Variation of the peak concentration following single and repeated drug administrations in investigations of bioavailability and bioequivalence.

Contrasts were evaluated for the maximum blood or plasma concentration (C(max)) of drugs measured after repeated and single oral administrations. Variances of C(max) were calculated and also simulated for a single drug as well as the comparison of two formulations, i.e., for the analysis of investigations of both bioavailability and bioequivalence. The coefficient of variation (CV) of C(max) was higher in the steady state than after a single drug administration when the variability of the disposition rate constant (k) was substantially larger than that of the absorption rate constant (k(a)). In turn, the CV of C(max) was substantially lower following repeated than after single drug administration when the variability of k(a) dominated that of k. The latter condition often prevails in practice since the relative variation of absorption rates generally substantially exceeds that of clearance (the latter being proportional to k). The statistical insensitivity is superimposed on the low kinetic sensitivity exhibited by C(max) following repeated drug administrations. Consequently, bioequivalence trials conducted in the steady state generally permit a declaration of equivalence even between drug products that have very different absorption rates.