ABSTRACT
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11.1 INTRODUCTION
In modern drug development, companies wish to make rational decisions as to whether to proceed with or abandon further development based on the likelihood of the compound meeting its target profile. These decisions are made most rapidly in early-phase development, and most compounds rejected during clinical development are discarded in this phase. One of the most common reasons
for rejection of a drug candidate is unsuitable pharmacokinetics;
hence, the assessment of pharmacokinetics in early-phase drug development is strategically important. Some of the drug development issues that are likely to be answered at least in part by a thoughtful interpretation of pharmacokinetic data include the following:
1. Is the compound adequately absorbed to elicit a therapeutic effect? 2. Is the compound absorbed at a speed consistent with the desired clinical response? 3. Is there evidence of a formulation problem? 4. Does the compound stay in the body long enough to be consistent with the desired duration of
action? 5. Is the within-or between-subject variability acceptable, given the likely therapeutic index of the
compound? What factors contribute to the variability? 6. Is a dose range covering the plasma (or tissue) concentrations likely to be associated with a desired
clinical response or give rise to safety concerns? 7. Does a relationship exist between plasma concentrations and a relevant measure of drug effect? 8. Are metabolites produced that may confound the therapeutic response or complicate the safety
profile? 9. In terms of absorption, metabolism, and excretion profiles, do subsets of the target population
behave differently from the general population? 10. Considering the above issues, what is a suitable dosing regimen for clinical efficacy trials?
