Controversy I: Patients or Healthy Volunteers for Pharmacokinetic Studies?

Many factors should be considered when choosing an appropriate population for a pharmacokinetic trial. Although there are some generalities that apply to most studies, each investigation must be judged separately, since the relevant considerations will vary depending on the particular study, the nature of the drug, and the population that will receive it for therapeutic benefit. Some of the most important information that is generated from pharmacokinetic studies concerns the pharmacokinetic variability among patients and the factors that can influence this variability under the conditions that the drug will be used. This information can best be obtained from a combination of baseline studies to define the variability within the patient population(s) and comparative studies to determine the impact of specific variables on the disposition of the drug and its pharmacokinetic variability. These data can provide valuable information to the clinician that can be used to individualize drug dosage and optimize therapy as well as to identify populations who may be at high risk of therapeutic failure or drug toxicity. It is our feeling that baseline studies in patients are necessary for understanding the pharmacokinetics of a drug, whereas the objectives of most comparative studies can be achieved using healthy volunteers. For most comparative studies, the data obtained from healthy volunteers will reflect what will occur in patients, especially if the variable of interest is drug absorption. This is particularly important when practical and ethical considerations preclude the use of patients. When considering studies in the elderly, one must decide whether the variable of interest may be influenced by age. Baseline pharmacokinetic studies in both patients and healthy volunteers should be conducted, whenever possible, before undertaking comparative studies in order that the data generated can provide a basis for choosing the population for subsequent, more rigorous studies. It is imperative to sufficiently understand the pharmacokinetics of the drug so that one can judge whether a given population will provide information that can be applied to patients who will use the drug for therapy. If the study objective can be successfully fulfilled without the need for a specific patient population, and if the data from healthy volunteers can be extrapolated to patients, practical considerations would suggest that healthy subjects should be used.