Cardiovascular Program

Recent advancements in the field of cardiovascular therapeutics have led to a better understanding of the basic pathophysiologic mechanisms that underlie and manifest from a number of cardiovascular diseases. This renaissance has led to the emergence of a greater number of pharmacologic treatment options to manage conditions such as acute myocardial infarction, angina pectoris, heart failure, coronary artery disease and hypertension. Since many cardiovascular diseases are systemic in nature, it is unlikely that any one single therapy will offer a complete treatment response. In heart failure for instance, although the primary problem is related to an abnormality in the myocardium, many of the associated signs and symptoms are related to dysfunction of other organs such as the lungs, liver and kidneys. In addition, the complex interaction between myocardial dysfunction, activation of neurohormonal systems, and disease progression further complicate the design of multi-drug treatment regimens.

Pharmacokinetic and pharmacodynamic (PK-PD) modeling can be utilized to relate the time course of drug in the systemic circulation to the time course of one or more cardiovascular response measurements. Such an approach allows for characterization of the complex inter-relationships between the primary response(s) of interest and other homeostatic mechanisms that may impact the magnitude and time course of treatment response. In addition, PK-PD modeling may be used to characterize the underlying baseline response in the absence of treatment and can be used to quantitatively assess disease progression.

Mechanistic PK-PD models are particularly advantageous since they incorporate both elements of the physiologic system of interest as well as the pharmacologic properties of the drug. Mathematical modeling and structural characterization of the physiologic system establishes a platform that can be used to simultaneously assess the effects of multiple drugs that either have similar mechanisms of action or exert their effects via separate pathways. Mechanistic models may also be used to both describe and provide a physiologic interpretation of phenomena such as homeostatic mechanisms involved in the regulation of drug response, pharmacologic tolerance, and rebound.

The ultimate goal is to be able to use these mechanistic PK-PD models to identify optimal drug dosing regimens. Simulations performed using mechanistic PK-PD models can be used to assess the impact of changes in factors related to study design and drug therapy (e.g., dose amount, frequency of dosing, inclusion and inter-changeability of drugs in multi-drug treatment regimens), underlying physiology (disease severity, rate of disease progression, alterations in targeted drug receptor levels) and both the timing and extent of activation of neurohormonal or other adaptive feedback mechanisms.