# Presentation: 160854

## Trends in risk assessment

- Major emphasis on hazard identification
- Apical tests for detection of toxicity
- Empirical cross species extrapolation
- Dose metrics often unrelated to assessment of biological response
- Methods for hazard identification in animals often different from man
- Predictive value of animal data questioned

- Increasing emphasis on hazard characterization
- Exploration of mechanisms at cellular and molecular level
- Rational mechanism-based risk assessment
- Selection of dose metrics based on integration with assessment of biological response
- Methods for assessment of safety in human more in line with those used in animals
- Better correlation between observations in animals and humans

**PRESENT**

**FUTURE**

## Potential utility of biomarkers to discovery and development of new pharmaceuticals

- selection of superior leads for development
- reduced failure rate in development
- enhanced understanding of potential hazard(s) to patients
- improved risk communication at all stages of development process
- exclusion of patients at risk of serious adverse effects
- improved risk management pre- and post- marketing
- more cost effective delivery of medicines to patients in need

## Potential utility of biomarkers to risk assessment

- improved hazard identification and hazard characterization
- mechanistic understanding of toxic process(es)
- enhanced study designs
- identification of appropriate dose metrics (PK/TK/PD)
- risk assessment based on rational cross species extrapolation
- continuous refinement of predictive value of animal data
- continuous refinement of predictive value of human data

## A conceptual view of biomarkers

- Biomarkers of hazard
- conventional tests, e.g., ALT, CBC
- distal indicators of toxicity
- novel assays, e.g., cytokines, mRNA, cDNA
- proximal indicators of biological activity
- Biomarkers of efficacy
- primary pharmacology (MOA)
- intrinsic potency
- species sensitivity
- secondary pharmacology (NSA)
- specificity/selectivity
- unique species differences
- Biomarkers of exposure
- products of endogenous metabolism
- unique products of biotransformation

**A biomarker is an indicator of response by a biological system to the specific and/or non-specific**
**activity resulting from exposure to an exogenously applied substance at a given dose or**
**concentration over a prescribed period of time.**

## Source of materials and methodologiesfor assessment of biomarkers

- Biofluids
- urine, serum, saliva
- bronchoalveolar lavage
- Cells
- peripheral blood cells
- cell culture
- Tissue
- necropsy
- biopsy

- Biofluid MRS
- RT-PCR/Taq Man
- In situ hybridization
- MRI/MRS of tissue
- Microarrays
- 2-D gel electrophoresis
- Flow cytometry

**MATERIAL**

**METHODOLOGY**

## Biomarkers of hazard: specific examples

**HAZARD**
**testicular toxicity**
**thyroid tumors**
**carcinoid tumors**
**phospholipidosis**
**reduced fertility**
**bone marrow toxicity**
**arterial toxicity**
**fluid retention**
**cardiac hypertrophy**

**BIOMARKER**
**serum testosterone**
**serum TSH, T3, T4**
**serum gastrin**
**cytoplasmic inclusions in PBLs**
**serum estrogen/progesterone**
**reticulocyte counts**
**von Willebrand factor**
**hematocrit**
**brain natriuretic peptide**

## Products of altered gene and protein expression

## Biomarkers: extrapolation between animals and man

## Biomarkers: cross species extrapolation

- Congruent pattern of response across species
- Significant difference in animal species sensitivity
- Therapeutic ratio similar across species
- Dose-response relationships unknown in man

## Biomarkers: milestones on the exposure-response curve

- Species diversity in biological and toxicological response
- Congruent and      non-congruent effect on biomarkers across species

## Biomarkers: cross species extrapolationfor risk assessment

**(  )  AUC at no toxic effect dose in animal species relative**
**to AUC at therapeutic dose in human.**

## Biomarkers:  application to risk assessment

## Biomarkers:  application to risk assessment

## Biomarkers of effects induced by Thiazolidinediones

**D/E**

**R**

**Biomarker of**
**Physiologic Effect**

**Plasma**
**Volume**

**Hct**

**Biomarker of**
**Toxicologic Effect**

**Cardiac**
**hypertrophy**
**(MRI)**

## Plasma von Willebrand factorrats given 60 mg/kg SKF-82526

**Hours Post-Dose**

**n = 6-10/group/timepoint**

**0**

**2**

**6**

**24**

**% of Normal Rat Pool [mean + S.E.M.]**

**100**

**110**

**120**

**130**

**140**

**150**

**160**

**170**

**180**

**190**

**200**

**Control**

**60 mg/kg**

## Heart weight in different models of cardiac hypertrophy

## LV-cTnT concentration in differencemodels of cardiac hypertrophy