endpoints). Time dependent changes (e.g. development of tolerance) and influence of intrinsic and extrinsic factors should also be reflected in the model. 

In general, multiple (up to 30-40) blood samples can be obtained per subject to measure dmg and metabolite concentrations as well as biomarkers in these phase I clinical trials. Furthermore, pharmacodynamic measurements can be included to get a first impression on the drug effect in humans, however, limited by the fact that healthy volunteers were studied and not patients. As strict inclusion and exclusion criteria are used, the demographic characteristics of the healthy volunteers do not provide sufficient spread to investigate the effect of intrinsic factors. Therefore, phase I trials provide very rich data to develop pharmacokinetic and pharmacodynamic models on biomarker, but cannot be used to develop models for efficacy, safety, influence of patient factors on PK and/or PD and disease progression. 

Data destined for pharmacokinetic analysis consist of one or more drug concentration vs. time observations, while pharmacodynamic data consist of specific concentration levels corresponding to a specific therapeutic effect or its validated biomarker. One distinguishes two types of data ... 

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. 

Ideally biomarkers of activity should be identified at various times over the course of the study to support the pharmacodynamic activity (e.g., normalization of insulin, improvement in beta cell function as measured by C-peptide level, or control of glucose following transplantation of P pancreatic islet cells) improvement of motor coordination in mice with spinal cord damage following transplant of neurons or repair of heart function (e.g., functional measures such as LV ejection fraction, pressure volume loops, ventricular pressure and heart wall thickness). Such markers may also be useful in subsequent clinical... 

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