Advantages of a steady-state crossover design in assessment of bioequivalence of highly variable drugs: propafenone

Bioequivalence of highly variable drugs (i.e. high clearance drugs) is difficult to assess by means of conventional study designs. This paper reports a study on bioequivalence of two immediate release formulations of the antiarrhythmic drug propafenone in which a steady-state crossover design was used. The decision on bioequivalence was made with regard to the data of propafenone. Bioavailability data of the active metabolite, 5-hydroxypropafenone, and circadian pharmacokinetics of both analytes are also discussed. Following 5 days of administration (300 mg twice daily) to 20 volunteers, all parameters measured for estimating bioequivalence (AUC, C max and PTF) were determined for both propafenone and 5-hydroxypropafenone during two consecutive dosage intervals. All target parameters obtained after administration of the test formulation were within the defined limits of bioequivalence when compared to reference for both parent compound and active metabolite for both dosage intervals. Basing on the calculated 90% confidence intervals it can be concluded that the two formulations are bioequivalent. Moreover, the steady-state study design may be applicable to other compounds with similar pharmacokinetic behaviour and seems to be generally advantageous for bioequivalence studies of highly variable drugs.