047: Population Pharmacokinetic Modeling to Establish Exposure Equivalence Between Two Formulations of Albuterol Dry Powder Inhaler

Statement of Purpose: BACA RESPICLICK® (albuterol sulphate) is a multi-dose dry powder inhaler (MDPI), prescribed to treat or prevent reversible obstructive airway disease and exercise induced bronchospasm in people who have reversible airway obstruction. The Clinical program for BACA was performed with supplies manufactured at 2 sites (site A for Phase 1 and B for subsequent clinical studies). The marketed product was planned to be manufactured only from Site A since Site B was suddenly discontinued. The purpose of this modeling and simulation exercise was to investigate PK comparability of batches from the 2 sites utilizing PK data previously collected during the clinical program.

Description of Methods & Materials: To support demonstration of therapeutic equivalence between two formulations via PK similarity, population pharmacokinetic (PopPK) modeling and simulation analysis was applied to available in vivo PK data from the two manufacturing sites. The PK data from Site A formulation was from a Phase 1 study in adults with asthma to characterize safety and efficacy of several drug administrations producing the desired cumulative exposure over 24 h. While PK data from Site B formulation was from a Phase 3 study in adults with asthma, a patient subset underwent PK sampling on first day of dosing. A total of 38 patients with 924 plasma samples at various time points were included in the analysis. A PopPK analysis was performed using nonlinear mixed-effects modeling approach with NONMEM. First-order conditional estimation method with interaction and user-defined subroutine (ADVAN4 TRANS4) was used to obtain estimates for the PopPK model parameters including population mean values, interindividual variability and residual variability. Covariate modeling was performed using the stepwise forward addition and backward elimination method.

Data & Results: Among the various models tested, a 2-compartment model with first-order absorption and lag time was best for characterizing the albuterol PK. Body weight was included a priori using allometric scaling in the PK parameters of central clearance (CL), central volume of distribution (V2), peripheral clearance (Q) and peripheral volume of distribution (V3). To fit the model, the estimates for Q and V3 were fixed to values obtained from the best fit. Formulation, which was the main covariate of interest, was not significant. Diagnostic plots and the visual predictive checks supported the adequacy of the model. Post-hoc PK parameters were calculated using the model and exposures of single doses from the two formulations simulated (Figure 1).

Interpretation, Conclusion or Significance: Bioequivalence criteria were used to assess comparability. Upon evaluating post-hoc PK parameters and simulated exposures of the two formulations, there was around 50% difference in both PK parameters and exposure (Figure 1); however it was not possible to identify covariates as significant factors to explain the source of variability in the exposure, the difference in study design and quality of data likely affected ability to estimate PK parameters. Based on these analyses it was concluded that this cross study approach was not sufficient to show PK comparability, therefore a relative bioavailability study would be necessary.

Disclosures: