Methodological Aspects

The impact of disease on the pharmacokinetics can be evaluated either in specific studies or by population pharmacokinetic analysis of data from phase II-III studies. However, the many inclusion and exclusion criteria in today's phase III studies may limit the possibility to use a population approach. Such an approach requires that a sufficiently large number of patients with different degrees of dysfunction are included in the study, otherwise the results are of limited value. When sufficient data are available, results from population analysis alone are fully sufficient for labeling purposes.

When designing or assessing a study in a specific patient population, there are often a number of pharmacokinetic issues that need to be considered, including:

• Relationship between concentration and response (both desirable and undesirable effects) i.e., how much can the concentration change without influencing the efficacy or safety of the drug.

• Given the intended therapeutic use of the drug, what is the major concern: concentration-dependent side effects or lack of efficacy?

• Variability in the population (are outliers cause for concern?)

• Is it reasonable to assume that the pharmacodynamics is the same in different subpopulations?

Obviously, the answers to the questions above and the selected study design should be based on the pharmacokinetic/pharmacodynamic characteristics of the drug. The additional issues that need to be considered include:

• Are there any nonlinear properties that would justify steady-state studies? A multiple-dose study is desirable when the drug or an active/toxic metabolite is known to exhibit nonlinear or time-dependent pharmacokinetics. Otherwise a single-dose study is sufficient.

• Dose selection. In single-dose studies, a dose within the therapeutic dosage range should be used. For multiple-dose studies, lower or less frequent dosing may be needed to avoid unsafe accumulation of drug and/or metabolites.

• Which pharmacokinetic parameters are of greatest concern? Extent of bioavailability (F) and clearance (CL) are often most important, usually measured as AUG. When appropriate, emphasis should also be given to rate of absorption or other "secondary" parameters such as Cmax.

• Should only the parent compound be measured or should also the active/toxic metabolites be determined? If the metabolites are active or toxic, the impact of disease states on these metabolites should be evaluated. Evaluation of inactive metabolites should be considered when appropriate.

• Should the pharmacokinetics be based on total or unbound drug? For example, when plasma protein binding may be altered, the pharmacokinetics should be described and analyzed with respect to the unbound concentrations of the drug and active metabolites in addition to total concentration, unless the drug or metabolites exhibit relatively low extent of plasma protein binding.

In addition to selecting which trials should be conducted, the sponsor must also decide when to perform the studies. If available, information on influence of disease on the pharmacokinetics of the drug could be of value when designing the phase III programme. On the other hand, there may be financial as well as ethical reasons to perform these studies late in phase III or even after a regulatory approval of the medicinal product. In the latter situation, a specific subgroup may be contraindicated pending availability of this information.

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