Several conferences and publications starting in the early 1990s until recently have emphasized the crucial role that pharmacokinetic-pharmacodynamic (PK/PD) modeling and the use of surrogate marker can have in streamlining the drug development process [1-9]. In particular, the advent of pharmacogenomics and biotechnology-derived drug products are thought to accelerate and facilitate the use of these techniques in making the drug development process and regulatory decision-making more rational and efficient [5, 8].
PK/PD modeling attempts to establish quantitative (e.g., mathematical and/or statistical) relationships between dosing regimen and pharmacological (PD) responses, and possibly clinical outcomes (see also Chapter 11).
As shown on Fig. 1, PK relates the dosing regimens of the drug product (e.g., dose, dosing interval, rate, and route of administration) with drug or metabolite concentrations in the body, typically measured in plasma. Both
Dosing Regimen Pharmacogenetics (PK) Drug Concentration in the Body ("Exposure")
Pharmacodynamics (PD) PD Response ("Surrogate Marker") Therapeutics Clinical Outcome
FIGURE 1 Surrogate markers in clinical pharmacology (exposure-response paradigm) and sources of variability.
dosing regimens and/or systemic concentrations are reflective of drug exposure to the patient: The assigned dosing regimen to a patient may reflect nominal exposure, while systemic concentrations (e.g., AUC, Cnax? etc.) reflect systemic exposure. The latter exposure measure is more closely related to drug/metabolite concentrations at the receptor site(s) responsible for the drug-induced pharmacological effect(s). It also allows to compare patients based on variability in medication adherence (compliance), as well as drug absorption and disposition that may be affected by patient covariates and contribute to the overall variability in drug response (see Chapters 8 and 9).
On the other hand, PD relates the drug concentrations in the body to any observable (multivariate) pharmacological response. A pharmacological response can be any physiological, biochemical, or pharmacogenomic endpoint that can be measured and is temporally and causally related to the drug. This PK/PD relationship is also referred to as the exposure-response (ER) relationship. Any variability in this relationship within and between patients contributes to the overall variability in drug response. In general, the PD responses are mediated by the mechanism(s) of action (MOA) of the drug. Nevertheless, a drug may have additional PD effects that are not mediated by the primary MOA such as hepatotoxicity.
Finally, the PD response(s) may be related to the ultimate clinical outcome(s), i.e., clinical efficacy and toxicity. If so, these (special) PD responses are surrogate markers that may substitute for clinical outcomes, since they usually are easier to measure and allow appropriate dosingregimen adjustments without having to accept adverse clinical outcomes.
It is one of the basic tenets of clinical pharmacology that an exposure-response relationship exists for clinical outcomes; namely, that changing the dose, etc., (exposure) has a tangible impact on outcomes. As a corollary, it is essential to optimize the dosing regimen according to the known PK/PD covariates.
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