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The usefulness of a limited sampling method (LSM) to determine the bioequivalence of highly variable drugs with long half-lives was investigated. The LSM uses multiple linear regression of observed drug plasma concentrations versus area under the curve (AUC) or C(max) (peak plasma concentration) to obtain a best set of coefficients, concentration times and intercept based upon the regression coefficient, R(2), to predict the selected pharmacokinetic parameter (i.e. AUC or C(max)). The LSM, used successfully in clinical settings, has also been suggested for data analysis of in vivo bioequivalence studies. Because the method has not yet been thoroughly tested under many conditions likely to be encountered in bioequivalence studies, a further investigation of the method's applicability to bioequivalence determination was undertaken. In the present study, training and test data sets incorporating various levels of intrasubject variability in clearance (CL) with different ratios for fraction absorbed (Fa) of test and reference drug formulations were used to further evaluate the applicability of the limited sampling method (LSM) to the evaluation of bioequivalence for drugs with long half-lives of elimination. Both simulated (a one-compartment pharmacokinetic (PK) model with first-order elimination) and experimental data were used in the study. The results indicated that the determination of bioequivalence using the LSM was significantly influenced by the ratio of Fa(test)/Fa(reference) and by the level of intrasubject error (variability) in CL. Therefore, use of the LSM to determine bioequivalence of drugs with long half-lives and highly variable in CL seems suitable only for formulations that have point estimates of Fa(test)/Fa(reference) within the range of 0.9-1.10. Because the Fa ratio range would have to be verified through use of observed data obtained from a pilot study, the practical utility of the LSM in the determination of bioequivalence would be severely limited.

In bioequivalence studies, the first blood or plasma sample taken after dosing sometimes yields a higher assayed drug concentration than any samples drawn thereafter. This circumstance ('first C(max)' or 'FCM'), is usually considered undesirable, since a 'true C(max)' requires that the sampled concentrations immediately preceding and immediately after the 'true C(max)' concentration should be lower than the 'true C(max)' concentration. Therefore, a question arises whether the presence of FCM in a bioequivalence study affects the power and accuracy of the computed statistical confidence interval (CI) for C(max). This study examines what effect, if any, the inclusion or exclusion of FCM data has on the statistical power and accuracy of the 90% CI computed for C(max) in the analysis of results for in vivo bioequivalence studies. Actual experimental study data as well as data from simulated studies were evaluated. In the simulated studies, up to half of the study subjects exhibited FCM, and various levels of intrasubject variability were incorporated into the absorption rate constant. The two one-sided tests procedure was used to assess equivalence of C(max) for the test versus reference products when either a complete set of C(max) data was analysed (designated 'CC(max)'), which included subjects with FCM profiles; or a truncated set of data was analysed (designated 'TC(max)'), that excluded all subjects with FCM. The results showed that the CC(max) metric had greater statistical power and comparable or greater statistical accuracy compared to TC(max) for both bioequivalent and non-bioequivalent drug product formulations. Even when up to 50% of the study subjects had FCM, the power and accuracy of the 90% CI for rate of absorption (i.e. C(max)) was not significantly affected. Consequently, this study shows that, in the analysis of data from conventional in vivo bioequivalence studies, the inclusion of 50% of the subjects exhibiting FCM does not greatly impact the statistical results obtained for C(max). Published in 2000 by John Wiley & Sons, Ltd.

Two nonlinear pharmacokinetic models were simulated to investigate the relationship between single and multiple dose bioequivalency parameters for drugs such as phenytoin and propranolol which exhibit either saturable elimination kinetics or a capacity limited first pass effect. Mean Tmax, Cmax and area under the plasma-concentration time curve values from 0 to infinity (AUC 0-infinity) were compared after a single and multiple dose(s) of a test or reference drug. The aim was to determine if there were systematic changes in the limits of the single dose confidence interval at steady state that would limit the usefulness of confidence intervals following a single dose in accurately predicting bioavailability following multiple dosing. The 90 per cent confidence interval expressed as a percentage of the reference mean for Tmax, Cmax, and AUC 0-infinity showed model dependent changes from single to multiple dosing in response to the level of data error and changes in absorption. Changes in clearance also seemed to have a marked effect on the observed limits of the single and multiple dose confidence intervals especially for Cmax which showed a characteristic change in the intervals as a function of the clearance ratio. The model used to describe phenytoin had confidence intervals for Cmax and AUC 0-infinity from single to multiple dosing that were similar to that seen for the experimental data. However, the model predictions for Tmax confidence intervals following single and multiple dosing was at variance with the experimental data for formulations A and B.