Pharmacokinetic characteristics for extent of absorption and clearance in drug/drug interaction studies.

Many aspects of drug/drug interaction studies, including aspects of the design, choice of pharmacokinetic characteristics, and statistical analysis can be adapted from bioequivalence studies [Steinijans et al. 1991]. However, an important difference between drug/drug interaction studies and bioequivalence studies is that two formulations in bioequivalence studies generally do not differ with respect to the clearance of the drug under investigation, but in drug/drug interaction studies an effect of one drug on the clearance of another drug is not only possible, but the likely mechanism of interaction for many classes of drugs. Thus, while in bioequivalence studies two formulations are conventionally compared with respect to the rate and extent of absorption of the drug, in drug/drug interaction studies equivalence has to be shown with respect to not only the rate and extent of absorption, but also, and in particular, with respect to the clearance of the drug. Consequently, in drug/drug interaction studies the area under the curve is not a pure characteristic of the extent of absorption, but a composite characteristic of extent of absorption and clearance. This should be taken into account when interpreting the results of drug/drug interaction studies. Apart from standard characteristics such as Cmax and AUC used in bioequivalence studies, for drug/drug interaction studies we suggest the elimination half-life as a characteristic for the clearance, and the ratio of AUC and the elimination half-life as a characteristic for the extent of absorption of a drug.