(M-107) Feasibility of predicting regional lung exposure from systemic pharmacokinetic data of generic orally inhaled drug products (OIDPs) via population pharmacokinetic and non-compartmental approaches

Yongzhen Zhang – College of Pharmacy – University of Florida; Xindi Shan – University of Florida; Günther Hochhaus – University of Florida; Jürgen Bulitta – University of Florida

Objectives: OIDPs are essential for managing chronic obstructive pulmonary disease and asthma, which are major causes of respiratory morbidity. Establishing bioequivalence (BE) for these locally acting drugs remains challenging, as methods should be able to assess potential differences in regional lung deposition, the delivered dose and other performance tests. We aimed to assess the ability of an integrated physiologically based pharmacokinetics (PBPK), population pharmacokinetic (popPK) modeling, and non-compartmental analysis (NCA) approach to characterize differences between various dry powder inhaler (DPI) formulations of fluticasone propionate (FP).

Methods: We determined whether systemic PK data of FP are sensitive to differences in regional lung deposition, dissolution rate, and dose between test and reference formulations. For each scenario, 50 to 200 virtual datasets with 48 subjects each were generated by Monte Carlo simulations based on a PBPK model that adapted equations from Mimetikos Preludium (Emmace Consulting, Sweden). This PBPK model included 23 lung generations with between subject variability (BSV) of the deposited dose in each generation. We varied formulation properties (particle size distribution, solubility, permeability), and bioanalytical assay properties. Virtual datasets were analyzed by NCA and popPK models that had different drug dissolution kinetics and included or lacked mucociliary clearance in central lung. The sensitivity of the peak plasma concentration (Cmax) and of area under curve (AUC) metrics (including partial AUC metrics) to characterize differences in regional lung deposition and absorption from different FP formulations was evaluated. We systematically varied the BSV of the regional lung deposition fractions for the 23 lung generations (with CVs from 15 to 100%) to match the observed variability of NCA PK parameters for FP DPIs in humans.[1-3]

Results: The popPK estimated fractions of drug absorption from peripheral lung matched the PBPK-simulated formulation differences in peripherally absorbed drug well under all scenarios (accuracy: ±1%; precision: ±2.5%). Differences in central lung deposition and absorption were more difficult to estimate via popPK, since absorption from central lung only accounted for < 10% of total pulmonary absorption. Both Cmax and partial AUC metrics were sensitive to regional lung deposition. A change in MMAD from 4.5 µm to 3.0 µm increased Cmax by 60% and AUC0–1h by 58%. CVs of 30 and 40% for the 23 lung deposition fractions yielded CVs of 27 to 37% for Cmax, of 27 to 37% for AUC0-1h, and of 25 to 33% for AUC0-24h.

Conclusions: This integrated PBPK, popPK, and NCA approach provided meaningful insights into regional pulmonary drug exposure based on systemic PK data. Peripheral lung deposition was reliably characterized by popPK, Cmax, and partial AUC metrics. Due to rapid mucociliary clearance and slow absorption from central lung, formulation differences in central lung were more difficult to estimate. These findings highlight that partial AUC metrics and popPK may effectively complement traditional PK endpoints (i.e., Cmax and AUC) in supporting alternative BE methodologies, particularly when integrated with mechanistic lung PBPK simulations.

Citations: [1] Goyal N, and Hochhaus G. Demonstrating Bioequivalence Using Pharmacokinetics: Theoretical Considerations Across Drug Classes. Respiratory Drug Delivery 2010. 1:261–272.
[2] Drescher SK, Jiao Y, Chen M-J, Kurumaddali A, Shao J, Hochhaus G, and Bulitta JB. Central and Peripheral Lung Deposition of Fluticasone Propionate Dry Powder Inhaler Formulations in Humans Characterized by Population Pharmacokinetics. Pharm Res 2023. 40:1177-1191.
[3] Hochhaus G, Chen MJ, Kurumaddali A, Schilling U, Jiao Y, Drescher SK, Amini E, Berger SM, Kandala B, Tabulov C, Shao J, Seay B, Abu-Hasan MN, Baumstein SM, Winner L, Shur J, Price R, Hindle M, Wei X, Carrasco C, Sandell D, Oguntimein O, Kinjo M, Delvadia R, Saluja B, Lee SL, Conti DS, and Bulitta JB. Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate? AAPS J 2021. 23:48.

Keywords: Orally inhaled drug products; Pulmonary bioequivalence; lung PBPK