RESUMEN
This report summarizes the proceedings for Day 3 of the workshop titled "Current State and Future Expectations of Translational Modeling Strategies toSupportDrug Product Development, Manufacturing Changes and Controls". From a drug product quality perspective, patient-centric product development necessitates the development of clinically relevant drug product specifications (CRDPS). In this regard, Physiologically Based Biopharmaceutics modeling (PBBM) is a viable tool to establish links between in-vitro to in-vivo data, and support with establishing CRDPS. The theme of day 3 was practical applications of PBBM to support drug product quality. In this manuscript, case studies from US FDA, EMA and pharmaceutical industry on applications of PBBM in drug product quality are summarized which include 1) regulatory agency's perspectives on establishing the safe space and achieving study waivers, 2) model-informed risk assessment on the effects of acid reducing agents, bridging of dissolution methods, food effect, and formulation selection, and 3) understanding clinical formulation performance. Breakout session discussions focused on four topics - 1) terminologies related to physiologically based modeling in support of drug product quality, 2) regulatory harmonization on evidentiary standards, 3) CRDPS approaches and 4) bridging between biorelevant and quality control (QC) dissolution methods.
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Biofarmacia , Preparaciones Farmacéuticas , Humanos , Modelos Biológicos , Informe de Investigación , SolubilidadRESUMEN
To establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, and anti-tumor efficacy of RAF265. We conducted a multicenter, open-label, phase-I, dose-escalation trial of RAF265, an orally available RAF kinase/VEGFR-2 inhibitor, in patients with advanced or metastatic melanoma. Pharmacokinetic (PK) analysis, pharmacodynamics (PD) and tumor response assessment were conducted. We evaluated metabolic tumor response by 18[F]-fluorodeoxyglucose-positron-emission tomography (FDG-PET), tissue biomarkers using immunohistochemistry (IHC), and modulators of angiogenesis. RAF265 has a serum half-life of approximately 200 h. The MTD was 48 mg once daily given continuously. Among 77 patients, most common treatment-related adverse effects were fatigue (52%), diarrhea (34%), weight loss (31%) and vitreous floaters (27%). Eight of 66 evaluable patients (12.1%) had an objective response, including seven partial and one complete response. Responses occurred in BRAF-mutant and BRAF wild-type (WT) patients. Twelve of 58 (20.7%) evaluable patients had a partial metabolic response. On-treatment versus pretreatment IHC staining in 23 patients showed dose-dependent p-ERK inhibition. We observed a significant temporal increase in placental growth factor levels and decrease in soluble vascular endothelial growth factor receptor 2 (sVEGFR-2) levels in all dose levels. RAF265 is an oral RAF/VEGFR-2 inhibitor that produced antitumor responses, metabolic responses, and modulated angiogenic growth factor levels. Antitumor activity occurred in patients with BRAF-mutant and BRAF-WT disease. Despite low activity at tolerable doses, this study provides a framework for the development of pan-RAF inhibitors and modulators of angiogenesis for the treatment of melanoma.
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Antineoplásicos/uso terapéutico , Imidazoles/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Biomarcadores , Monitoreo de Drogas , Femenino , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Imidazoles/farmacocinética , Masculino , Dosis Máxima Tolerada , Melanoma/genética , Melanoma/mortalidad , Persona de Mediana Edad , Terapia Molecular Dirigida , Mutación , Metástasis de la Neoplasia , Estadificación de Neoplasias , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas B-raf/genética , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/farmacocinética , Resultado del TratamientoRESUMEN
The synthesis and biological evaluation of novel Tie-2 kinase inhibitors are presented. Based on the pyrrolopyrimidine chemotype, several new series are described, including the benzimidazole series by linking a benzimidazole to the C5-position of the 4-amino-pyrrolopyrimidine core and the ketophenyl series synthesized by incorporating a ketophenyl group to the C5-position. Medicinal chemistry efforts led to potent Tie-2 inhibitors. Compound 15, a ketophenyl pyrrolopyrimidine urea analog with improved physicochemical properties, demonstrated favorable in vitro attributes as well as dose responsive and robust oral tumor growth inhibition in animal models.
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Descubrimiento de Drogas , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Receptor TIE-2/antagonistas & inhibidores , Animales , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Estructura Molecular , Neoplasias/enzimología , Neoplasias/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/síntesis química , Pirimidinas/química , Pirroles/síntesis química , Pirroles/química , Ratas , Ratas Sprague-Dawley , Receptor TIE-2/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development.
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Adenosina Trifosfato/fisiología , Amidas/síntesis química , Aminoquinolinas/síntesis química , Antineoplásicos/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Amidas/farmacocinética , Amidas/farmacología , Aminoquinolinas/farmacocinética , Aminoquinolinas/farmacología , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Perros , Ratones , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Quantitative prediction of human pharmacokinetics is critical in assessing the viability of drug candidates and in determining first-in-human dosing. Numerous prediction methodologies, incorporating both in vitro and preclinical in vivo data, have been developed in recent years, each with advantages and disadvantages. However, the lack of a comprehensive data set, both preclinical and clinical, has limited efforts to evaluate the optimal strategy (or strategies) that results in quantitative predictions of human pharmacokinetics. To address this issue, the authors conducted a retrospective analysis using 50 proprietary compounds for which in vitro, preclinical pharmacokinetic data and oral single-dose human pharmacokinetic data were available. Five predictive strategies, involving either allometry or use of unbound intrinsic clearance from microsomes or hepatocytes, were then compared for their ability to predict human oral clearance, half-life through predictions of systemic clearance, volume of distribution, and bioavailability. Use of a single-species scaling approach with rat, dog, or monkey was as accurate as or more accurate than using multiple-species allometry. For those compounds cleared almost exclusively by P450-mediated pathways, scaling from human liver microsomes was as predictive as single-species scaling of clearance based on data from rat, dog, or monkey. These data suggest that use of predictive methods involving either single-species in vivo data or in vitro human liver microsomes can quantitatively predict human in vivo pharmacokinetics and suggest the possibility of streamlining the predictive methodology through use of a single species or use only of human in vitro microsomal preparations.
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Evaluación Preclínica de Medicamentos/métodos , Modelos Biológicos , Farmacocinética , Administración Oral , Animales , Área Bajo la Curva , Disponibilidad Biológica , Biometría , Semivida , Hepatocitos/metabolismo , Humanos , Tasa de Depuración Metabólica , Microsomas Hepáticos/metabolismo , Reproducibilidad de los Resultados , Estudios Retrospectivos , Especificidad de la Especie , Xenobióticos/farmacocinéticaRESUMEN
Based on a high throughput screening hit, pyrrolopyrimidine inhibitors of the Akt kinase are explored. X-ray co-crystal structures of two lead series results in the understanding of key binding interactions, the design of new lead series, and enhanced potency. The syntheses of these series and their biological activities are described. Spiroindoline 13j is found to have an Akt1 kinase IC(50) of 2.4+/-0.6 nM, Akt cell potency of 50+/-19 nM, and provides 68% inhibition of tumor growth in a mouse xenograft model (50 mg/kg, qd, po).
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinas/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Animales , Antineoplásicos/química , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Diseño de Fármacos , Concentración 50 Inhibidora , Ratones , Conformación Molecular , Estructura Molecular , Pirimidinas/química , Pirroles/química , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
OBJECTIVE: Our objective was to assess the contribution of 6',7'-dihydroxybergamottin (DHB) to the inhibitory effect of grapefruit juice toward intestinal cytochrome P450 (CYP) 3A4. METHODS: An aqueous extract was prepared from grapefruit juice by centrifugation, filtration, and repeated washing of the particulate with water. The concentrations of various furanocoumarins in this grapefruit juice "serum" and in whole grapefruit juice were measured by HPLC and their identities confirmed by liquid chromatography-tandem mass spectrometry. Five healthy volunteers were given a single tablet of felodipine (10 mg) with whole grapefruit juice, orange juice-containing serum, or plain orange juice (control). The pharmacokinetic outcomes of felodipine were evaluated by noncompartmental methods. The effects of serum and purified DHB (at the same concentrations as those measured in the orange juice-containing serum used in the clinical study) were compared, in vitro, with regard to (1) the reversible and mechanism-based inhibition of the catalytic activity of complementary deoxyribonucleic acid-expressed CYP3A4 and (2) the time-dependent loss of immunoreactive CYP3A4 protein in modified Caco-2 cells. RESULTS: The concentration of DHB in serum was comparable to that measured in whole grapefruit juice (38 micromol/L versus 43 micromol/L), and the concentrations of other known furanocoumarins were well below the lowest published concentration required to inhibit catalytic activity by 50%. Relative to plain orange juice, orange juice-containing serum significantly increased the median felodipine area under the plasma concentration-time curve by 1.9-fold (P =.04) and increased the maximum concentration by 1.7-fold (P =.01). In vitro, serum and purified DHB had similar inhibitory effects toward CYP3A4 activity with respect to both reversible inhibition (95% confidence interval, 85% +/- 5.7% and 75% +/- 4.5%, respectively) and mechanism-based inhibition after a 15-minute preincubation (95% confidence interval, 79% +/- 6.8% and 78% +/- 5.7%, respectively). In Caco-2 cells the time-averaged extents of CYP3A4 protein loss caused by serum and purified DHB were identical (43%). CONCLUSION: The interaction between grapefruit juice serum and felodipine can be attributed largely to DHB. This establishes DHB as an important contributor to the grapefruit juice effect.