RESUMO
γ-Secretase mediates amyloid production in Alzheimer's disease (AD) and oncogenic activity of Notch. γ-Secretase inhibitors (GSIs) are thus of interest for AD and oncology. A peripheral biomarker of Notch activity would aid determination of the therapeutic window and dosing regimen for GSIs, given toxicities associated with chronic Notch inhibition. This study examined the effects of GSI MK-0752 on blood and hair follicle transcriptomes in healthy volunteers. The effects of a structurally diverse GSI on rhesus blood and hair follicles were also compared. Significant dose-related effects of MK-0752 on transcription were observed in hair follicles, but not blood. The GSI biomarker identified in follicles exhibited 100% accuracy in a clinical test cohort, and was regulated in rhesus by a structurally diverse GSI. This study identified a translatable, accessible pharmacodynamic biomarker of GSI target engagement and provides proof of concept of hair follicle RNA as a translatable biomarker source.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Derivados de Benzeno/farmacologia , Monitoramento de Medicamentos , Folículo Piloso/efeitos dos fármacos , Propionatos/farmacologia , Inibidores de Proteases/farmacologia , Receptores Notch/antagonistas & inibidores , Sulfonas/farmacologia , Transcrição Gênica/efeitos dos fármacos , Adolescente , Adulto , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Baltimore , Derivados de Benzeno/administração & dosagem , Derivados de Benzeno/sangue , Derivados de Benzeno/farmacocinética , Biomarcadores Farmacológicos/sangue , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Monitoramento de Medicamentos/métodos , Perfilação da Expressão Gênica/métodos , Folículo Piloso/metabolismo , Voluntários Saudáveis , Humanos , Macaca mulatta , Masculino , Modelos Animais , Terapia de Alvo Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Propionatos/administração & dosagem , Propionatos/sangue , Propionatos/farmacocinética , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/sangue , Inibidores de Proteases/farmacocinética , RNA Mensageiro/biossíntese , RNA Mensageiro/sangue , Receptores Notch/metabolismo , Sulfonas/administração & dosagem , Sulfonas/sangue , Sulfonas/farmacocinética , Adulto JovemRESUMO
MK-7246, an antagonist of the chemoattractant receptor on T helper type 2 (Th2) cells, is being developed for the treatment of respiratory diseases. In a first-in-human study, we investigated whether genetic polymorphisms contributed to the marked intersubject variability in the pharmacokinetics of MK-7246 and its glucuronide metabolite M3. Results from in vitro enzyme kinetic studies suggested that UGT2B17 is probably the major enzyme responsible for MK-7246 metabolism in both the liver and the intestine. As compared with those with the UGT2B17*1/*1 wild-type genotype, UGT2B17*2/*2 carriers, who possess no UGT2B17 protein, had 25- and 82-fold greater mean dose-normalized values of area under the plasma concentration-time curve (AUC) and peak concentration of MK-7246, respectively, and a 24-fold lower M3-to-MK-7246 AUC ratio. The apparent half-life of MK-7246 was not as variable between these two genotypes. Therefore, the highly variable pharmacokinetics of MK-7246 is attributable primarily to the impact of UGT2B17 genetic polymorphisms and extensive first-pass metabolism of MK-7246.