Pharmacokinetic and Pharmacodynamic Evaluation of the Suitability of Using Fluticasone and an Acute Rat Lung Inflammation Model to Differentiate Lung Versus Systemic Efficacy

Chiang, Po‐Chang; Hu, Yonghan; Thurston, Archie; Sommers, Cynthia D.; Guzova, Julia A.; Kahn, Larry E.; Lai, Yurong; Blom, Jason D.

doi:10.1002/jps.21714

Cited by 10 publications

(5 citation statements)

References 23 publications

(29 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…First of all, it is believed that the glucocorticoid receptors in lung and systemic tissues are responsible for therapeutic benefit and side effects, respectively. Likely, the inhibition of neutrophil infiltration in response to LPS challenge is not sensitive enough (PMN assay), which requires higher drug concentration than needed in clinical to achieve effectiveness [20]. As a result, the effective IT dose preclinically results in a higher systemic exposure which explains the systemic inhibition (whole blood assay).…”

Section: Resultsmentioning

confidence: 99%

“…To make a nanosuspension formulation of fluticasone, a bench scale wet milling (micronization) device was used [20,21] with an appropriate amount of glass beads. Tween 80 (0.5%, w/w) in phosphate-buffered saline (pH 7.4) was added in a scintillation vial.…”

Section: Methodsmentioning

confidence: 99%

“…A nanosuspension drug delivery formulation was used to administer fluticasone and ciclesonide intratracheally (IT) to rats. Recently, utilization of nano drug delivery for both efficacy and safety evaluation has drawn lots of attentions from researchers, and its advantages were widely accepted by industry [20-26]. In our study, the acute LPS rat model was used to establish the dose–response curves for efficacy.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Evaluating the Suitability of Using Rat Models for Preclinical Efficacy and Side Effects with Inhaled Corticosteroids Nanosuspension Formulations

Chiang

Blom

et al. 2010

Nanoscale Res Lett

Self Cite

View full text Add to dashboard Cite

Inhaled corticosteroids (ICS) are often prescribed as first-line therapy for patients with asthma Despite their efficacy and improved safety profile compared with oral corticosteroids, the potential for systemic side effects continues to cause concern. In order to reduce the potential for systemic side effects, the pharmaceutical industry has begun efforts to generate new drugs with pulmonary-targeted topical efficacy. One of the major challenges of this approach is to differentiate both efficacy and side effects (pulmonary vs. systemic) in a preclinical animal model. In this study, fluticasone and ciclesonide were used as tool compounds to explore the possibility of demonstrating both efficacy and side effects in a rat model using pulmonary delivery via intratracheal (IT) instillation with nanosuspension formulations. The inhibition of neutrophil infiltration into bronchoalveolar lavage fluid (BALF) and cytokine (TNFα) production were utilized to assess pulmonary efficacy, while adrenal and thymus involution as well as plasma corticosterone suppression was measured to assess systemic side effects. Based on neutrophil infiltration and cytokine production data, the ED50s for ciclesonide and fluticasone were calculated to be 0.1 and 0.03 mg, respectively. At the ED50, the average adrenal involution was 7.6 ± 5.3% for ciclesonide versus 16.6 ± 5.1% for fluticasone, while the average thymus involution was 41.0 ± 4.3% for ciclesonide versus 59.5 ± 5.8% for fluticasone. However, the differentiation became less significant when the dose was pushed to the EDmax (0.3 mg for ciclesonide, 0.1 mg for fluticasone). Overall, the efficacy and side effect profiles of the two compounds exhibited differentiation at low to mid doses (0.03–0.1 mg ciclesonide, 0.01–0.03 mg fluticasone), while this differentiation diminished at the maximum efficacious dose (0.3 mg ciclesonide, 0.1 mg fluticasone), likely due to overdosing in this model. We conclude that the rat LPS model using IT administration of nanosuspensions of ICS is a useful tool to demonstrate pulmonary-targeted efficacy and to differentiate the side effects. However, it is only suitable at sub-maximum efficacious levels.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Evaluating the Suitability of Using Rat Models for Preclinical Efficacy and Side Effects with Inhaled Corticosteroids Nanosuspension Formulations

Chiang

Blom

et al. 2010

Nanoscale Res Lett

Self Cite

View full text Add to dashboard Cite

show abstract

“…This enabled the determination of a pre-clinical therapeutic index with the additional benefits of reducing both animal numbers and the variability in data that would be attributed to dosing separate animals for different end points. Similar models have been described in the literature to assess other mechanisms, for exampleinhaled corticosteroids (efficacy versus HPA axis suppression) [10].…”

Section: Discussionmentioning

confidence: 99%

In vitro and In vivo Assessment of Pi3Kγ Inhibitors for Anti-Inflammatory Indications: Challenges of Selectivity over Pi3Kα

Lunn¹

2013

J Pulm Respir Med

View full text Add to dashboard Cite

Class 1 PI3Ks are a growing area of interest as pharmacological targets across a number of disease mechanisms. We have assessed the feasibility of developing selective PI3Kgamma inhibitors based upon the ATP-binding hinge site. Following full file screening, 8800 analogues representing 25 chemotypes were further analysed across a panel of PI3K enzymes and cellular assays. Despite this we did not identify a series of compounds which possessed all required criteria of potency, selectivity, metabolic stability and solubility. We profiled the best 3 compounds in vivo to assess their anti-inflammatory efficacy versus PI3Kalpha driven perturbations in glucose/insulin homeostasis. Each compound dose-dependently inhibited LPS elicited pulmonary neutrophilia in rat with a marginal therapeutic index over a subsequent increase in glucose and insulin elevation. In our opinion these studies provide no evidence of a divergence from enzyme selectivity to an in vivo therapeutic index over insulin and glucose perturbations and therefore there is no evidence to suggest ATP competitive hinge binding site PI3Kgamma inhibitors will afford sufficient in vivo TI worthy of clinical progression for inflammatory indications.

show abstract

“…For pulmonary administration, NSs can be nebulized using jet or mesh nebulizers or aerosolized via metered dose inhalers [ 100 ] and dry powder inhalers [ 101 ]. For pulmonary administration, itraconazole [ 102 , 103 ], budesonide [ 104 , 105 , 106 ], and fluticasone NSs have been developed [ 107 ]. Previous studies have shown that nebulized NSs have acceptable aerodynamic performance and several advantages over conventional micronized drugs, including the ability to shorten nebulization time, improve patient compliance, and promote uniform distribution of drugs in the lungs by rapid diffusion [ 100 , 105 ].…”

Section: Administration Routes Of Nanosuspensionsmentioning

confidence: 99%

Formulation Strategies of Nanosuspensions for Various Administration Routes

et al. 2023

View full text Add to dashboard Cite

Nanosuspensions (NSs), which are nanosized colloidal particle systems, have recently become one of the most interesting substances in nanopharmaceuticals. NSs have high commercial potential because they provide the enhanced solubility and dissolution of low-water-soluble drugs by means of their small particle sizes and large surface areas. In addition, they can alter the pharmacokinetics of the drug and, thus, improve its efficacy and safety. These advantages can be used to enhance the bioavailability of poorly soluble drugs in oral, dermal, parenteral, pulmonary, ocular, or nasal routes for systemic or local effects. Although NSs often consist mainly of pure drugs in aqueous media, they can also contain stabilizers, organic solvents, surfactants, co-surfactants, cryoprotectants, osmogents, and other components. The selection of stabilizer types, such as surfactants or/and polymers, and their ratio are the most critical factors in NS formulations. NSs can be prepared both with top-down methods (wet milling, dry milling, high-pressure homogenization, and co-grinding) and with bottom-up methods (anti-solvent precipitation, liquid emulsion, and sono-precipitation) by research laboratories and pharmaceutical professionals. Nowadays, techniques combining these two technologies are also frequently encountered. NSs can be presented to patients in liquid dosage forms, or post-production processes (freeze drying, spray drying, or spray freezing) can also be applied to transform the liquid state into the solid state for the preparation of different dosage forms such as powders, pellets, tablets, capsules, films, or gels. Thus, in the development of NS formulations, the components/amounts, preparation methods, process parameters/levels, administration routes, and dosage forms must be defined. Moreover, those factors that are the most effective for the intended use should be determined and optimized. This review discusses the effect of the formulation and process parameters on the properties of NSs and highlights the recent advances, novel strategies, and practical considerations relevant to the application of NSs to various administration routes.

show abstract

Pharmacokinetic and Pharmacodynamic Evaluation of the Suitability of Using Fluticasone and an Acute Rat Lung Inflammation Model to Differentiate Lung Versus Systemic Efficacy

Cited by 10 publications

References 23 publications

Evaluating the Suitability of Using Rat Models for Preclinical Efficacy and Side Effects with Inhaled Corticosteroids Nanosuspension Formulations

Evaluating the Suitability of Using Rat Models for Preclinical Efficacy and Side Effects with Inhaled Corticosteroids Nanosuspension Formulations

In vitro and In vivo Assessment of Pi3Kγ Inhibitors for Anti-Inflammatory Indications: Challenges of Selectivity over Pi3Kα

Formulation Strategies of Nanosuspensions for Various Administration Routes

Contact Info

Product

Resources

About