Validation of a General <i>In Vitro</i> Approach for Prediction of Total Lung Deposition in Healthy Adults for Pharmaceutical Inhalation Products

Olsson, Bo; Borgström, Lars; Lundbäck, Hans; Svensson, Mårten

doi:10.1089/jamp.2012.0986

Cited by 117 publications

(77 citation statements)

References 17 publications

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“…In vitro-in vivo correlation (IVIVC) is critical if in vitro methods are to be used to predict in vivo performance, e.g., total lung deposition (4). To predict clinical outcomes, however, realistic test conditions with regard to the patient are necessary, e.g., the realistic oropharyngeal geometry for the testing apparatus, matching the inspiratory flow rate to a wide range of different patients (children to adults; different types and extent of lung disease) and consideration of how devices are used clinically, e.g., with a spacer.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Testing for Orally Inhaled Products: Developments in Science-Based Regulatory Approaches

Forbes

Bäckman

Christopher

et al. 2015

AAPS J

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Abstract. This article is part of a series of reports from the "Orlando Inhalation Conference-Approaches in International Regulation" which was held in March 2014, and coorganized by the University of Florida and the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS). The goal of the conference was to foster the exchange of ideas and knowledge across the global scientific and regulatory community in order to identify and help move towards strategies for internationally harmonized, science-based regulatory approaches for the development and marketing approval of inhalation medicines, including innovator and second entry products. This article provides an integrated perspective of case studies and discussion related to in vitro testing of orally inhaled products, including in vitro-in vivo correlations and requirements for in vitro data and statistical analysis that support quality or bioequivalence for regulatory applications.

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Section: Introductionmentioning

confidence: 99%

In Vitro Testing for Orally Inhaled Products: Developments in Science-Based Regulatory Approaches

Forbes

Bäckman

Christopher

et al. 2015

AAPS J

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“…In contrast, multiple other studies are pursuing an experimental approach that allows for reproduction of the full inspiratory profile together with constant flow through a cascade impactor using a mixing inlet arrangement. (74,75,99) Additional studies are needed to evaluate the use of a constant representative flow rate calculated as AVG(PIFR, Mean) vs. reproducing different inspiratory profiles for in vitro aerosol size characterization and predictions of lung dose.…”

mentioning

confidence: 99%

Validating Whole-Airway CFD Predictions of DPI Aerosol Deposition at Multiple Flow Rates

Longest

Tian

Khajeh-Hosseini-Dalasm

et al. 2016

Journal of Aerosol Medicine and Pulmonary Drug Delivery

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Background: The objective of this study was to compare aerosol deposition predictions of a new whole-airway CFD model with available in vivo data for a dry powder inhaler (DPI) considered across multiple inhalation waveforms, which affect both the particle size distribution (PSD) and particle deposition. Methods: The Novolizer DPI with a budesonide formulation was selected based on the availability of 2D gamma scintigraphy data in humans for three different well-defined inhalation waveforms. Initial in vitro cascade impaction experiments were conducted at multiple constant (square-wave) particle sizing flow rates to characterize PSDs. The whole-airway CFD modeling approach implemented the experimentally determined PSDs at the point of aerosol formation in the inhaler. Complete characteristic airway geometries for an adult were evaluated through the lobar bronchi, followed by stochastic individual pathway (SIP) approximations through the tracheobronchial region and new acinar moving wall models of the alveolar region. Results: It was determined that the PSD used for each inhalation waveform should be based on a constant particle sizing flow rate equal to the average of the inhalation waveform's peak inspiratory flow rate (PIFR) and mean flow rate [i.e., AVG(PIFR, Mean)]. Using this technique, agreement with the in vivo data was acceptable with <15% relative differences averaged across the three regions considered for all inhalation waveforms. Defining a peripheral to central deposition ratio (P/C) based on alveolar and tracheobronchial compartments, respectively, large flow-rate-dependent differences were observed, which were not evident in the original 2D in vivo data. Conclusions: The agreement between the CFD predictions and in vivo data was dependent on accurate initial estimates of the PSD, emphasizing the need for a combination in vitro-in silico approach. Furthermore, use of the AVG(PIFR, Mean) value was identified as a potentially useful method for characterizing a DPI aerosol at a constant flow rate.

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“…For instance, the web application might be used to probe if potential differences in the in vitro behavior (e.g., dissolution rate differences, pulmonary dose, or cascade impactor profiles) between T and R product affect the bioequivalence if sufficient data on in vitro and in vivo correlation are available for the user to allow predicting the effect of such in vitro differences on PK. An in vitro and in vivo relationship between cascade impactor data and pulmonary deposited dose has been recently reported (30). In general, more efforts need to be invested into establishing of in vitro/in vivo correlations before physiological PK models will be reliable predictors of the outcome of bioequivalence studies.…”

Section: Discussionmentioning

confidence: 99%

“…Scenarios where both T and R FP inhalers represented the FP Diskus inhaler were simulated in a crossover design for 10,20,30,40,50,60, and 70 subjects. These scenarios, which can be interpreted as testing different lots of the R product against each other, were used to determine the sample size that is needed to achieve a statistical power of 90% to conclude bioequivalence when T and R are identical.…”

Section: Series 1: Two Identical Productsmentioning

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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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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Validation of a General In Vitro Approach for Prediction of Total Lung Deposition in Healthy Adults for Pharmaceutical Inhalation Products

Cited by 117 publications

References 17 publications

In Vitro Testing for Orally Inhaled Products: Developments in Science-Based Regulatory Approaches

In Vitro Testing for Orally Inhaled Products: Developments in Science-Based Regulatory Approaches

Validating Whole-Airway CFD Predictions of DPI Aerosol Deposition at Multiple Flow Rates

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

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