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'Highly variable drugs' have been defined as those drugs for which the within-subject variability (WSV) equals or exceeds 30% of the maximum concentration (C m a x ) and/or the area under the concentration versus time curve (AUC). Despite the fact that highly variable drugs are generally safe with flat dose response curves, the bioequivalence of their formulations is a problem because the high variability means that large numbers of subjects are required to give adequate statistical power. Highly variable drug products are poor quality formulations where high within-formulation variability (e.g. tablet to tablet variability) poses a problem rather than high innate WSV of the drug itself. A further problem caused by high variability is that a subset of the population may respond differently to the two formulations producing a significant subject x formulation interaction. Practical examples are shown using replicate designs. The methods proposed to deal with the problems posed by highly variable drugs include: (i) Drug regulatory jurisdictions states that the 90% confidence interval (90% CI) around the test to reference geometric mean ratio (GMR) is required to fit with bioequivalence acceptance limits of 0.8 -1.25 for both C m a x and AUC. The WSV for single point estimation of C m a x is often greater than that for AUC. One strategy therefore is not to require a 90% CI for Cmax of drugs that do not exhibit a toxicity associated with C m a x and merely require the GMR to fall within the acceptance limits. (ii) To arbitrarily broaden the bioequivalence acceptance limits. For example, to permit a sponsor to justify the use of wider limits e.g the 90% CI around the GMR of C m a x values might be required to fit within acceptance limits of 0.75 - 1.33 or even 0.70 -1.42. (iii) A more systematic approach would be to broaden the acceptance limits by scaling to either the residual variance from a 2-period design or to the WSV of the reference product in a replicate design. Subsequent evaluations of scaling procedures have demonstrated that smaller numbers of subjects are required for bioequivalence studies on formulations of highly variable drugs. A disadvantage of scaling is that the method is less sensitive to differences between the means compared with unsealed treatment, such that the GMR may prove to be unacceptably low or high. This possibility has let to a suggestion that the GMR must fall within acceptance limits of 0.8 - 1.25 in scaled treatments. (iv) A similar method is to scale the metric rather than the acceptance limits. This method was proposed by the United States' Food and Drug Administration in the context of Individual bioequivalence, but may also be applied (v) to average bioequivalence. (vi) To carry out bioequivalence studies at steady state whenever a multiple dose regimen is ethically acceptable for healthy volunteers. This solution is based on the observation that high variability in a single dose study tends to be dampened at steady state, thus increasing statistical power. Drug regulators have not favored this approach on the grounds that bioequivalence testing should be based on the most discriminating test possible. (vii) Finally the use of metabolite data has been proposed since in many (but by no means all) cases, metabolite is less highly variable than that of the parent drug. This subject remains controversial except when the administered substance is a prodrug which converted by metabolism into the active drug.

Objective: To examine the effect of the exposure measures C m a x (peak exposure), AUC E (early exposure) and AUC (total exposure) on the bioequivalence of two sustained release formulations of bupropion (i) in the fastedstate and (ii), after a high fat meal. The ratio C m a x /AUC (sensitive to rate of absorption) was also evaluated. Methods: A two-formulation, two-sequence, four-period replicate design study was performed in 29 healthy men and women after an overnight fast. Similarly, a two-period study was performed in 20 healthy men and women after ingestion of a high fat breakfast. Plasma concentrations of bupropion were measured by HPLC/MS/MS and the data were analyzed (SAS PROC MIXED) by the Schuirmann-Sattersthwaite procedure (four-period study) and by the two one-sided test procedure (SAS PROC GLM) (two-period study). Standard bioequivalence limits of 80 - 125% were applied to all measures including AUC E and C m a x /AUC. Results: In the fasting study, the mean plasma concentration vs. time curves from (including over the first 24 hours) following the two administrations of each formulation were similar although there was a significant difference in median t m a x between formulations. This may have contributed to a low estimate of geometric mean ratio (GMR) for AUC E (69%) which was judged to have failed bioequivalence. There was also rather low GMRs for C m a x (88%) and C m a x /AUC (89%) but these measure passed because the within-subject variabilities (WSV) were relatively low (19.6% and 11.2%, respectively). Total exposure (AUC l a s t ) met standard bioequivalence limits of 80 - 125% easily. The raw data from the two-period fed also showed differences in the shapes of the plasma concentration vs. time curves around C m a x although there was no difference in median t m a x . The WSV at median t m a x was high (34%) as was the GMR (117%) for AUC E which failed, as did C m a x (GMR 112%). The WSV was very high at early time points before settling into a "plateau" at about 11%. Discussion: There was no "spike" in the plasma concentration vs. time profiles up to median t m a x or beyond and therefore there was no evidence of dose dumping of the test formulation in either fasted or fed states. No bioequivalence limits have been set for AUC E but the application of standard BE limits of 80 to 125% meant that the fed study was clearly underpowered given the high WSV at early time points. Conclusions: More research is needed on the interesting concept of early exposure. The WSV is often high at median t m a x which means that standard bioequivalence limits of 80 - 125% may be inappropriate. Despite the lack of dose dumping, application of AUC E to the fasting study, would have resulted in failure to declare bioequivalence since the GMR for this measure was only 69.5%. Application of a 90% confidence interval to AUC E to the fed study would have required powering to cope with the fact that this measure was highly variable.

The role of metabolites in bioequivalence studies has been a contentious issue for many years. Many papers have published recommendations for the use of metabolite data based on anecdotal evidence from the results of bioequivalence studies. Such anecdotal evidence has validity, but the arguments lack weight because the "correct" answers are always unknown. A more promising area of exploration is recommendations based on simulated bioequivalence studies for which the "correct" answers are known, given the assumptions. A review of the literature, however, reveals scant evidence of attempts to apply to real data the pharmacokinetic principles on which the recommendations from simulated studies relied. We therefore applied those principles (based on estimates of intrinsic clearance after oral administration of the parent drug) to four bioequivalence studies from our archives, in which the parent drug and at least one metabolite were monitored. In each case, the outcome is discussed in the context of the complexity of the metabolic processes that impact on the parent drug and the metabolite(s) during the first passage from the intestinal lumen to the systemic circulation. Our observation is that no simple generalization can be made such that each drug/metabolite combination must be examined individually. Our recommendation, however, is that in the interests of safety, bioequivalence decision-making should be based on the parent drug whenever possible.

Cardiac dysrhythmias are a diverse group of disorders and many are associated with significant morbidity and mortality. Because their recent therapeutic management has not been adequately described, this study details the antiarrhythmia drugs that were dispensed to patients who had not received therapy in the preceding two years, and it evaluates the potential indications for the drugs as well as whether the therapy is consistent with the recommended procedures.Patients who were dispensed a [Vaughn Williams?] class I or class III antiarrhythmia drug in 1993 or 1994, but not during the two previous years, were identified from the Saskatchewan prescription drug datafile. The drug data were linked with other information that was obtained from the provincial administrative health care utilization datafiles. Further clinical data were obtained from hospital charts and, to a limited extent, from physicians' records.Most patients were elderly (median age of 70 years) and were men (58.0%), although sotalol was prescribed more frequently to women (53.0%). A potential indication was identified for 63.8% of the patients and, of these, the most common was atrial fibrillation (65.3%). Almost half of the patients had a history of myocardial infarction, congestive heart failure or cardiomyopathy, and one-quarter of those were treated with amiodarone.While it is not possible to prove a direct link, the results of the present study are broadly consistent with the 'evidence-based' lessons of the Cardiac Arrhythmia Suppression Trial and other studies. The increasing use of propafenone, however, may indicate a lack of appreciation for the fact that, as a class IC drug, there is at least the potential for an adverse outcome when propafenone is used in patients with structural heart disease.

This study demonstrated that the mere fact that two multisource drug formulations are bioequivalent with the same reference formulation does not guarantee that they are bioequivalent with each other. The present unscaled bioequivalence limits (BEL) of 0.80 to 1.25 permitted far greater deviation from unity of the geometric mean ratio (GMR) for multisource formulations with low within-subject variabilities than for drugs with high variabilities. Scaling the BEL drastically reduced the maximum deviation from unity of GMRs for two multisource formulations each bioequivalent with the same reference product while broadening the BEL for highly variable drugs. It was concluded that scaling was consistent with the principle of switchability for toxic drugs with low variability and for safe, highly variable drugs. On the other hand, scaling need not be applied to safe drugs with low variability and should not be applied in the unusual case of a highly variable drug with a narrow therapeutic range.