Choice of Dose and Dosage Regimen

The pharmacokinetics after repeated administration of the highest dose level in the anticipated therapeutic dose range should be adequately described, since more prominent changes are expected to occur at higher dose levels. It is prudent to include one or two lower dose levels, to fully establish the pharmacokinetic properties of the drug at steady state, after repeated dosing. The pharmaceutical formulation of an oral dosage form should preferably be similar to the formulation used in the later clinical trials in the patient population. However, if the results from the singledose trials call for the development of a modified release or extended release formulation, a smaller trial at an adequate dose level using an immediate release formulation could be considered. If apparent nonlinearities in the steadystate pharmacokinetics of the drug are observed at a later stage, such a pilot study could be used to the differentiate between apparent nonlinearities due to time-dependencies in drug metabolism, and the effects of the altered release profile by the pharmaceutical formulation.

The dosing regimen, i.e., the time-interval between doses, is governed by the exposure (pharmacokinetic)-response (pharmacodynamic) relation-ship of the drug. If relationship is known, the clearance and terminal tV of the drug can be used in the calculations of the optimal-dose regimen [1, 23]. Although the exposure-response relationship may be less well-characterized, the information about the pharmacokinetic properties of the drug will aid the choice of dosage regimen. A drug with a short terminal tV and high clearance, where the desired effect is more likely to be related to the AUC rather than Cmax, will require more frequent dose intake than a drug with a longer terminal tV and a lower clearance. The reader is also referred to relevant chapters in the Biopharmaceutics section of this book, for pertinent information regarding waivers and bioequivalence studies that may be needed to fulfill all requirements for an NDA, if major changes in the pharmaceutical formulations have been made during the development program.

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