usefulness of mabel concepts - agah · 2019. 6. 8. · what is mabel? minimum anticipated...
TRANSCRIPT
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Usefulness of MABEL conceptsBart LaurijssensClinical Pharmacology Modelling and SimulationGlaxoSmithKline
29 April 2009 AGAH – Club Phase 1, 3rd joint annual meeting
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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
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What constitutes Safety?
Dose
PREDICTABLE
Conc
Primary Pharmacology
Secondary Pharmacology
Non-specific Effects
? AE
? AE
? AE
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Pharmacology & Toxicology
[Jennifer Sims, ABPI/BIA Early Clinical Trials Taskforce, slideset]
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Mechanistic Classification of Biomarkers
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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
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An example
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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!
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Mechanism of Action of TGN1412
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Dose Rational from the Protocol
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Receptor Occupancy of TGN1412 at starting Dose
[Jennifer Sims, ABPI/BIA Early Clinical Trials Taskforce, slideset]
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Conclusion
Pharmacology
Human! Pharmacology
Case by Case
Guidelines are Guidelines
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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