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1.
J Appl Toxicol ; 39(9): 1348-1361, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31231834

RESUMEN

CJ-12,918, a 5-lipoxygenase (5-LO) inhibitor, caused cataracts during a 1-month safety assessment studies in rats whereas the structurally similar ZD-2138 was without effect. For CJ-12,918 analogs, blocking different sites of metabolic liability reduced (CJ-13,454) and eliminated (CJ-13,610) cataract formation in both rats and dogs. Using this chemical series as a test set, models and mechanisms of toxicity were first explored by testing the utility of ex vivo rat lens explant cultures as a safety screen. This model overpredicted the cataractogenic potential of ZD-2138 due to appreciably high lens drug levels and was abandoned in favor of a mechanism-based screen. Perturbations in lens sterol content, from a decline in lathosterol content, preceded cataract formation suggesting CJ-12,918 inhibited lens cholesterol biosynthesis (LCB). A 2-day bioassay in rats using ex vivo LCB assessments showed that the level of LCB inhibition was correlated with incidence of cataract formation in animal studies by these 5-LO inhibitors. Thereafter, this 2-day bioassay was applied to other pharmaceutical programs (neuronal nitric oxide synthase, sorbitol dehydrogenase inhibitor, squalene synthetase inhibitor and stearoyl-CoA desaturase-1 inhibitors/D4 antagonists) that demonstrated cataract formation in either rats or dogs. LCB inhibition >40% was associated with a high incidence of cataract formation in both rats and dogs that was species specific. Bioassay sensitivity/specificity were further explored with positive (RGH-6201/ciglitazone/U18666A) and negative (tamoxifen/naphthalene/galactose) mechanistic controls. This body of work over two decades shows that LCB inhibition was a common mechanism of cataract formation by pharmaceutical agents and defined a level of inhibition >40% that was typically associated with causing cataracts in safety assessment studies typically ≥1 month.


Asunto(s)
Catarata/inducido químicamente , Colesterol/biosíntesis , Colesterol/toxicidad , Inhibidores Enzimáticos/toxicidad , Cristalino/efectos de los fármacos , Cristalino/metabolismo , Tiazolidinedionas/toxicidad , Animales , Animales de Laboratorio , Catarata/metabolismo , Perros , Femenino , Masculino , Preparaciones Farmacéuticas , Ratas , Ratas Sprague-Dawley
2.
Exp Eye Res ; 93(3): 256-64, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21376717

RESUMEN

Better control of intraocular pressure (IOP) is the most effective way to preserve visual field function in glaucomatous patients. While prostaglandin FP analogs are leading the therapeutic intervention for glaucoma, new target classes also are being identified with new lead compounds being developed for IOP reduction. One target class currently being investigated includes the prostaglandin EP receptor agonists. Recently PF-04217329 (Taprenepag isopropyl), a prodrug of CP-544326 (active acid metabolite), a potent and selective EP(2) receptor agonist, was successfully evaluated for its ocular hypotensive activity in a clinical study involving patients with primary open angle glaucoma. In the current manuscript, the preclinical attributes of CP-544326 and PF-0421329 have been described. CP-544326 was found to be a potent and selective EP(2) agonist (IC(50) = 10 nM; EC(50) = 2.8 nM) whose corneal permeability and ocular bioavailability were significantly increased when the compound was dosed as the isopropyl ester prodrug, PF-04217329. Topical ocular dosing of PF-04217329 was well tolerated in preclinical species and caused an elevation of cAMP in aqueous humor/iris-ciliary body indicative of in vivo EP(2) target receptor activation. Topical ocular dosing of PF-04217329 resulted in ocular exposure of CP-544326 at levels greater than the EC(50) for the EP(2) receptor. PF-04217329 when dosed once daily caused between 30 and 50% IOP reduction in single day studies in normotensive Dutch-belted rabbits, normotensive dogs, and laser-induced ocular hypertensive cynomolgus monkeys and 20-40% IOP reduction in multiple day studies compared to vehicle-dosed eyes. IOP reduction was sustained from 6 h through 24 h following a single topical dose. In conclusion, preclinical data generated thus far appear to support the clinical development of PF-04217329 as a novel compound for the treatment of glaucoma.


Asunto(s)
Acetatos/farmacología , Antihipertensivos/farmacología , Modelos Animales de Enfermedad , Glaucoma de Ángulo Abierto/tratamiento farmacológico , Glaucoma/tratamiento farmacológico , Presión Intraocular/efectos de los fármacos , Profármacos/farmacología , Subtipo EP2 de Receptores de Prostaglandina E/agonistas , Sulfonamidas/farmacología , Acetatos/farmacocinética , Administración Tópica , Animales , Antihipertensivos/farmacocinética , Humor Acuoso/metabolismo , Disponibilidad Biológica , Calcio/metabolismo , Cuerpo Ciliar/metabolismo , Córnea/metabolismo , AMP Cíclico/metabolismo , Perros , Evaluación Preclínica de Medicamentos , Glaucoma/metabolismo , Humanos , Iris/metabolismo , Macaca fascicularis , Masculino , Soluciones Oftálmicas/farmacocinética , Soluciones Oftálmicas/farmacología , Profármacos/farmacocinética , Conejos , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Sulfonamidas/farmacocinética , Tonometría Ocular
3.
J Pharmacol Exp Ther ; 331(2): 627-35, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19690190

RESUMEN

Developing a population-based pharmacokinetic-pharmacodynamic (PKPD) model is a challenge in ophthalmology due to the difficulty of obtaining adequate pharmacokinetic (PK) samples from ocular tissues to inform the pharmacodynamic (PD) model. Using limited PK data, we developed a preclinical population-based PD model suitable for capturing the time course of dog intraocular pressure (IOP) that exhibited time-dependent sensitization after topical administration of PF-04475270 [5-{3-[(2S)-2-{(3R)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-5-oxopyrrolidin-1-yl]propyl}thiophene-2-carboxylate]. A physiologically relevant PK model was chosen to simultaneously capture the concentration profiles of CP-734432, a potent EP4 agonist and the active metabolite of PF-04475270, sampled from three ocular tissues of the anterior chamber: cornea, aqueous humor, and iris-ciliary body. Two population-based PD models were developed to characterize the IOP lowering profiles: model I, a standard indirect-response model (IRM); and model II, an extension of a standard IRM that empirically incorporated a response-driven positive feedback loop to account for the observed PD sensitization. The PK model reasonably described the PK profiles in all three ocular tissues. As for the PD, model I failed to capture the overall trend in the population IOP data, and model II more adequately characterized the overall data set. This integrated PKPD model may have general utility when PD sensitization is observed and is not a result of time-dependent PK. In addition, the model is applicable in the ophthalmology drug development setting in which PK information is limited but a population-based PD model could reasonably be established.


Asunto(s)
Presión Intraocular/efectos de los fármacos , Hipertensión Ocular/tratamiento farmacológico , Pirrolidinonas/farmacología , Receptores de Prostaglandina E/agonistas , Tiofenos/farmacología , Algoritmos , Animales , Humor Acuoso/metabolismo , Cuerpo Ciliar/metabolismo , Perros , Femenino , Glaucoma/metabolismo , Humanos , Masculino , Modelos Estadísticos , Hipertensión Ocular/fisiopatología , Profármacos/farmacocinética , Profármacos/farmacología , Pirrolidinonas/uso terapéutico , Subtipo EP4 de Receptores de Prostaglandina E , Tiofenos/uso terapéutico
4.
Exp Eye Res ; 89(5): 608-17, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19445930

RESUMEN

Prostaglandins are widely used to lower intraocular pressure (IOP) as part of the treatment regimen for glaucoma. While FP and EP2 agonists are known to lower IOP, we investigated the ocular hypotensive activity and ocular drug distribution of PF-04475270, a novel EP4 agonist following topical administration in normotensive Beagle dogs. PF-04475270 is a prodrug of CP-734432, which stimulated cAMP formation in HEK293 cells expressing EP4 receptor and beta-lactamase activity in human EP4 expressing CHO cells transfected with a cAMP response element (CRE) with an EC(50) of 1 nM. Prodrug conversion and transcorneal permeability were assessed in rabbit corneal homogenates and a human corneal epithelial cell (cHCE) model. The compound underwent rapid hydrolysis to CP-734432 in corneal homogenates, and exhibited good permeability in the cHCE model. The descending order of ocular exposure to CP-734432 after topical dosing of PF-04475270 in dogs was as follows: cornea > aqueous humor >or= iris/ciliary body. When administered q.d., PF-04475270 lowered IOP effectively in the dog IOP model both after single and multiple days of dosing. A maximum decrease in IOP with PF-04475270 was between 30 and 45% at 24h post-dose relative to that observed with vehicle. In conclusion, PF-04475270 is a novel ocular hypotensive compound which is bioavailable following topical dosing, effectively lowering IOP in dogs. EP4 agonists could be considered as potential targets for lowering IOP for the treatment of glaucoma and ocular hypertension.


Asunto(s)
Ojo/efectos de los fármacos , Presión Intraocular/efectos de los fármacos , Profármacos/farmacocinética , Pirrolidinonas/farmacocinética , Receptores de Prostaglandina E/agonistas , Tiofenos/farmacocinética , Administración Tópica , Animales , Disponibilidad Biológica , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Ojo/metabolismo , Ojo/patología , Humanos , Hidrólisis , Hiperemia/inducido químicamente , Modelos Animales , Soluciones Oftálmicas , Permeabilidad , Profármacos/administración & dosificación , Profármacos/toxicidad , Pirrolidinonas/administración & dosificación , Pirrolidinonas/toxicidad , Conejos , Receptores de Prostaglandina E/genética , Subtipo EP4 de Receptores de Prostaglandina E , Tiofenos/administración & dosificación , Tiofenos/toxicidad , Transfección
5.
Cutan Ocul Toxicol ; 28(1): 1-18, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19514919

RESUMEN

The ability to predict ocular side effects of systemically delivered drugs is an important issue for pharmaceutical companies. Although animal models involving standard clinical ophthalmic examinations and postmortem microscopic examinations of eyes are still used to identify ocular issues, these methods are being supplemented with additional in silico, in vitro, and in vivo techniques to identify potential safety issues and assess risk. The addition of these tests to a development plan for a potential new drug provides the opportunity to save time and money by detecting ocular issues earlier in the program. This review summarizes a current practice for minimizing the potential for systemically administered, new medicines to cause adverse effects in the eye.


Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Ojo/efectos de los fármacos , Pruebas de Toxicidad , Animales , Bioensayo , Colesterol/biosíntesis , Técnicas de Diagnóstico Oftalmológico , Humanos , Cristalino/metabolismo , Relación Estructura-Actividad
6.
Toxicol Sci ; 143(1): 116-25, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25326243

RESUMEN

Crizotinib (Xalkori) is a tyrosine kinase inhibitor of both anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition factor (c-Met). Though not predicted from standard nonclinical toxicological evaluation, visual disturbance became a frequently observed adverse event in humans. To understand the possible mechanism of this vision effect, an in vivo electroretinogram (ERG) study was conducted to assess retinal functional changes following oral administration of crizotinib. Immunohistochemical (IHC) staining of ALK and c-Met in the neural retinas of human, non-human primate, dog, rat, and mouse was used to aid in the animal model selection. ALK IHC staining was identified predominantly in the ganglion cell and inner nuclear layers of most species evaluated, in the inner plexiform layer in human and rodent, and in the nerve fiber layer in human and rat only. There was no apparent staining of any layer of the neural retina for c-Met in any of the species evaluated. ERG measurements identified a significant reduction in b-wave amplitude during the initial phase of dark adaptation in the crizotinib-treated rats. ERGs were also taken following oral administration of PF-06463922 (an ALK-selective inhibitor), for an understanding of potential kinase involvement. ERG effects were not observed in PF-06463922-treated animals when comparable exposures in the vitreous humor were achieved. Collectively, our results suggest that the ERG b-wave amplitude decreases during dark adaption following crizotinib administration may be related to signaling changes within the retina in rats, likely independent of ALK inhibition.


Asunto(s)
Adaptación a la Oscuridad/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Retina/efectos de los fármacos , Administración Oral , Quinasa de Linfoma Anaplásico , Animales , Crizotinib , Perros , Electrorretinografía , Potenciales Evocados , Humanos , Inmunohistoquímica , Luz , Macaca fascicularis , Masculino , Ratones , Estimulación Luminosa , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirazoles/administración & dosificación , Piridinas/administración & dosificación , Ratas Long-Evans , Ratas Sprague-Dawley , Proteínas Tirosina Quinasas Receptoras/metabolismo , Retina/enzimología , Transducción de Señal/efectos de los fármacos , Factores de Tiempo
7.
Pharm Res ; 23(7): 1554-63, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16783662

RESUMEN

PURPOSE: This study was conducted to develop and validate a dog colon model that predicts colon permeability in humans. METHODS: The following compounds were studied: Class 1 highly soluble (HS)/highly permeable (HP): aminophylline, propranolol, CP-409092; Class 2 LS/HP: nifedipine; trovafloxacin, sertraline; Class 3 HS/LP: azithromycin, atenolol, CP-331684, CP-424391; Class 4 LS/LP: CJ-13610. Administration to dogs was made 30 cm cranial to the anal sphincter with a lubricated Schott Model VFS-5 flexible endoscope. The bioavailability of the compound following the colon administration in dogs, relative to the same formulation administered orally (relative bioavailability), was determined. RESULTS: Except for atenolol, a small hydrophillic molecule, the relative bioavailability from administration to the colon of the dog correlated well with the following compound properties: high solubility and high, passive permeability > high solubility, low permeability > low solubility, high, passive permeability approximately low solubility, low permeability. CONCLUSION: The dog colon model is proposed as a surrogate for human intubation studies when the controlled release candidate falls in BCS Classes 2 (LS/HP), 3 (HS/LP), and 4 (LS/LP). However, no human intubation or dog colon studies are required for Class 1 (HS/HP), as these compounds are likely to be well absorbed from the colon.


Asunto(s)
Aminofilina/farmacocinética , Atenolol/farmacocinética , Colonoscopía , Imidazoles/farmacocinética , Absorción Intestinal , Modelos Animales , Nifedipino/farmacocinética , Sulfuros/farmacocinética , Administración Oral , Administración Rectal , Aminofilina/administración & dosificación , Aminofilina/química , Animales , Atenolol/administración & dosificación , Atenolol/química , Disponibilidad Biológica , Preparaciones de Acción Retardada , Perros , Tránsito Gastrointestinal , Humanos , Imidazoles/administración & dosificación , Imidazoles/química , Modelos Biológicos , Nifedipino/administración & dosificación , Nifedipino/química , Permeabilidad , Solubilidad , Sulfuros/administración & dosificación , Sulfuros/química
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