Effect of length of sampling schedule and washout interval on magnitude of drug carryover from period 1 to period 2 in two-period, two-treatment bioequivalence studies and its attendant effects on determination of bioequivalence.
The relationships between post-dosing blood sampling schedules and length of washout interval on the percent of drug carryover into period 2, in a two-treatment, two-period, crossover bioequivalence study was investigated. Observed simulations were done using a two-compartment model with a beta half-life of 100 h, sampling to 200 and 300 h, followed by 1 to 4 washout half-lives. These data were compared with simulations with sampling for 200 and 300 h and no carryover between periods (i.e. true data) and used to establish the per cent carryover. Pseudo-observed concentration period 2 data were also generated for an experimental amiodarone bioequivalence study by adding either 5%, 10% or 50% of the period 2 C(max) value to the observed concentrations of selected subjects (i.e. those with longest half-lives) to give a pseudo-plasma concentration profile. Further investigation via simulation was done by including or excluding subjects with time 0 concentrations of 1%-10% of period 2 C(max). The simulated data indicated that up to a 3% carryover of AUC into the second period of a bioequivalence study had no effect on the power of the 90% CI for AUC and C(max). For amiodarone, second period pre-dose drug concentrations equal to as much as 50% of the observed period 2 C(max) value had less effect on the 90% CI (i.e. compared with the true data) for AUC and C(max) than did subject deletion.
Dhariwal
Kuldeep
K
Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD 20857, USA.
Jackson
Andre
A
D000293:Adolescent; D000328:Adult; D000638:Amiodarone / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D003198:Computer Simulation; D018592:Cross-Over Studies; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008954:Models, Biological; D009010:Monte Carlo Method; D011336:Probability; D013810:Therapeutic Equivalency; D013997:Time Factors
D000638:Amiodarone