title: Batch-to-batch pharmacokinetic variability confounds current bioequivalence regulations: A dry powder inhaler randomized clinical trial.
abstract: 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.
authors.affiliation: Oriel Therapeutics, Inc, Berkeley, California, USA.
authors.forename: E
authors.initials: E
authors.lastname: Burmeister Getz
authors.affiliation: KJC Statistics, Stockport, Cheshire, UK.
authors.forename: K J
authors.initials: KJ
authors.lastname: Carroll
authors.affiliation: Novartis Pharma, Basel, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Jones
authors.affiliation: University of California, San Francisco, California, USA.
authors.forename: L Z
authors.initials: LZ
authors.lastname: Benet
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001993:Bronchodilator Agents; D018592:Cross-Over Studies; D058995:Dry Powder Inhalers; D005260:Female; D000068297:Fluticasone-Salmeterol Drug Combination / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D001993:Bronchodilator Agents; D000068297:Fluticasone-Salmeterol Drug Combination