At the core of the drug development process is a fundamental understanding of the clinical pharmacology of the drug substance. Clinical pharmacology can be thought of as a translational science in which basic information about the relationship between a drug's dose, local or systemic exposure and response (related to either efficacy or safety) is applied in the context of patient care. Knowledge of this relationship, which is a key to successful therapeutics, and how it is altered by the intrinsic (age, gender, renal function, etc.) and extrinsic (diet, drugs, life-style) factors of an individual patient is one of the major contributions of clinical pharmacology to drug development and regulatory decision-making.
Once a lead compound with the intended pharmacological action is identified, the step-wise process to characterize and potentially optimize its pharmacokinetic (PK) properties (i.e., absorption, distribution, metabolism, and excretion), as well as to minimize its pharmacokinetic limitations (e.g., poor absorption), begins in humans as part of phase I human clinical trials. Soon after, other principles of clinical pharmacology [e.g., pharmacokinetic-pharmacodynamic (PD) relationships] become critical to the evaluation and selection of the most appropriate dosing regimen of the drug in a carefully selected target population enrolled in phase II clinical trials. These trials form the scientific rationale for subsequent dose selection in large-scale phase III clinical trials where the primary goal is to provide adequate evidence of efficacy and relative safety of the drug. Phase III trials are the most expensive and time-consuming component of the overall drug development process and many believe that paying careful attention to doing clinical pharmacology "homework" has the greatest potential to reduce the failure rate of new drugs at this near-final stage of development.
Often, in parallel with phase III clinical trials, a group of clinical pharmacology studies, such as those in special populations, are conducted in human volunteers to develop a knowledge database of factors influencing drug exposure. These data are crucial for an understanding of when, and how much, to adjust dosage regimens. Because these studies typically focus on changes in systemic exposure, as a surrogate marker for either efficacy or toxicity, the availability and the intelligent use of exposure (e.g., dose, PK measurements)-response (e.g., biomarkers, surrogate clinical endpoints, clinical outcomes, PD) relationships to interpret the results of these studies become critical to information for various sections of the product label. These studies can be broadly classified into two broad categories: (1) those dealing with patient-intrinsic factors that include gender, age, race, diseases states (primarily renal and/or hepatic impairment), and genetic (e.g., activity of cytochrome P450 enzymes) factors, and (2) those dealing with patient-extrinsic factors that include drug-, herbal- and nutrient-drug interactions, environmental variables (e.g., smoking, diet), and lifestyle factors.
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