Linear vs Non-linear System

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Presentation transcript:

Linear vs Non-linear System single kinetic study + linearity  can predict response to any input, including getting to SS NON-linear systems: CL, V, etc. not constant; depend on CSS, Dose requires testing at different doses; models time to SS not predicted by single dose study Common non-linearities Saturation kinetics (Michaelis-Menten) Saturable plasma protein, tissue binding Threshold effects (e.g., glucose spilling) Induction: Neuronal/hormonal regulation

“Non-linear Kinetics” Example

Pharmacokinetics Half Life (t1/2) 3

PK/DP Modeling PK/PD Modeling Procedure: Purpose: Estimate exposure and examine correlation between PD other endpoints (including AE rates) Use mechanistic models Purpose: Estimate therapeutic window Dose selection Identify mechanism of action Model probability of AE as function of exposure (and covariates) Inform the label of the medicine

SPECIFIC CONDIDERATIONS

Specific considerations of PD/PK Patient populations Paediatric, gender, elderly Other medications and foods Drug-drug Drug-food Pharmacogenomics Genetic polymorphism – Codeine Cyp2D6 ultrarapid Other diseases, Co-infections, etc