How sequential studies inform drug development: evaluating the effect of food intake on optimal bioavailability of...

Determining a drug dosing regimen that produces consistent bioavailability and patient effects is one of the goals of the drug development process. Food consumption is one factor that can significantly alter the bioavailability of some drugs. This manuscript describes a research approach to determine what recommendations to give patients regarding taking oral ziprasidone in relation to food consumption. Four pharmacokinetic studies, the first three in volunteers and the fourth in patients at steady-state on the maximum recommended daily dose of ziprasidone, investigated the relationship between food intake and ziprasidone absorption. These studies illustrate how sequential studies are used in drug development to investigate increasingly precise questions using data from one study to refine the question being addressed by the next. In the first study, the absorption of ziprasidone was shown to double when taken following a high-calorie, high-fat meal versus the fasting state. The second study showed that the difference in absorption between the fasting and fed states increased with dose. The third study suggested that calorie rather than fat content was the critical variable. This finding was confirmed in the fourth study over a wider variety of meals and under clinically relevant dosing conditions. That study also found reduced pharmacokinetic variability (i.e., more consistent absorption) when ziprasidone was administered with 500-1000 kcal meals without regard to fat content rather than under fasting or low-calorie meal conditions. These results have several clinically important implications. First, the effect of taking ziprasidone in a fasting state cannot be overcome simply by increasing the dose. Second, significant swings in ziprasidone concentration and hence efficacy and tolerability may occur on a day-to-day basis if diet is not controlled. Third, patients should be advised to take ziprasidone with a meal containing at least 500 calories (without regard to fat content) to ensure adequate ziprasidone bioavailability and thus achieve optimal efficacy. These four studies illustrate the sequential and incremental nature of drug development research and what is meant by the concept of bioequivalence.