Study Design

An open-label, randomized crossover design is usually chosen if more than one dose-level is included in the study. The number of subjects participating in the study should be based on data regarding variability from earlier studies. Study drug should be administered according to the chosen dosage regimen, based on the currently available pharmacokinetic and pharmacodynamic information. Concomitant food and drug intake during the investigational days is usually restricted, and the drug is administered in the fasting state or the drug and food intake is separated by a time-interval of approximately two to four hours.

Blood samples for drug analysis should be collected to adequately describe the attainment of steady state (samples collected immediately prior to the next dose intake during 3-4 dosing intervals, i.e., trough concentrations) and the full plasma/serum drug concentration profile during one, usually the last, dosing interval at steady state. It is recommended that the blood sampling is continued to adequately describe the terminal phase after the last dose intake, e.g., the collection be continued up to at least four terminal tV of the drug and/or active metabolites.

Investigational periods are usually separated by an adequate washout interval (>5tV) to ensure that elimination is complete before a second-dose regimen is initiated. Alternate designs, where the subsequent study periods are immediately initiated, without a washout period, should be carefully considered, and only be used if the lack of time-dependent changes in the pharmacokinetics of the drug has been established. An alternate approach is to combine a single-dose and the repeated-dosing regimen in the same subject. In that case, adequate blood sampling should be performed after the first dose, and the repeated dosing is started immediately after the last blood sample of the single-dose period, and blood sampling is performed when steady state has been attained, as described above.

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