Microdosing in Translational Medicine: Pros and Cons

Published by: CHI Insight Pharma Reports

Published: May. 1, 2006 - 125 Pages

Table of Contents

Chapter 1. Introduction: The Quest for Early Human Data

1.1 A Quicker and Safer Way to Develop New Drugs is Needed

1.2 The Basic Dilemma: Extrapolating from Animals to Humans

1.3 Better Software Will Help, But Solutions for Judging Effects on Humans are Needed Now

1.4 The Concept of Microdosing

Chapter 2. Microdosing and Clinical Pharmacology

2.1 The Benefit of Early Human Pharmacodynamic Information

2.2 Expected Relations between Microdoses and Clinically Effective Doses

2.3 Microdosing Known Compounds to Assess Investigational Drug Effects

2.4 Bioanalytical Support: Constraints and Perspectives

Accelerator Mass Spectrometry

Tandem Liquid Chromatography/Mass Spectroscopy

Positron-Emission Tomography

2.5 Using Microdosing-Type Analytical Methods in Safety Pharmacology

Chapter 3. Microdosing Studies as a Strategic Tool

3.1 Microdosing as a Tool to Weigh Drug Development Options

3.2 A Fruitful Marriage with in silico Optimization Techniques and “-omics”

3.3 Option for Studies in Unconventional Populations

Chapter 4. Microdosing as a Regulatory Challenge and Opportunity

4.1 The EMEA Position Paper on Microdosing

4.2 The FDA Exploratory IND Guideline

4.3 Other Regulatory Guidelines for Studies Using Radioactive Drugs

4.4 Benefits in Costs, Time, and Logistics

4.5 The Ethical Aspect: Reducing the Burden on Volunteers and the Use of Animals

Chapter 5. Practical Experience and Planning-Stage Projects with Microdosing

5.1 Proof of Concept through In Vitro and Animal Studies

5.2 Collaborative Industry and Public/Private Efforts

The Consortium for Resourcing and Evaluating AMS Microdosing

Azidothymidin Study by Radiant Research and Vitalea Sciences

The EU Microdose AMS Partnership Programme (EUMAPP)

5.3 Pharmaceutical Companies as Sponsors of Microdosing Studies

GlaxoSmithKline

Servier

Speedel Pharmaceuticals

Tripep

Neurocrine Biosciences

Industry Opinions on the Acceptance of Microdosing

Chapter 6. Expert Roundtable Commentaries

Dr. Ali Arjomand, President and COO, Accium Biosciences

Dr. Stephen Dueker, President, Vitalea Science

Dr. Jon Ruckle, Medical Director, Early Phase Research, Radiant Research

Dr. Lloyd Stevens, Business Support Manager, Pharmaceutical Profiles

Prof. Dr. Colin Garner, CEO, Xceleron

Question 1: Do you see possibilities for modifying current microdosing protocals to make them more predictive?

Question 2: Do you see additional potential in evaluating other parameters relevant to drug development, such as drug interactions?

Question 3: How do you estimate the potential of isotopes other than 14C?

Question 4: How do you see the relationship between AMS and LC/MS/MS developing?

Question 5: What role do you see for imaging technologies, expecially PET, in microdosing studies?

Question 6: Could human microdosing be accepted to such an extent that it becomes a routine screening tool for drug leads in a streamlined clinical development process?

Question 7: Could you comment on the potential feedback loops between human microdosing studies, the various “-omics,” and in silico methods?

Question 8: Do you see opportunities for microdosing in formal preclinical study programs?

Question 9: With EMEA and FDA guidelines in place, how do you think the scenery will develop geographically during the next few years?

Question 10: What are your optimistic and pessimistic estimates for the dollar volume of the microdosing market by 2010 and 2015?

Question 11: What share of this market do you estimate your company will capture by 2010 and 2015?

Chapter 7. Conclusion: Cambridge Healthtech Associates’ Scenario for Microdosing in Drug Development

7.1 Today’s Outlook Depends on Where You Are in the Drug Development Process

7.2 Along the Way: Getting Over Nonscientific and Noneconomic Factors

7.3 An Exciting New Tool

Appendix A. Companies Offering Microdosing Services

Appendix B. Cambridge Healthtech Associates - Microdosing Survey - April 2006-04-24

References

Company Index with Web Addresses

List of Figures

Figure 1.1: Conventional and Microdosing Approach to Drug Candidate Selection

Figure 2.1: Survey Results: Strong Kinetics Predicability in Human Microdosing.

Figure 2.2: Pharmacokinetics of Vitamin B12 in Human Plasma Following Administration of a 1.5 µg Dose.

Figure 2.3: Layout of a Tandem Accelerator Mass Spectrometer

Figure 2.4: The Principle of Positron-Electron Annihilation

Figure 3.1: Survey Results: Microdosing Studies in 2005

Figure 3.2: Survey Results: Microdosing Studies in 2006 and Beyond

Figure 5.1: Dose-Normalized Concentration-Versus-Time Graphs for Intravenous Microdose (0.1 mg) and Intravenous Therapeutic Dose of Diazepam

Figure 5.2: Dose-Normalized Concentration-Versus-Time Graphs for Oral Microdose and Oral Therapeutic Dose of Midazolam

Figure 5.3: Dose-Normalized Concentration-Versus-Time Graphs for Oral Microdose and Oral Therapeutic Dose of Warfarin

Figure 5.4: Plasma Concentrations of Investigational Renin Inhibitor SPP601 after Oral Microdosing of 0.1 mg

Figure 5.5: Projected Time Frame for Microdosing Integration

Figure 6.1: Survey Results: Industry Specialists See Strong Microdosing Future

List of Tables

Table 4.1: Itemized Comparison of Typical Chemistry, Manufacture and Control (CMC) Costs and Timelines in Preparation of Conventional Phase I and Microdosing Trials

Table 4.2: Upsides and Downsides of Microdosing vs. Conventional Pathway to First-Time- in-Human Milestone

Table 5.1: Summary of the CREAM Trial Results Source: Xceleron, Modified

Abstract

• What the CREAM trial and other HMD studies say about the linearity of PK results.
• Comparative assessment of EMEA and FDA guidelines governing HMD — which offers the more hospitable pathway?
• Use of HMD in synergy with in silico and other predictive technologies.
• Assessment of current detection technologies and emerging improvements.
• Use of PET in HMD to study ligand displacement.
• Which sector will adopt HMD first --- big pharma or biotechs?
• Applications of HMD using oral, IV, and other routes of administration.
• Examination of cost-benefit, risk management, regulatory and ethical aspects of HMD.

• Roundtable interviews with CEOs of the leading CROs specializing in HMD.
• A survey of the views, actions and planned activities of R&D managers at pharma and biotech companies with responsibility for selecting candidates for Phase I.
• Forecast of the market for HMD services and timelines to adoption by pharma and biotech companies.

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