The dose linearity over the intended therapeutic dose range should be fully investigated, and included in an NDA submission. However, in the early stages of drug development the therapeutic dose range is usually not well established, and therefore it is advisable to investigate the pharmacokinetics of a new chemical entity over a wide, although reasonable, dose range. Especially the upper parts of the dose range is of interest, since the breakpoint for potentially clinically relevant nonlinearities in the pharmacoki-netics of a drug should be captured and quantified as early as possible in the development program.
An adequate number of dose levels (>3) should be examined, but a fixed number of dose levels are not required. It may not be necessary to repeat the dose-linearity study with the to-be-marketed pharmaceutical formulation unless substantial formulation changes have been made, or potential nonlinearities have been identified. However, the reader is referred to Part B: Biopharmaceutics for relevant information regarding waivers and bioequivalence requirements.
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