Pharmacodynamics clinical endpoint

The terms proof of principle and proof of concept are used more or less synonymously and pertain to the criteria that must be fulfilled in human studies before an NME can be considered to be a candidate for FD. These are particularly useful terms when applied to a drug thought to act by a novel mechanism of action. Eor example, a drug may be the first known inhibitor of a particular enzyme or receptor and the proof of principle will be a demonstration that such inhibition results in a desired pharmacodynamic or clinical endpoint. The terms are perhaps less... 

Pharmacodynamic equivalence as demonstrated by validated surrogate markers or primary clinical endpoints. 

A number of limitations related to PK/PD modeling are also a reality in situations where predictability of the animal model to man is questionable, where the time course of the pharmacodynamic effect cannot be assessed for drug candidates and when, for example, no accessible/ valid pharmacodynamic endpoint for PK/PD is available. The relevance of the animal model for human could be addressed to some extent at least by measuring relative potency in animal versus man in vitro. In situations where no relevant PD endpoint is available (e.g., for CNS efficacy models), effects at target level (i.e., enzyme inhibition, receptor occupancy) might represent a valuable alternative. In this context however the level and duration of target effect required for clinical efficacy requires careful considerations. 

Clinical pharmacokinetic drug interaction protocols increasingly incorporate pharmacodynamic endpoints into the study design such that the dynamic... 

For the clinical pharmacologist, neither of these racemic drug mixtures is problematic for drug therapy in the clinic if a pharmacodynamic endpoint (e.g., decrease in blood pressure with propranolol or improvement in arthritic pain with ibuprofen) is used to establish drug dose. However, to effectively characterize the pharmacokinetics of the active isomer, an endeavor that may be useful during drug development, administration, and/or specific determination of the active isomer is required. Such data... 

Phase I Clinical pharmacology in small numbers (tens) of healthy non-patient (or patient) volunteers to assess tolerability, preliminary safety, pharmacokinetics, and pharmacodynamics where practicable (i.e. biological effect using surrogate endpoints [see later] or, rarely, therapeutic effect)... 

Ha Clinical pharmacology in patients with the target disease (small numbers - tens to 100-200) to assess pharmacodynamics, pharmacokinetics, and dose-(or concentration-) effect responses for preliminary efficacy and safety, and to validate surrogate endpoints... 

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