Search

We previously demonstrated pharmacokinetic differences among manufacturing batches of a US Food and Drug Administration (FDA)-approved dry powder inhalation product (Advair Diskus 100/50) large enough to establish between-batch bio-inequivalence. Here, we provide independent confirmation of pharmacokinetic bio-inequivalence among Advair Diskus 100/50 batches, and quantify residual and between-batch variance component magnitudes. These variance estimates are used to consider the type I error rate of the FDA's current two-way crossover design recommendation. When between-batch pharmacokinetic variability is substantial, the conventional two-way crossover design cannot accomplish the objectives of FDA's statistical bioequivalence test (i.e., cannot accurately estimate the test/reference ratio and associated confidence interval). The two-way crossover, which ignores between-batch pharmacokinetic variability, yields an artificially narrow confidence interval on the product comparison. The unavoidable consequence is type I error rate inflation, to ∼25%, when between-batch pharmacokinetic variability is nonzero. This risk of a false bioequivalence conclusion is substantially higher than asserted by regulators as acceptable consumer risk (5%). [ABSTRACT FROM AUTHOR]

Current pharmacokinetic (PK) bioequivalence guidelines do not account for batch-to-batch variability in study design or analysis. Here we evaluate the magnitude of batch-to-batch PK variability for Advair Diskus 100/50. Single doses of fluticasone propionate and salmeterol combinations were administered by oral inhalation to healthy subjects in a randomized clinical crossover study comparing three different batches purchased from the market, with one batch replicated across two treatment periods. All pairwise comparisons between different batches failed the PK bioequivalence statistical test, demonstrating substantial PK differences between batches that were large enough to demonstrate bio- inequivalence in some cases. In contrast, between-replicate PK bioequivalence was demonstrated for the replicated batch. Between-batch variance was ∼40-70% of the estimated residual error. This large additional source of variability necessitates re-evaluation of bioequivalence assessment criteria to yield a result that is both generalizable and consistent with the principles of type I and type II error rate control. [ABSTRACT FROM AUTHOR]

The ionic title complex, bis(mu-ethylene glycol)-kappa(3)O,O':O';kappa(3)O:O,O'-bis[(ethylene glycol-kappa(2)O,O')(ethylene glycol-kappaO)sodium] bis(ethylene glycolato-kappa(2)O,O')copper(II), [Na(2)(C(2)H(6)O(2))(6)][Cu(C(2)H(4)O(2))(2)], was obtained from a basic solution of CuCl(2) in ethylene glycol and consists of discrete ions interconnected by O-H...O hydrogen bonds. This is the first example of a disodium-ethylene glycol complex cation cluster. The cation lies about an inversion center and the Cu(II) atom of the anion lies on another independent inversion center.