RESUMEN
OBJECTIVE: To compare the pharmacokinetics and glucodynamics of three rapid-acting insulin analogs (aspart, glulisine, and lispro) injected subcutaneously with or without recombinant human hyaluronidase (rHuPH20). RESEARCH DESIGN AND METHODS: This double-blind six-way crossover euglycemic glucose clamp study was conducted in 14 healthy volunteers. Each analog was injected subcutaneously (0.15 units/kg) with or without rHuPH20. RESULTS: The commercial formulations had comparable insulin time-exposure and time-action profiles as follows: 50% exposure at 123-131 min and 50% total glucose infused at 183-186 min. With rHuPH20, the analogs had faster yet still comparable profiles: 50% exposure at 71-79 min and 50% glucose infused at 127-140 min. The accelerated absorption with rHuPH20 led to twice the exposure in the first hour and half the exposure beyond 2 h, which resulted in 13- to 25-min faster onset and 40- to 49-min shorter mean duration of insulin action. CONCLUSIONS: Coinjection of rHuPH20 with rapid-acting analogs accelerated insulin exposure, producing an ultra-rapid time-action profile with a faster onset and shorter duration of insulin action.
Asunto(s)
Hialuronoglucosaminidasa/farmacocinética , Hipoglucemiantes/farmacocinética , Insulina de Acción Corta/farmacocinética , Insulina/análogos & derivados , Insulina/farmacocinética , Adulto , Estudios Cruzados , Método Doble Ciego , Interacciones Farmacológicas , Femenino , Humanos , Hialuronoglucosaminidasa/administración & dosificación , Hipoglucemiantes/administración & dosificación , Inyecciones Subcutáneas , Insulina/administración & dosificación , Insulina de Acción Corta/administración & dosificación , MasculinoRESUMEN
BACKGROUND: This study was designed to test the hypothesis that co-administration of recombinant human hyaluronidase (rHuPH20) with regular insulin or insulin lispro will reduce intrasubject variability in pharmacokinetic end points compared with lispro alone. METHODS: Healthy adult volunteers (18-55 years old) were enrolled in this phase 1, randomized, double-blind, crossover study. Subjects were administered two injections, each on a separate occasion, of three treatments during six euglycemic clamps. Treatments were 0.15 U/kg insulin lispro, 0.15 U/kg insulin lispro with 5 µg/mL rHuPH20, and 0.15 IU/kg regular insulin with 5 µg/mL rHuPH20. Insulin formulations were administered at a concentration of 40 U/mL. Serum immunoreactive insulin levels, blood glucose concentration, and glucose infusion rate determinations were made at baseline and for approximately 8 h after study drug administration. Intrasubject variability was assessed using a general linear mixed model with a fixed effect for treatment using a compound symmetric covariance matrix. RESULTS: Co-injection of rHuPH20 with lispro significantly reduced intrasubject root mean square differences in time to peak serum insulin, time to early 50% peak serum insulin (t(50%)), and time to late t(50%) levels compared with lispro alone. Also, the intrasubject coefficient of variation for percentage of total area under the plasma concentration-versus-time curve for early time intervals compared with lispro alone was reduced. Intrasubject variability for regular insulin with rHuPH20 for most pharmacokinetic parameters was similar to the variability of lispro alone, although variability in early exposure was significantly reduced. CONCLUSIONS: Co-administration of rHuPH20 with lispro significantly reduced the variability of insulin pharmacokinetics relative to insulin lispro alone.
Asunto(s)
Hialuronoglucosaminidasa/farmacología , Insulina Lispro/administración & dosificación , Insulina Lispro/farmacocinética , Adolescente , Adulto , Glucemia/metabolismo , Péptido C/sangre , Estudios Cruzados , Método Doble Ciego , Sinergismo Farmacológico , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Hialuronoglucosaminidasa/administración & dosificación , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacología , Adulto JovenRESUMEN
BACKGROUND: Several authors, mostly on the basis of nonrandomized studies, have suggested dietary trivalent chromium supplementation as an attractive option for the management of type 2 diabetes and for glycemic control in persons at high risk of type 2 diabetes. OBJECTIVE: The study aimed to determine the effect of chromium on glucose and insulin responses in healthy subjects and in individuals with glucose intolerance or type 2 diabetes. DESIGN: The study design was a systematic review and meta-analysis of randomized clinical trials (RCTs). RESULTS: The authors identified 20 reports of RCTs assessing the effect of chromium on glucose, insulin, or glycated hemoglobin (Hb A(1c)). This review summarizes data on 618 participants from the 15 trials that reported adequate data: 193 participants had type 2 diabetes and 425 were in good health or had impaired glucose tolerance. The meta-analysis showed no association between chromium and glucose or insulin concentrations among nondiabetic subjects. A study of 155 diabetic subjects in China showed that chromium reduced glucose and insulin concentrations; the combined data from the 38 diabetic subjects in the other studies did not. Three trials reported data on Hb A(1c): one study each of persons with type 2 diabetes, persons with impaired glucose tolerance, and healthy subjects. The study of diabetic subjects in China was the only one to report that chromium significantly reduced Hb A(1c). CONCLUSIONS: Data from RCTs show no effect of chromium on glucose or insulin concentrations in nondiabetic subjects. The data for persons with diabetes are inconclusive. RCTs in well-characterized, at-risk populations are necessary to determine the effects of chromium on glucose, insulin, and Hb A(1c).