iBCS: 4. Application of the Inhalation Biopharmaceutics Classification System to the Development of Orally Inhaled Drug Products.

This is the fourth paper in a series describing an inhalation biopharmaceutics classification system (iBCS), an initiative supported by the Product Quality Research Institute. The paper examines the application of the inhalation Biopharmaceutics Classification System (iBCS) through the drug discovery, development, and postapproval phases for orally inhaled drug products (OIDP) and for the development of generic OIDPs. We consider the implication of the iBCS class in terms of product performance and identify the practical gaps that must be filled to enable the classification system to be adopted into day-to-day practice.

iBCS: 3. A Biopharmaceutics Classification System for Orally Inhaled Drug Products.

In this article, we specify for the first time a quantitative biopharmaceutics classification system for orally inhaled drugs. To date, orally inhaled drug product developers have lacked a biopharmaceutics classification system like the one developed to navigate the development of immediate release of oral medicines. Guideposts for respiratory drug discovery chemists and inhalation product formulators have been elusive and difficult to identify due to the complexity of pulmonary physiology, the intricacies of drug deposition and disposition in the lungs, and the influence of the inhalation delivery device used to deliver the drug as a respirable aerosol.

Central and peripheral lung deposition of fluticasone propionate dry powder inhaler formulations in humans characterized by population pharmacokinetics.

This study aimed to gain an in-depth understanding of the pulmonary fate of three experimental fluticasone propionate (FP) dry powder inhaler formulations which differed in mass median aerodynamic diameters (MMAD; A-4.5 µm, B-3.8 µm and C-3.

Mechanistic modeling of generic orally inhaled drug products: A workshop summary report.

In silico mechanistic modeling approaches have been designed by various stakeholders with the goal of supporting development and approval of generic orally inhaled drug products in the United States. This review summarizes the presentations and panel discussion that comprised a workshop session concentrated on the use of in silico models to predict various outcomes following orally inhaled drug product administration, including the status of such models and how model credibility may be effectively established.

iBCS: 2. Mechanistic Modeling of Pulmonary Availability of Inhaled Drugs versus Critical Product Attributes.

This work is the second in a series of publications outlining the fundamental principles and proposed design of a biopharmaceutics classifications system for inhaled drugs and drug products (the iBCS). Here, a mechanistic computer-based model has been used to explore the sensitivity of the primary biopharmaceutics functional output parameters: (i) pulmonary fraction dose absorbed () and (ii) drug half-life in lumen () to biopharmaceutics-relevant input attributes including dose number (Do) and effective permeability (). Results show the nonlinear sensitivity of primary functional outputs to variations in these attributes.

iBCS: 1. Principles and Framework of an Inhalation-Based Biopharmaceutics Classification System.

For oral drugs, the formulator and discovery chemist have a tool available to them that can be used to navigate the risks associated with the selection and development of immediate release oral drugs and drug products. This tool is the biopharmaceutics classification system (giBCS). Unfortunately, no such classification system exists for inhaled drugs.

Systematic Evaluation of the Effect of Formulation Variables on In Vitro Performance of Mometasone Furoate Suspension-Metered Dose Inhalers.

The therapeutic benefits of metered dose inhalers (MDIs) in pulmonary disorders are mainly driven by aerosol performance, which depends on formulation variables (drug and excipients), device design, and patient interactions. The present study provides a comprehensive investigation to better understand the effect of formulation variables on mometasone furoate (MF) suspension-based MDI product performance. The effects of MF particle size (volume median diameter; X) and excipient concentration (ethanol and oleic acid, cosolvent, and surfactant, respectively) on selected critical quality attributes (delivered dose (DD), fine particle dose of particles lesser than 5 µm (FPD < 5), ex-throat dose and median dissolution time (MDT)) were studied.

Optimization of the Transwell System for Assessing the Dissolution Behavior of Orally Inhaled Drug Products through In Vitro and In Silico Approaches.

The aim of this study was to further evaluate and optimize the Transwell system for assessing the dissolution behavior of orally inhaled drug products (OIDPs), using fluticasone propionate as a model drug. Sample preparation involved the collection of a relevant inhalable dose fraction through an anatomical mouth/throat model, resulting in a more uniform presentation of drug particles during the subsequent dissolution test. The method differed from previously published procedures by (1) using a 0.

Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?

In the context of streamlining generic approval, this study assessed whether pharmacokinetics (PK) could elucidate the pulmonary fate of orally inhaled drug products (OIDPs). Three fluticasone propionate (FP) dry powder inhaler (DPI) formulations (A-4.5, B-3.

Semi-mechanistic PK/PD model to assess pulmonary targeting of beclomethasone dipropionate and its active metabolite.

Purpose: The objective of this study was to describe the pulmonary targeting of beclomethasone dipropionate (BDP) and its active metabolite beclomethasone 17-monopropionate (BMP) in rats using a semi-mechanistic PK/PD model.

Methods: Rat plasma and tissue concentrations of BDP and BMP, and tissue receptor occupancies of BMP after systemic and pulmonary delivery of BDP and BMP were integrated in a newly developed semi-mechanistic PK/PD model.

Results: After IV administration of BDP, 95.

Evaluation of the Sensitivity and Robustness of Modified Chi-Square Ratio Statistic for Cascade Impactor Equivalence Testing Through Monte Carlo Simulations.

The objective of this work was to study the performance of the modified chi-square ratio statistic (mCSRS test) proposed for cascade impactor (CI) profile equivalence testing. The test (T) and reference (R) CI profile datasets were generated from different typical CI profile patterns either with or without inter-site correlation (ISC) through Monte Carlo simulations. The mCSRS test pass rate outcome employing previously published critical values was compared with that of critical values derived from different types of datasets.

Huntington's Disease Progression: A Population Modeling Approach to Characterization Using Clinical Rating Scales.

Development of effective therapeutics that slow Huntington's disease progression is a research priority that requires an understanding of natural disease progression. We applied a population-modeling approach to describe the progression of 2 routinely used rating scales - the total motor score and the total functional capacity score. Models were fitted to data from research participants aged ≥ 18 years with Huntington's disease stage I or II at study entry (total functional capacity score ≥ 7), from a controlled clinical trial (CARE-HD) and 2 observational studies (COHORT and Registry).

Quantitative Assessment of Pulmonary Targeting of Inhaled Corticosteroids Using Ex Vivo Receptor Binding Studies.

The goal of locally acting inhaled corticosteroids is to achieve distinct pulmonary effects with reduced systemic side effects. The present work using an ex vivo receptor binding model in rats was interested in assessing pulmonary targeting for several commercially available corticosteroids by monitoring receptor occupancies in the lung and systemic organs (liver, kidney, spleen, and brain) after intravenous (IV) injection or intratracheal (IT) instillation of a dry powder administration at a dose of 100 μg/kg. Pulmonary targeting, defined as the difference in cumulative receptor occupancies (AUC) between the lung and kidney after pulmonary delivery, differed across the investigated corticosteroids (ΔAUC range, 33 ± 46 to 143 ± 52% *h) with the highest degree found for corticosteroids with high systemic clearance and pronounced lipophilicity (presumably allowing a long pulmonary residence time).

Cascade Impactor Equivalence Testing: Comparison of the Performance of the Modified Chi-Square Ratio Statistic (mCSRS) with the Original CSRS and EMA's Average Bioequivalence Approach.

The performances of three statistical approaches for assessing in vitro equivalence was evaluated with a set of 55 scenarios of realistic test (T) and reference (R) cascade impactor (CI) profiles (originally employed by the Product Quality Research Institute to evaluate the chi-square ratio statistic: CSRS) by comparing the outcomes against experts' opinion (surrogate for the truth). The three methods were (A) a stepwise aerodynamic particle size distribution (APSD) equivalence test integrating population bioequivalence (PBE) testing of impactor-sized mass (ISM) with the CSRS (PBE-CSRS approach), previously suggested by the USFDA; (B) the combination of PBE testing of single actuation content and ISM with the newly suggested modified CSRS (PBE-mCSRS approach), a method employing reference variance scaling; and (C) EMA's average bioequivalence (ABE approach). Based on Monte-Carlo simulations, both PBE-CSRS and ABE approaches resulted in high misclassification rates, the former with highest false-pass rate and the latter with highest false-fail rate at both ≥ 50% and ≥ 80% classification threshold values (the % of simulations or experts necessary to judge a given scenario as equivalent).

Pharmacokinetic and pharmacodynamic modeling of gut hormone peptide YY after pulmonary delivery.

Peptide YY (PYY) is an endogenous appetite suppressing peptide. The present research was to perform pharmacokinetic/pharmacodynamic (PK/PD) analysis for predicting the concentration- and response-time profiles of PYY after systemic and pulmonary delivery in mice, with the goal of suggesting a potential pulmonary dosing regimen in humans. A PK/PD model was developed to describe PYY plasma concentration - and relative food intake rate ratio (as % of control) - time profiles after intraperitoneal and subcutaneous administration, and inhalation in mice.

Fetal Concentrations of Budesonide and Fluticasone Propionate: a Study in Mice.

The study goal was to evaluate the transplacental transfer of two corticosteroids, budesonide (BUD) and fluticasone propionate (FP), in pregnant mice and investigate whether P-glycoprotein (P-gp) might be involved in reducing BUD transplacental transfer. Pregnant mice (N = 18) received intravenously either low (104.9 μg/kg) or high (1049 μg/kg) dose of [H]-BUD or a high dose of [H]-FP (1590 μg/kg).

Characterization of a dextran-budesonide prodrug for inhalation therapy.

Reducing the dosing frequency of corticosteroids may increase compliance and increase pulmonary targeting. The objective of this study was to evaluate whether a high molecular weight dextran-budesonide conjugate might be suitable for pulmonary slow release of the otherwise fast absorbed budesonide. An array of dextran-spacer-budesonide conjugates was prepared that differed in the molecular weight of dextran (20 kDa or 40 kDa) and the length of the dicarboxylic spacer (succinic, glutaric, and adipic anhydride).

Predicting Pulmonary Pharmacokinetics from In Vitro Properties of Dry Powder Inhalers.

Purpose: The ability of two semi-mechanistic simulation approaches to predict the systemic pharmacokinetics (PK) of inhaled corticosteroids (ICSs) delivered via dry powder inhalers (DPIs) was assessed for mometasone furoate, budesonide and fluticasone propionate.

Methods: Both approaches derived the total lung doses and the central to peripheral lung deposition ratios from clinically relevant cascade impactor studies, but differed in the way the pulmonary absorption rate was derived. In approach 1, the rate of in vivo drug dissolution/absorption was predicted for the included ICSs from in vitro aerodynamic particle size distribution and in vitro drug solubility estimates measured in an in vivo predictive dissolution medium.

Effects of lipid formulations on clove extract spray dried powders: comparison of physicochemical properties, storage stability and in vitro intestinal permeation.

Clove is an aromatic plant spice with potent antioxidant and anti-inflammatory activity. Eugenol is the main compound which contributes to such medicinal and nutritional benefits. To date, the formulation of unstable, volatile and poorly water-soluble compounds remains a challenging task.

Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator.

Background: Amyloid-β (Aβ) 42 has been implicated as the initiating molecule in the pathogenesis of Alzheimer's disease (AD); thus, therapeutic strategies that target Aβ42 are of great interest. γ-Secretase modulators (GSMs) are small molecules that selectively decrease Aβ42. We have previously reported that many acidic steroids are GSMs with potencies ranging in the low to mid micromolar concentration with 5β-cholanic acid being the most potent steroid identified GSM with half maximal effective concentration (EC50) of 5.

Quantitative characterization of circadian rhythm of pulmonary function in asthmatic patients treated with inhaled corticosteroids.

The aim of this study was to characterize the circadian rhythm observed for forced expiratory volume in 1 s (FEV1) in patients with persistent asthma being treated with inhaled corticosteroids. The database included 3379 FEV1 measurements from 189 patients with mild to moderate asthma. A model using the sum of two Sine functions with periods of 12 and 24 h and a constant component of mean circadian rhythm adequately described the circadian rhythm in FEV1 measurements over time.

Evaluation of the Transwell System for Characterization of Dissolution Behavior of Inhalation Drugs: Effects of Membrane and Surfactant.

Assessing the dissolution behavior of orally inhaled drug products (OIDs) has been proposed as an additional in vitro test for the characterization of innovator and generic drug development. A number of suggested dissolution methods (e.g.