Relative Bioavailability of Inhaled Fluticasone Propionate and Salmeterol – is Population Pharmacokinetic Modelling a Relevant Alternative to a Non-Compartmental Approach?

Johan Rosenborg,1 Per Bäckman,2 Thomas Bengtsson,1 Scott Haughie3 1StatMind AB, Lund, Sweden; 2Emmace Consulting AB, Lund, Sweden; 3Viatris, Mylan Pharma UK Ltd, Sandwich, UKCorrespondence: Johan Rosenborg, Email [email protected] Per Bäckman, Email [email protected]: Conventional statistical analysis of clinical data based on standard methods suggests that fixed combinations of fluticasone propionate (FP) and salmeterol (SALM) inhaled via Wixela® Inhub® dry powder (test) are therapeutically and pharmacokinetically equivalent to Advair® Diskus® (reference). Assessment of bioequivalence, test/reference, based on empirical population pharmacokinetic modelling was compared with published outcomes based on a non-compartmental analysis (NCA) approach.Methods: Three inhalations of FP/SALM were administered to healthy subjects with 7-day washouts via test and reference and delivered doses of 100/50, 250/50, or 500/50 μg (total matched doses of 300/150, 750/150, or 1500/150 μg) in studies 1, 2, and 3, respectively. Empirically derived pharmacokinetic structural models, considering random effects of subject (FP, SALM) or study (SALM), emulating linear first-order input, disposition and elimination were fitted to plasma concentrations with a frequentist approach, by study/dose of FP, and across studies of SALM, using product as categorical covariate. Bioequivalence was assessed using individually predicted relative systemic extent of bioavailability (F4_rel) and ratio of individually predicted peak concentrations (Cmax).Results: The models adequately described plasma concentration versus time data. Descriptive statistics and bioequivalence assessments (90% confidence interval generally within 0.80– 1.25) reflected NCA-derived outcomes.Conclusion: Model- and NCA-based approaches to assess bioequivalence were consistent. However, a frequentist parametric approach that fully utilizes the population analysis potential and mechanistically predicts regional pulmonary deposition of FP and SALM would require a demographically more heterogenous data set and analysis including additional outcomes of parenteral and oral administration to discriminate presystemic from systemic disposition.Keywords: fluticasone propionate, salmeterol, inhalation, pharmacokinetics