ABSTRACT
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.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Receptors, G-Protein-Coupled/antagonists & inhibitors , Adult , Aged , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Dose-Response Relationship, Drug , Endpoint Determination , Humans , Least-Squares Analysis , Middle Aged , Models, Biological , Proof of Concept Study , Receptors, G-Protein-Coupled/metabolism , Treatment OutcomeABSTRACT
GS-9857, an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1-6 and improved coverage against commonly encountered NS3 resistance-associated variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS-9857 were evaluated in patients with chronic HCV genotype 1-4 infection. Patients with genotype 1-4 infection received placebo or once-daily GS-9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS-9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 laboratory abnormalities were observed in 17% of patients receiving GS-9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase levels. GS-9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median maximum reductions in HCV RNA of ≥3 log10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS-9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1-4 infection, GS-9857 exhibited linear PK and was associated with a median half-life of 29-42 h, supporting once-daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS-9857 support its further evaluation for treatment of patients with chronic HCV infection.
Subject(s)
Antiviral Agents/administration & dosage , Genotype , Hepacivirus/classification , Hepacivirus/genetics , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Macrocyclic Compounds/administration & dosage , Sulfonamides/administration & dosage , Adolescent , Adult , Aged , Aminoisobutyric Acids , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Cyclopropanes , Double-Blind Method , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Hepacivirus/isolation & purification , Humans , Lactams, Macrocyclic , Leucine/analogs & derivatives , Macrocyclic Compounds/adverse effects , Macrocyclic Compounds/pharmacokinetics , Macrocyclic Compounds/pharmacology , Male , Middle Aged , Placebos/administration & dosage , Proline/analogs & derivatives , Quinoxalines , Sulfonamides/adverse effects , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Treatment Outcome , Viral Load , Young AdultABSTRACT
The mood modules from the Primary Care Evaluation of Mental Disorders (PRIME-MD) and the Patient Health Questionnaire (PHQ) were administered to 17 (52%) female and 16 (48%) male adolescent (13-17 years old) psychiatric inpatients. The internal consistencies of both were good (KR-20 for PRIME-MD=.80, Cronbach coefficient alpha for Patient Health Questionnaire=.85). The correlation between the PRIME-MD and Patient Health Questionnaire total scores was .87 (p<.001), and the point-biserial correlation of both questionnaires' total scores with being diagnosed with a Major Depressive Disorder was .54 (p<.001). Both mood modules appeared to be equally effective in screening for a Major Depressive Disorder.