Effects of timing of administration and meal composition on the pharmacokinetic and pharmacodynamic characteristics of the short-acting oral hypoglycemic agent nateglinide in healthy subjects

These studies examined the influence of timing of administration of nategli nide on the glucose profile and beta -cell secretory response to a standard ized test meal and the effect of meal composition on the pharmacokinetic an d pharmacodynamic profile. In study 1, nateglinide (60 mg) or placebo was g iven orally at -10, -1, or +10 min to healthy subjects (n = 12), in relatio n to a standardized test meal (500 kcal) that commenced at 0 min. In study 2, also in healthy subjects (n = 12), a single oral dose (60 mg) of nategli nide was given either 10 min before or 10 min after the start of each of th ree different test meals (i.e. high in carbohydrate, fat, or protein). In b oth studies, the postmeal observation period was a minimum of 240 min. In t he first study premeal (-10, -1 min), administration of nateglinide led to earlier and higher peak plasma nateglinide concentrations, compared with po stprandial dosing (+10 min). A significantly lower maximum postprandial glu cose concentration was seen with preprandial dosing compared with either pl acebo (P < 0.01) or nateglinide given postprandially (P < 0.01). The impact on the glucose profile was consistent with the enhanced insulin profiles a fter nateglinide, resulting in higher peak plasma insulin concentrations co mpared with placebo (P < 0.01). Study 2 confirmed the greater impact of pre - vs. postprandial dosing on the glucose and insulin profiles, irrespective of meal type. Nateglinide administration, before a meal, resulted in a mor e rapid rise and higher peak nateglinide plasma concentrations, irrespectiv e of meal composition. Preprandial administration of nateglinide was more e ffective in reducing prandial glucose excursions, compared with postmeal do sing (+10 min), a consequence of the earlier insulin response.