RESUMO
GPR40 mediates free fatty acid-induced insulin secretion in beta cells. We investigated the safety, pharmacokinetics, and glucose response of MK-8666, a partial GPR40 agonist, after once-daily multiple dosing in type 2 diabetes patients. This double-blind, multisite, parallel-group study randomized 63 patients (placebo, n = 18; 50 mg, n = 9; 150 mg, n = 18; 500 mg, n = 18) for 14-day treatment. The results showed no serious adverse effects or treatment-related hypoglycemia. One patient (150-mg group) showed mild-to-moderate transaminitis at the end of dosing. Median MK-8666 Tmax was 2.0-2.5 h and mean apparent terminal half-life was 22-32 h. On Day 15, MK-8666 reduced fasting plasma glucose by 54.1 mg/dL (500 mg), 36.0 mg/dL (150 mg), and 30.8 mg/dL (50 mg) more than placebo, consistent with translational pharmacokinetic/pharmacodynamic model predictions. Maximal efficacy for longer-term assessment is projected at 500 mg based on exposure-response analysis. In conclusion, MK-8666 was generally well tolerated with robust glucose-lowering efficacy.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Adulto , Idoso , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Relação Dose-Resposta a Droga , Determinação de Ponto Final , Humanos , Análise dos Mínimos Quadrados , Pessoa de Meia-Idade , Modelos Biológicos , Estudo de Prova de Conceito , Receptores Acoplados a Proteínas G/metabolismo , Resultado do TratamentoRESUMO
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
The Mantel-Haenszel (M-H) procedure is commonly used to compare two treatments in a stratified binomial trial. However, this procedure is asymptotically optimal only if the odds ratio is constant across strata. We propose an alternative analytic strategy based on the simultaneous use of two statistics, ZS and ZI, each involving a weighted averaging of within-stratum differences between proportions. The two treatments are declared significantly different at overall level alpha if either min(ZS, ZI) > Zalpha/2 or max(ZS, ZI) > Zalpha*/2, where alpha* is data dependent. Our strategy is shown to be more powerful than the M-H and other related procedures. Numerical examples are provided for illustration.