Pharmacokinetic Models for Inhaled Fluticasone Propionate and Salmeterol Xinafoate to Quantify Batch-to-Batch Variability.
AAPS J
; 26(3): 56, 2024 04 26.
Article
in En
| MEDLINE
| ID: mdl-38671158
ABSTRACT
Advair Diskus is an essential treatment for asthma and chronic obstructive pulmonary disease. It is a dry powder inhaler with a combination of fluticasone propionate (FP) and salmeterol xinafoate (SX). However, the pharmacokinetics (PK) batch-to-batch variability of the reference-listed drug (RLD) hindered its generic product development. This work developed the PK models for inhaled FP and SX that could represent potential batch variability. Two batches each of the reference and the test product (R1, R2, T1, T2) of Advair Diskus (100 µg FP/50 µg SX inhalation) were administered to 60 healthy subjects in a 4-period, 4-sequence crossover study. The failure of the bioequivalence (BE) between R1 and R2 confirmed the high between-batch variability of the RLD. Non-linear mixed effect modeling was used to estimate the population mean PK parameters for each batch. For FP, a 2-compartment model with a sequential dual zero-order absorption best described the PK profile. For SX, a 2-compartment model with a first-order absorption model best fit the data. Both models were able to capture the plasma concentration, the maximum concentration, and the total exposure (AUCinf) adequately for each batch, which could be used to simulate the BE study in the future. In vitro properties were also measured for each batch, and the batch with a higher fraction of the fine particle (diameter < 1 µm, < 2 µm) had a higher AUCinf. This positive correlation for both FP and SX could potentially assist the batch selection for the PK BE study.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Bronchodilator Agents
/
Therapeutic Equivalency
/
Cross-Over Studies
/
Dry Powder Inhalers
/
Fluticasone-Salmeterol Drug Combination
/
Models, Biological
Limits:
Adult
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
AAPS J
Journal subject:
FARMACOLOGIA
/
TERAPIA POR MEDICAMENTOS
Year:
2024
Type:
Article
Affiliation country:
United States