Pharmacokinetic, pharmacodynamic, efficacy, and safety data from two randomized, double-blind studies in patients with asthma and an in vitro study comparing two dry-powder inhalers delivering a combination of salmeterol 50 μg and fluticasone propionate 250 μg: Implications for establishing bioequivalence of inhaled products

Daley‐Yates, Peter T.; Parkins, David A.; Thomas, Marian J.; Gillett, Benjamin; House, Karen; Ortega, Héctor

doi:10.1016/j.clinthera.2009.02.007

Cited by 49 publications

(31 citation statements)

References 11 publications

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“…Overall, the sensitivity of the PK metrics in evaluating bioequivalence between T and R OIDPs is much higher than observed for the currently recommended clinical studies that are generally not sensitive to varying doses of FP and as consequence will also be unable to show sensitivity toward rate of availability nor regional deposition differences (24)(25)(26).…”

Section: Discussionmentioning

confidence: 88%

“…While AUC and C max are sensitive to detect differences in the pulmonary dissolution rate constant and the central-toperipheral lung deposition ratio, respectively, the predicted sensitivity is somewhat smaller than that for the deposited dose (Fig. 3), but certainly much more sensitive than for clinical studies (24)(25)(26). While the observed sensitivity of AUC and C max to differences in the total lung deposition for FP can be generalized to all inhaled drugs with negligible oral bioavailability, the sensitivity of AUC and C max to differences in the central-to-peripheral lung deposition ratio and the pulmonary dissolution rate constant, respectively, need to be considered more carefully.…”

Section: Discussionmentioning

confidence: 99%

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A Systematic Analysis of the Sensitivity of Plasma Pharmacokinetics to Detect Differences in the Pulmonary Performance of Inhaled Fluticasone Propionate Products Using a Model-Based Simulation Approach

Weber

Hochhaus

2015

AAPS J

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Abstract. The role of plasma pharmacokinetics (PK) for assessing bioequivalence at the target site, the lung, for orally inhaled drugs remains unclear. A validated semi-mechanistic model, considering the presence of mucociliary clearance in central lung regions, was expanded for quantifying the sensitivity of PK studies in detecting differences in the pulmonary performance (total lung deposition, central-toperipheral lung deposition ratio, and pulmonary dissolution characteristics) between test (T) and reference (R) inhaled fluticasone propionate (FP) products. PK bioequivalence trials for inhaled FP were simulated based on this PK model for a varying number of subjects and T products. The statistical power to conclude bioequivalence when T and R products are identical was demonstrated to be 90% for approximately 50 subjects. Furthermore, the simulations demonstrated that PK metrics (area under the concentration time curve (AUC) and C max ) are capable of detecting differences between T and R formulations of inhaled FP products when the products differ by more than 20%, 30%, and 25% for total lung deposition, central-to-peripheral lung deposition ratio, and pulmonary dissolution characteristics, respectively. These results were derived using a rather conservative risk assessment approach with an error rate of <10%. The simulations thus indicated that PK studies might be a viable alternative to clinical studies comparing pulmonary efficacy biomarkers for slowly dissolving inhaled drugs. PK trials for pulmonary efficacy equivalence testing should be complemented by in vitro studies to avoid false positive bioequivalence assessments that are theoretically possible for some specific scenarios. Moreover, a user-friendly web application for simulating such PK equivalence trials with inhaled FP is provided.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

A Systematic Analysis of the Sensitivity of Plasma Pharmacokinetics to Detect Differences in the Pulmonary Performance of Inhaled Fluticasone Propionate Products Using a Model-Based Simulation Approach

Weber

Hochhaus

2015

AAPS J

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“…However even when significant difference in the PK profiles are present when the same doses of a test and reference product are administered, no appreciable clinical differences are observed [19,20]. Hence, PK studies, unlike clinical efficacy studies are more sensitive to identify differences between formulations and assess equivalence.…”

Section: Discussionmentioning

confidence: 99%

Molecular Electrophilicity Index - A Promising Descriptor for Predicting Toxicological Property

Shalini¹,

Tandon²,

Chakraborty³

2017

J Bioequiv Availab

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“…Nonoral drug administration by topical [9], inhalation [10,11], and intranasal [12] routes are common. However, comparative bioavailability studies based on systemic exposure are not always possible.…”

Section: Bioavailabilitymentioning

confidence: 99%

“…However, changes in elimination half-life (t 1/2 ) are measurable and may reflect changes in clearance when apparent volume of distribution is assumed to be constant between dose administrations. Expressing clearance in terms of elimination half-life and volume of distribution (CL = 0.693 × V d /t 1/2 ) and substituting into Equation 10.4 yields…”

Section: Variability In Bioavailability Estimatesmentioning

confidence: 99%

Bioavailability and Bioequivalence

Amore¹

2012

Encyclopedia of Drug Metabolism and Interactions

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From a pharmacokinetic perspective, bioavailability relates systemic exposure to drug absorption, while helping understand mechanisms underlying drug distribution, transport, and metabolism. Bioavailability studies are also designed to demonstrate bioequivalence of test and reference formulations for both new drug and generic drug products. This chapter provides an overview of the interrelated concepts of bioavailability and bioequivalence and their application to characterize human drug disposition. Additionally, for oral drugs, the determinants of bioavailability leading to malabsorption and presystemic elimination by the gut mucosa and liver are described.

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Cited by 49 publications

References 11 publications

A Systematic Analysis of the Sensitivity of Plasma Pharmacokinetics to Detect Differences in the Pulmonary Performance of Inhaled Fluticasone Propionate Products Using a Model-Based Simulation Approach

A Systematic Analysis of the Sensitivity of Plasma Pharmacokinetics to Detect Differences in the Pulmonary Performance of Inhaled Fluticasone Propionate Products Using a Model-Based Simulation Approach

Molecular Electrophilicity Index - A Promising Descriptor for Predicting Toxicological Property

Bioavailability and Bioequivalence

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