Pharmacodynamics endpoints

The extension of PBPK simulation to include pharmacodynamic endpoints is very powerful at this stage to guide the project team with respect to the key properties to consider for optimization, as demonstrated in the example below. 

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... 

Table 3 Options for Pharmacodynamic Endpoints in Kinetic-Dynamic Studies of GABA-Benzodiazepine Agonist Drugs...

Studies can usually be open label (unblinded), unless pharmacodynamic endpoints (e.g., adverse events whose interpretation is potentially subject to bias) are part of the assessment of the interaction. 

Over the past several years new techniques have vastly expanded the potential of flow cytometry to provide pharmacodynamic endpoints for a variety of... 

Ad 4) Pharmacodynamic endpoints for high dose selection will be highly compound-specific. The high dose selected should produce a pharmacodynamic response in dosed animals of such magnitude as would preclude further dose escalation. However, the dose should not produce disturbances of physiol-... 

The use of pharmacodynamic end points for high-dose selection is considered to be highly compound specific and is considered for individual study designs on the basis of scientific merit. The high dose should produce a pharmacodynamic response in the test species that precludes further dose escalation but does not produce disturbances of physiology or homeostasis that would compromise the validity of the carcinogenicity study. Examples of such pharmacodynamic endpoints include hypotension and inhibition of blood clotting. 

Several of the PK/PD models described in Chapter 19 have been employed to explore the relationship between circulating protein concentrations and pharmacodynamic endpoints. For example, a dog model of hemophilia was used to study the activity of recombinant FIX (79). Activity was determined in a bioassay, a modified one-stage partial thromboplastin time assay with pooled human plasma as the internal standard. As shown in Figure 32.14, the relationship between activity and recombinant FIX (BeneFIX) concentration was linear (r = 0.86), suggesting that for every 34.5 ng/mL of FIX, there would be a corresponding 1% increase in FIX activity. In 11 males with hemophilia B, it was necessary to use a sigmoid Emax... 

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... 

Pharmacodynamic endpoints (e.g. sedation at high dose levels)... 

When a topically applied compound induces a biological response following skin absorption, the quantitation of that response may provide a basis for assessing skin absorption. Indeed, such physiological or pharmacological responses have been employed as endpoints in assessing skin absorption in vivo, and perhaps the most successful example is the vasoconstrictor response to topical corticosteroids. However, while these pharmacodynamic endpoints may be very sensitive and selective for defined classes of compounds, it should be noted that the parameter measured is the product of both the quantity and the potency of the compound under investigation and may not necessarily reflect the extent of skin absorption, cutaneous metabolism, or disposition. 

I study of a novel proteasome inhibitor with pharmacodynamic endpoints. Proc. Am. Soc. Clin. Oncol. 20 336 (Abstr.)... 

A common issue is to communicate the relative importance of covariates in the explanation of unexplained variability in parameters, exposure, or pharmacodynamic endpoints. Consider the following schematic piece of code ... 

In many instances the variability in clearance reflects the variability in exposure, which makes Figure 7.28 relevant. If the exposure measure is not mirroring clearance, for example, time above a certain concentration, or if the focus is on the variability in a pharmacodynamic endpoint, the measures of variability can be obtained through simulations from the final model(s). 

For locally acting drugs, such as pulmonary and topical drugs, the assessment based on PK exposures AUC and Cmax is not appropriate. In such situations, plasma concentrations may be irrelevant to efficacy and even unavailable. In the case of metered dose inhalers (MDIs), the US Food and Drug Administration has been basing BE assessment on the dose-scale approach (2), which assesses the relative bioavailabUity (F) of the test and reference drug based on a pharmacodynamic (PD) endpoint, that is, the fraction of the test product dose that causes the same response in the pharmacodynamic endpoint as one dose of the reference product does. Approval of abbreviated new drug applications (ANDAs) would be based on the 90% confidence interval of F. 

We first discuss BE assessment in the presence of sparsely sampled subjects and then discuss pharmacodynamic endpoint bioequivalence. 

The approaches that may be appropriate and are acceptable for dose selection include toxicity-based endpoints such as the MTD, pharmacokinetic endpoints, saturation of absorption, pharmacodynamic endpoints, maximum feasible dose, and additional scientifically defensible endpoints. For toxicitybased endpoints, general study design characteristics to establish the MTD include that... 

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