RESUMEN
A cross-industry survey was conducted by EFPIA/IQ DruSafe in 2018 to provide information on photosafety evaluation of pharmaceuticals after implementation of ICH S10. This survey focused on the strategy utilized for photosafety risk assessment, the design of nonclinical (in vitro and in vivo) and clinical evaluations, the use of exposure margins in risk assessment, and regulatory interactions. The survey results indicated that a staged approach for phototoxicity assessment has been widely accepted by regulatory authorities globally. The OECD-based 3T3 NRU Phototoxicity Test is the most frequently used in vitro approach. Modifications to this assay suggested by ICH S10 are commonly applied. For in-vitro-positives, substantial margins from in vitro IC50 values under irradiation to Cmax (clinical) have enabled further development without the need for additional photosafety data. In vivo phototoxicity studies typically involve dosing rodents and exposing skin and eyes to simulated sunlight, and subsequently evaluating at least the skin for erythema and edema. However, no formal guidelines exist and protocols are less standardized across companies. A margin-of-safety approach (based on Cmax at NOAEL) has been successfully applied to support clinical development. Experience with dedicated clinical phototoxicity studies was limited, perhaps due to effective de-risking approaches employed based on ICH S10.
Asunto(s)
Dermatitis Fototóxica/patología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Organización para la Cooperación y el Desarrollo Económico/normas , Preparaciones Farmacéuticas/normas , Luz Solar/efectos adversosRESUMEN
Phototoxicity is a relatively common phenomenon and is an adverse effect of some systemic drugs. The fundamental initial step of photochemical reactivity is absorption of a photon; however, little guidance has been provided thus far regarding how ultraviolet-visible (UV-vis) light absorption spectra may be used to inform testing strategies for investigational drugs. Here we report the results of an inter-laboratory study comparing the data from harmonized UV-vis light absorption spectra obtained in methanol with data from the in vitro 3T3 Neutral Red Uptake Phototoxicity Test. Six pharmaceutical companies submitted data according to predefined quality criteria for 76 compounds covering a wide range of chemical classes showing a diverse but "positive"-enhanced distribution of photo irritation factors (22%: PIF<2, 12%: PIF 2-5, 66%: PIF>5). For compounds being formally positive (PIF value above 5) the lowest reported molar extinction coefficient (MEC) was 1700 L mol⻹ cm⻹ in methanol. However, the majority of these formally positive compounds showed MEC values being significantly higher (up to almost 40,000 L mol⻹ cm⻹). In conclusion, an MEC value of 1000 L mol⻹ cm⻹ may represent a reasonable and pragmatic threshold warranting further experimental photosafety evaluation.
Asunto(s)
Dermatitis Fototóxica/etiología , Drogas en Investigación/toxicidad , Animales , Células 3T3 BALB , Colorantes/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/normas , Ratones , Rojo Neutro/metabolismo , Estándares de Referencia , Espectrofotometría Ultravioleta/normas , Luz SolarRESUMEN
The cognitive impairments observed in Alzheimer's disease (AD) are in part a consequence of reduced acetylcholine (ACh) levels resulting from a loss of cholinergic neurons. Preclinically, serotonin 4 receptor (5-HT(4)) agonists are reported to modulate cholinergic function and therefore may provide a new mechanistic approach for treating cognitive deficits associated with AD. Herein we communicate the design and synthesis of potent, selective, and brain penetrant 5-HT(4) agonists. The overall goal of the medicinal chemistry strategy was identification of structurally diverse clinical candidates with varying intrinsic activities. The exposure-response relationships between binding affinity, intrinsic activity, receptor occupancy, drug exposure, and pharmacodynamic activity in relevant preclinical models of AD were utilized as key selection criteria for advancing compounds. On the basis of their excellent balance of pharmacokinetic attributes and safety, two lead 5-HT(4) partial agonist candidates 2d and 3 were chosen for clinical development.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Trastornos del Conocimiento/tratamiento farmacológico , Indoles/síntesis química , Piperidinas/síntesis química , Piranos/síntesis química , Agonistas del Receptor de Serotonina 5-HT4/síntesis química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Enfermedad de Alzheimer/psicología , Animales , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/biosíntesis , Perros , Agonismo Parcial de Drogas , Células HEK293 , Haplorrinos , Humanos , Técnicas In Vitro , Indoles/farmacocinética , Indoles/farmacología , Células de Riñón Canino Madin Darby , Masculino , Microsomas Hepáticos/metabolismo , Permeabilidad , Piperidinas/farmacocinética , Piperidinas/farmacología , Isoformas de Proteínas/metabolismo , Piranos/farmacocinética , Piranos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina 5-HT4/metabolismo , Agonistas del Receptor de Serotonina 5-HT4/farmacocinética , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The discovery of two histamine H(3) antagonist clinical candidates is disclosed. The pathway to identification of the two clinical candidates, 6 (PF-03654746) and 7 (PF-03654764) required five hypothesis driven design cycles. The key to success in identifying these clinical candidates was the development of a compound design strategy that leveraged medicinal chemistry knowledge and traditional assays in conjunction with computational and in vitro safety tools. Overall, clinical compounds 6 and 7 exceeded conservative safety margins and possessed optimal pharmacological and pharmacokinetic profiles, thus achieving our initial goal of identifying compounds with fully aligned oral drug attributes, "best-in-class" molecules.