RESUMEN

A novel inhalation exposure system was developed with the aim to increase the efficiency of pharmacokinetic (PK) evaluations of inhaled drugs in a large species such as the dog. It enables collecting PK data for multiple drug candidates in a single experiment by simultaneous administration of the drugs to the same animal. This facilitates a direct PK comparison of the same lung dose of different drugs using the same blood samples, which can be considered to be a refinement measure from an animal research perspective. The system design was inspired by a clinical precision dosing dosimeter systems, which enhance dosing precision by synchronizing the aerosol delivery from the jet nebulizer with the inhalation to maximize the inhaled fraction of the nebulized dose. The performance of the novel system was validated in an in-vivo study, which included a comparison of the same nebulized dose delivered as a fine and a coarse aerosol. The drugs selected for this study were developed for local treatment of the lung via inhalation and were known to have low oral bioavailability due to being extremely poorly soluble and therefore expected to also have low nasal bioavailability. This would result in systemic exposure derived primarily from pulmonary absorption, which facilitated the PK assessment applied to determine the lung deposited dose. The jet nebulizer selected to generate a fine aerosol was designed for alveolar lung deposition and approved by U.S. Food and Drug Administration for lung ventilation imaging, and the nebulizer selected to generate a coarse aerosol was a standard nebulizer. The drugs were wet milled to a particle size considerably smaller than the nebulized droplets and the dispersed drug particles were therefore homogenously distributed in the droplet size distribution. Higher initial plasma concentrations were observed for the fine aerosol. This was expected, as the smaller droplets should deposit more efficiently in the peripheral regions of the lung, which consequently should lead to a faster absorption compared with the coarse aerosol from the standard nebulizer that should deposit more centrally. The fact that this could be observed supports that the novel system is an excellent tool in PK evaluations. Our study indicated that there was no difference in the systemic exposure between the fine and the coarse aerosol for the same nebulized dose, and thus the lung deposition was also the same. The considerable difference in the nebulized size distribution within the range relevant for available inhalation devices resulted in a negligible difference in intranasal filtration. The fraction of the nebulized dose that deposited in the lung was observed to be high in this study (mean of 21-30% and about 50% for one dog with a distinguished slow and deep breathing), which supports that the intranasal filtration was low. That a high fraction of the nebulized dose deposited in the lung indicates that an enhanced dosing precision was obtained with the novel system. The similar achieved lung doses of all three drugs, shows that the simultaneous administration of multiple drugs worked well. That the intranasal filtration was low is an important finding considering that devices for oropharyngeal delivery in dogs are applied in order to eliminate intranasal filtration. Oropharyngeal dosing is more invasive compared with oronasal dosing and avoiding utilizing that method can be considered a refinement measure from an animal research perspective.

Asunto(s)

Pulmón , Nebulizadores y Vaporizadores , Administración por Inhalación , Administración Intranasal , Aerosoles , Animales , Perros , Diseño de Equipo , Tamaño de la Partícula

RESUMEN

Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.

Asunto(s)

Asma/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Sulfonamidas/uso terapéutico , Tiazoles/uso terapéutico , Animales , Asma/inducido químicamente , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Cristalografía por Rayos X , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Masculino , Estructura Molecular , Ovalbúmina , Fosfatidilinositol 3-Quinasas/metabolismo , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas Endogámicas BN , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética , Tiazoles/síntesis química , Tiazoles/metabolismo , Tiazoles/farmacocinética

RESUMEN

Translational pharmacokinetic (PK) models are needed to describe and predict drug concentration-time profiles in lung tissue at the site of action to enable animal-to-man translation and prediction of efficacy in humans for inhaled medicines. Current pulmonary PK models are generally descriptive rather than predictive, drug/compound specific, and fail to show successful cross-species translation. The objective of this work was to develop a robust compartmental modeling approach that captures key features of lung and systemic PK after pulmonary administration of a set of 12 soluble drugs containing single basic, dibasic, or cationic functional groups. The model is shown to allow translation between animal species and predicts drug concentrations in human lungs that correlate with the forced expiratory volume for different classes of bronchodilators. Thus, the pulmonary modeling approach has potential to be a key component in the prediction of human PK, efficacy, and safety for future inhaled medicines.

Asunto(s)

Broncodilatadores/administración & dosificación , Broncodilatadores/farmacocinética , Pulmón/fisiología , Administración por Inhalación , Administración Intravenosa , Animales , Perros , Evaluación Preclínica de Medicamentos , Volumen Espiratorio Forzado , Humanos , Masculino , Modelos Animales , Modelos Biológicos , Ratas , Ratas Sprague-Dawley

RESUMEN

Fostamatinib is a tyrosine kinase inhibitor with activity against spleen tyrosine kinase which has completed clinical trials for patients with rheumatoid arthritis. In clinical studies fostamatinib treatment was associated with a small elevation of systemic arterial blood pressure (BP), a similar finding to that seen with other kinase inhibitors, especially those that inhibit VEGFR2 signaling. We have investigated the link between fostamatinib-induced blood pressure elevation and plasma levels of the fostamatinib-active metabolite R940406 in conscious rats and found the time course of the BP effect correlated closely with changes in R940406 plasma concentration, indicating a direct pharmacological relationship. Free plasma levels of R940406 produced in these studies (up to 346 nmol/L) span the clinically observed mean peak free plasma concentration of 49 nmol/L. We have demonstrated that the blood pressure elevation induced by fostamatinib dosing can be successfully controlled by a variety of methods, notably simple drug withdrawal or codosing with a range of standard antihypertensive agents such as atenolol, captopril, and nifedipine. These findings support potential methods of maintaining patient safety while on fostamatinib therapy. Furthermore, we have demonstrated, using nifedipine as an example agent, that this blood pressure control was not achieved by reduction in plasma exposure of R940406, suggesting that potential benefits from the pharmacology of the investigational drug can be maintained while blood pressure control is managed by use of standard comedications.

RESUMEN

Although the anti-inflammatory role of the A2a receptor is well established, controversy remains with regard to the therapeutic value for A2a agonists in treatment of inflammatory lung diseases, also as a result of unwanted A2a-mediated cardiovascular effects. In this paper, we describe the discovery and characterization of a new, potent and selective A2a agonist (compound 2) with prolonged lung retention and limited systemic exposure following local administration. To support the lead optimization chemistry program with compound selection and profiling, multiple in vitro and in vivo assays were used, characterizing compound properties, pharmacodynamics (PD), and drug concentrations. Particularly, pharmacokinetic-PD modeling was applied to quantify the effects on the cardiovascular system, and an investigative toxicology study in rats was performed to explore potential myocardial toxicities. Compound 2, in comparison to a reference A2a agonist, UK-432,097, demonstrated higher solubility, lower lipophilicity, lower plasma protein binding, high rat lung retention (28% remaining after 24 h), and was efficacious in a lung inflammatory rat model following intratracheal dosing. Despite these properties, compound 2 did not provide a sufficient therapeutic index, that is, separation of local anti-inflammatory efficacy in the lung from systemic side effects in the cardiovascular system. The plasma concentration that resulted in induction of hypotension (half maximal effective concentration; EC50 0.5 nmol/L) correlated to the in vitro A2a potency (rIC50 0.6 nmol/L). Histopathological lesions in the heart were observed at a dose level which is threefold above the efficacious dose level in the inflammatory rat lung model. In conclusion, compound 2 is a highly potent and selective A2a agonist with significant lung retention after intratracheal administration. Despite its local anti-inflammatory efficacy in rat lung, small margins to the cardiovascular effects suggested limited therapeutic value of this compound for treatment of inflammatory lung disease by the inhaled route.