# Presentation: 217000

## Jerry M. Collins, Ph.D.

***Jerry M. Collins, Ph.D.***
**Laboratory of Clinical Pharmacology**
**Division of Applied Pharmacology Research**
**ACPS     October 19, 2004**

##      Critical Path Initiative

**March 2004: www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf **

**       *****Translational Research***

**     ****Critical Path Initiative**

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## Office of Testing and Research, OTR

**M. Khan, Director**

**Laboratory of Clinical Pharmacology,****    LCP**
**J.Collins, Director**

**Office of Testing and Research, OTR**
**Ajaz Hussain, Acting Director**

**Division of Applied Pharmacology Research, DAPR**
**J.Collins, Act.Dir.**

**Division of Pharmaceutical Analysis, DPA**
**L. Buhse, Director**

## Laboratory of Clinical Pharmacology    Programs		Goals	    Outcomes----------------------	   	----------------	      ------------------------Metabolism/	interpret	    Guidance x2 Interactions	data		    predict/manage              Hepatotoxicity	develop	    explain toxicity		   	models	    predict/manage                 PET Imaging      early 	    consulting reviewsfor Efficacy       	therapy	    PK-PD extensions			assessment    

## 
In vitro human liver studies identified
   drug interactions
Guidance developed greatly decreased potential for adverse effects
Markedly improved the efficiency and design of human clinical trials
Drug withdrawals from the market

**In vitro human liver studies identified**
**   ****drug interactions**
**Guidance developed greatly decreased potential for adverse effects**
**Markedly improved the efficiency and design of human clinical trials**
**Drug withdrawals from the market**

- Reducing Adverse Drug Interactions

**Notes:**
My first

## Inter-Agency Studies:  FDA-NCI

*** Memorandum of Understanding**
**   ****for Drug Metabolism Investigations**
**NCI Employee Working in FDA Lab**
*** FDA Lab Analyzing Drug Metabolites**
**   ****in NCI Phase 1 Trial.**

## Office of Testing & Research

**Laboratory of Clinical Pharmacology**

**Metabolism/Drug-Drug Interaction Studies in OTR Lab**

**Collaborative Clinical Studies of Metabolism-Based Drug-Drug Interactions**

**Input from Review Experiences**

## 		    HEPATOTOXICITYRegulatory SignificanceA leading source of serious adverse drug reactions.Recent examples producing liver failure or death include:  felbamate, troglitazone, and trovafloxacin. Scientific SignificanceReactive metabolites linked to many adverse events. Human liver tissue can help identify reactive metabolites.   Enzyme pathways can be modulated.Links to FDA: John Strong on Steering Committee for FDA’s Hepatotoxicity Initiative

## Slide 10

## PET Imaging for Efficacy

**Early Detection of Drug Action **
**Encouraging Innovation!**

## Regulatory Significance:  An emerging technology that is increasingly being applied to drug development. FDA/CDER’s long-standing interest in use of PK-PD principles for regulatory decision-making.               Scientific Significance:  Unique opportunity to examine PK-PD directly at level of drug target, rather than indirectly via plasma concentrations and/or downstream effectindicators.  Can determine drug distribution in body, or drug impact directly at receptors, enzymes, transporters, etc.

**PET Probes as Biomarkers for Efficacy**

## Frank & Hargreaves (2003)

## DAPR Molecular Toxicology Research

**MICROARRAY STANDARDS & QUALITY METRICS**
**Rat Mixed Tissue RNA Standard - Design & Testing**
**Collaborators:  Affymetrix, Agilent, GE, Amgen, Abbott, NIEHS, NCTR, Rosetta/Merck, Iconix**
**Gene Correlates of Sample Quality **
**CDER Statisticians, Affymetrix, GeneLogic****  **
**GENE MARKERS OF TOXICITY**
**Cardiotoxicity - Cross-Platform & Cross-Site**
**Affymetrix, Agilent, GE, Rosetta/Merck**
**Renal Toxicity (Current)**
**CDRH Animal Model of Subclinical Injury**
**Hepatotoxicity (Proposed, with LCP, NCI)**
**Mechanism of Anti-Cancer Drug Toxicity**
**Genomic Analysis for Hepatotox & Pediatric Tox**

## Incorporating Pharmacogenomic Technologies into Drug Development

**Lab Staff Connected to:**
**SSC Interest Group: N.Alderson**
**Inter-Center Working Group: L. Lesko**
**FDA-PhRMA Workshops #1, #2, #3**

## DAPR Preclinical Biomarkers Group

**Identification of blood biomarkers of  Phosphodiesterase Inhibitor-induced vascular injury**
**Evaluation of cardiac Troponin-T as a preclinical marker for cardiac injury**
**Evaluation of flow cytometric endpoints for prediction of drug hypersensitivity using the Lymph Node Proliferation Assay**
**Development of preclinical model system for assessment of differential pediatric toxicity**
**Identification of novel blood biomarkers for liver toxicity**

## Emphasis on Clinical Toxicities That Are Difficult to Monitor

**Bio-Markers**

***Bridging “One-at-a-Time” with Arrays of Indicators via Genomics/Proteomics***

## Slide 18

## Slide 19

## Slide 20

## Genes 

**DOX**

**DOX/DZR**

**DZR**

**Genes **
**(by category) significantly changed **
**by DOX **
**at 3 weeks and modulation of changes by**
**cardioprotectant**

**Cardiac muscle **
**function & structure  **

**Fatty acid metabolism**

**Glucose metabolism**

**Immune response**** **

**Stress induced **

- Color Scale (Log 2)

## PDEi-Induced Vascular Injury

- Unusual vascular injury caused by PDE-III, -IV, -V inhibitors, and some other vasoactive drugs.
- Characterized by small bleeds into vessel wall in anatomically restricted areas.
- Observed in rats, dogs, primates, and rarely mice.
- Goal of research is to identify biomarkers in blood associated with vascular injury.

## PDEi-Induced Vascular InjuryAssociation between proposed biomarkers and vascular injury

**TIMP-1**

**C-Reactive**
**Protein**

**IL-8**

**a1-Acid **
**Glycoprotein**

**Vascular Injury Histopathology Score**

## Summary of PDEi Blood Biomarkers

- Significant increases seen in at least 6 different proteins in serum following treatment with either of two unrelated PDE IV inhibitors.
- Changes are generally proportional to severity of pathological lesions.
- Changes are highly correlated between the two PDE IV inhibitors.
- These biomarkers represent a possible new tool for evaluating _preclinical_ safety.