RESUMEN
Systemic exposure to anticholinergics used for chronic obstructive pulmonary disease (COPD) may lead to side effects. This study assessed safety, tolerability, and pharmacokinetics of multiple doses of aclidinium bromide, a novel, long-acting antimuscarinic. Sixteen healthy participants received aclidinium bromide 200, 400, or 800 microg or placebo by dry-powder inhaler for 5 days, with > or =7 days washout. Aclidinium bromide and metabolite pharmacokinetics were assessed. Aclidinium bromide plasma levels were below the lower limit of quantification (LLOQ: 0.05 ng/mL) after 200 microg and in most participants after 400 microg. Plasma levels in all participants were below the LLOQ at all doses, including the highest dose, beyond 1 hour postdose. AUC(0-t) and C(max) at steady state were, respectively, 0.08 ng.h/mL and 0.12 ng/mL (aclidinium bromide), 0.40 ng.h/mL and 0.14 ng/mL (alcohol metabolite), and 13.47 ng.h/mL and 2.26 ng/mL (acid metabolite). The t(max) for aclidinium bromide 800 microg was 15 minutes (first kinetic time point). Adverse event frequency was comparable between treatment groups and placebo. The most commonly reported adverse events, probably treatment related, were coughing (n = 2) and dysphagia (n = 1); 94% of adverse events were mild. These data suggest a low systemic bioavailability and favorable safety profile for aclidinium bromide with repeated dosing for COPD.
Asunto(s)
Broncodilatadores/efectos adversos , Broncodilatadores/farmacocinética , Antagonistas Muscarínicos/efectos adversos , Antagonistas Muscarínicos/farmacocinética , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Tropanos/efectos adversos , Tropanos/farmacocinética , Administración por Inhalación , Adulto , Broncodilatadores/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Antagonistas Muscarínicos/administración & dosificación , Tropanos/administración & dosificaciónRESUMEN
CONTEXT: In response to a meal, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are released and modulate glycemic control. Normally these incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4). DPP-4 inhibitors are a novel class of oral antihyperglycemic agents in development for the treatment of type 2 diabetes. The degree of DPP-4 inhibition and the level of active incretin augmentation required for glucose lowering efficacy after an oral glucose tolerance test (OGTT) were evaluated. OBJECTIVE: The objective of the study was to examine the pharmacodynamics, pharmacokinetics, and tolerability of sitagliptin. DESIGN: This was a randomized, double-blind, placebo-controlled, three-period, single-dose crossover study. SETTING: The study was conducted at six investigational sites. PATIENTS: The study population consisted of 58 patients with type 2 diabetes who were not on antihyperglycemic agents. INTERVENTIONS: Interventions included sitagliptin 25 mg, sitagliptin 200 mg, or placebo. MAIN OUTCOME MEASURES: Measurements included plasma DPP-4 activity; post-OGTT glucose excursion; active and total incretin GIP levels; insulin, C-peptide, and glucagon concentrations; and sitagliptin pharmacokinetics. RESULTS: Sitagliptin dose-dependently inhibited plasma DPP-4 activity over 24 h, enhanced active GLP-1 and GIP levels, increased insulin/C-peptide, decreased glucagon, and reduced glycemic excursion after OGTTs administered at 2 and 24 h after single oral 25- or 200-mg doses of sitagliptin. Sitagliptin was generally well tolerated, with no hypoglycemic events. CONCLUSIONS: In this study in patients with type 2 diabetes, near maximal glucose-lowering efficacy of sitagliptin after single oral doses was associated with inhibition of plasma DPP-4 activity of 80% or greater, corresponding to a plasma sitagliptin concentration of 100 nm or greater, and an augmentation of active GLP-1 and GIP levels of 2-fold or higher after an OGTT.
Asunto(s)
Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Inhibidores de la Dipeptidil-Peptidasa IV , Polipéptido Inhibidor Gástrico/sangre , Pirazinas/farmacocinética , Triazoles/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Estudios Cruzados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Método Doble Ciego , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Femenino , Péptido 1 Similar al Glucagón/sangre , Prueba de Tolerancia a la Glucosa/métodos , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Placebos , Pirazinas/administración & dosificación , Pirazinas/efectos adversos , Pirazinas/uso terapéutico , Fosfato de Sitagliptina , Triazoles/administración & dosificación , Triazoles/efectos adversos , Triazoles/uso terapéuticoRESUMEN
The bioavailability of beta-aescin--the main active constituent of horse chestnut seed extract--in a nonretarded test medication in comparison with that in a retarded reference formulation was evaluated in 2 randomized crossover clinical trials involving 18 healthy volunteers each. Serum concentration/time curves derived under steady-state conditions and pharmacokinetic parameters measured during both studies showed no significant difference between absorption rates for the retarded versus nonretarded preparation. In the first study, investigators found a test-to-reference ratio of 1.06 (90% confidence interval [CI] range: 99-113) for the area under the curve (AUC; the primary outcome measure). Absorption rates were diminished during the night compared with daytime rates for both study preparations. In the second study, using AUC and maximum concentration (Cmax) as the primary characteristics, investigators analyzed bioavailability based on the mean of 2 consecutive daytime periods and obtained estimates of 1.07 for AUC (90% CI range: 0.96-1.19) and 1.05 for Cmax (90% CI range: 0.90-1.21). Bioequivalence of the test and reference drug preparations was thus established according to the Note for Guidance on the Investigation of Bioavailability and Bioequivalence. Both treatments were equally well tolerated.