Risk Versus Benefit Assessment

A quantitative assessment of risk and benefit relates the desired therapeutic endpoint with the undesired effects for a given new molecule. Delineation of risk versus benefit enables a greater appreciation of the therapeutic index and safety margins, thus enabling dose selection to be optimized. A risk versus benefit profile can be leveraged by an understanding of the PK properties of a given drug and exposure/response relationships for safety and efficacy. A conceptual framework for risk/benefit leveraging of a biomarker approach for safety and efficacy is presented in Figure 3.

It is quite common to encounter undesired safety issues for a new molecule in Phase I development where super-pharmacological doses are used to aid in the

Figure 3 Assessment of risk/benefit. Source: Adapted from Ref. 20. Courtesy of the American Society for Clinical Pharmacology and Therapeutics.

assessment of dose-limiting tolerability/safety findings. With the integration of biomarkers for safety and efficacy, one could leverage the information quantitatively with the aid of PK/PD modeling approaches, and as new data become available, the model can be further updated. These analyses can guide the development of the therapeutic index for a given molecule and provide dose focus for later Phase II/III trials, allowing for a more precise evaluation of toxicity and efficacy using an iterative process.

An example of a biomarker for safety is the QTc interval prolongation as a predictor for torsades de pointes. A PK/PD modeling approach can predict the extent of prolongation for a given molecule in the target population if sufficient information is available on the factors influencing the PK and / or PD variability for a drug response. A therapeutically meaningful dose or range of doses can then be identified by maximizing the efficacy while minimizing the risk for an observed incidence of QTc prolongation. An example for PK variability would be the increased exposure to a drug metabolized by CYP3A in a subject with hepatic insufficiency or in a subject with concomitant administration of ketoconazole, a CYP3A inhibitor. Chapter 7 illustrates the role of PK and PD variability in dose optimization.

Advances in mechanism-based modeling have allowed the flexibility of incorporating underlying pathophysiological processes for an observed PD response. In addition to providing a characterization of the concentration/ effect relationship, these approaches enable an effective delineation of risk/ benefit by providing a measure of potency/activity and undesired effects.

A good example of an application of mechanistic modeling in quantitative risk/benefit assessments comes from the literature on inhaled corticosteroids (43,44). While inhaled corticosteroids present a viable therapeutic option for asthma, there have been questions on their long-term safety. Specifically, these concerns stem from their potential to suppress development of the adrenal function. Consequently, a clear delineation of the benefit (for asthma) and risk (clinical adrenal suppression) is necessary for development of newer inhaled cor-ticosteroids. Here the benefit is a conglomeration of all favorable attributes of a molecule, including optimal PK properties, drug delivery properties, and increased residence in the lung, which may likely contribute to a more favorable systemic side-effect profile. An assessment of a quantitative risk/benefit value would entail the use of cortisol levels in plasma as a biomarker of the suppression in adrenal function. PK/PD modeling can then be performed integrating the biomarker, incorporating circadian rhythm, and any influence of down regulation. A model-based approach here would provide information on the degree of cortisol suppression for a range of efficacious doses and, thus, a therapeutic dose at which there is negligible cortisol suppression can then be identified.

Early identification of delineation of factors influencing risk and benefit is very useful as a clinical utility index is developed for a new molecule. This information may aid in the design of additional trials to further elucidate risk or benefit or add value in compound progression decisions.

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