Usefulness of MABEL conceptsBart LaurijssensClinical Pharmacology Modelling and SimulationGlaxoSmithKline

29 April 2009 AGAH – Club Phase 1, 3rd joint annual meeting

What is MABEL?

Minimum Anticipated Biological Effect Level

In Humans!

“[For a biological product], the estimation of the dose or exposure required at the bottom end of the dose response curve in man is more important than NOAEL. This might be termed the Minimum Anticipated Biological Effect Level (MABEL).”

Early Stage Clinical Trial Taskforce, Joint ABPI/BIA Report, July 2006

What constitutes Safety?

Dose

PREDICTABLE

Conc

Primary Pharmacology

Secondary Pharmacology

Non-specific Effects

? AE

? AE

? AE

Pharmacology & Toxicology

[Jennifer Sims, ABPI/BIA Early Clinical Trials Taskforce, slideset]

Mechanistic Classification of Biomarkers

How to Predict a Dose with Minimal Pharmacology?

Distribution to target(s) in Humans:Transporters (eg PgP)Extracellular vs Intracellular target

Interaction with the Human Target(s)Affinity (in vitro, ex vivo)Efficacy (agonism vs antagonism)

Human pharmacologyIn vitro, ex vivoAnimal models of physiology (or Disease)Direct vs Indirect effects

KnowledgeExperience with mechanism in HumansHuman physiologyGeneral Pharmacological Theory

An example

Biologics vs NCEs

No liver metabolism (hence no active metabolites)

Highly (species) specific for the target

High affinity (target mediated disposition)

Limited off target effects

Most AEs through Primary Pharmacology!

Mechanism of Action of TGN1412

Dose Rational from the Protocol

Receptor Occupancy of TGN1412 at starting Dose

[Jennifer Sims, ABPI/BIA Early Clinical Trials Taskforce, slideset]

Conclusion

Pharmacology

Human! Pharmacology

Case by Case

Guidelines are Guidelines

Mabel concept Useful?

Usefulness of MABEL conceptsWhat is MABEL?What constitutes Safety?Pharmacology & ToxicologyMechanistic Classification of BiomarkersHow to Predict a Dose with Minimal Pharmacology? An exampleBiologics vs NCEsMechanism of Action of TGN1412Dose Rational from the ProtocolReceptor Occupancy of TGN1412 at starting DoseConclusion