No influence of moderate hepatic impairment on the pharmacokinetics of lumiracoxib, an oral COX-2 selective inhibitor.

The aim of this study was to evaluate the influence of hepatic impairment on the pharmacokinetics (PK) of the novel cyclooxygenase-2 (COX-2) selective inhibitor lumiracoxib (Prexige), so that dose recommendations for clinical use can be provided. This was an open-label, single dose, case-controlled study in which eight subjects with liver cirrhosis classed as moderate hepatic impairment (Child-Pugh score: 7-9) and eight demographically-matched healthy subjects received a single oral 400 mg dose of lumiracoxib. Routine safety assessments were made and blood samples were taken for determination of lumiracoxib concentrations for 96 h post dose. The ex vivo binding of lumiracoxib to plasma proteins was determined pre dose and at 2 and 12 h post dose. An analysis of variance was used to detect differences in PK parameters (AUC, Cmax and Tmax) between the treatment groups. There were no significant differences between subjects with moderate hepatic insufficiency and healthy subjects in the area under the lumiracoxib plasma concentration-time curves (AUC(0-infinity)): 29.2 +/- 6.7 microg h ml(-1) versus 28.7 +/- 6.3 mircrog h ml(-1). The rate of absorption of lumiracoxib was not significantly altered by hepatic impairment based on Cmax and Tmax. The protein-bound fraction of lumiracoxib exceeded 98% both in healthy control subjects and in those with moderate hepatic insufficiency. A single dose of 400 mg lumiracoxib was well tolerated. In conclusion, no dose adjustments appear to be required when lumiracoxib is administered to patients with either mild or moderate hepatic impairment.

Mealtime glucose regulation with nateglinide in healthy volunteers: comparison with repaglinide and placebo.

OBJECTIVE: This study was designed to compare the pharmacodynamic effects of single doses of nateglinide (A-4166), repaglinide, and placebo on mealtime insulin secretion and glycemic control in healthy subjects. RESEARCH DESIGN AND METHODS: Fifteen healthy volunteers participated in this open-label five-period crossover study. They received single 10-min preprandial doses of 120 mg nateglinide, 0.5 or 2 mg repaglinide, or placebo or 1 min preprandially of 2 mg repaglinide. Subjects received each dose only once, 48 h apart. Pharmacodynamic and pharmacokinetic assessments were performed from 0 to 12 h postdose. RESULTS: Nateglinide induced insulin secretion more rapidly than 2 and 0.5 mg repaglinide and placebo (10 min preprandial), with mean rates of insulin rise of 2.3, 1.3, 1.15, and 0.8 microU x ml(-1) x min(-1), respectively, over the 0- to 30-min postmeal interval. After peaking, insulin concentrations decreased rapidly in the nateglinide-treated group and were similar to placebo within 2 h postdose. After 2 mg repaglinide, peak insulin concentrations were delayed and returned to baseline more slowly than with nateglinide treatment. Nateglinide treatment produced lower average plasma glucose concentrations in the 0- to 2-h postdose interval than either dose of repaglinide and placebo (P < 0.05 vs. 0.5 mg repaglinide and placebo). Plasma glucose concentrations returned more rapidly to predose levels with nateglinide treatment than with either dose of repaglinide. Treatment with repaglinide produced a sustained hypoglycemic effect up to 6 h postdose. CONCLUSIONS: In this single-dose study in nondiabetic volunteers, nateglinide provided a more rapid and shorter-lived stimulation of insulin secretion than repaglinide, resulting in lower meal-related glucose excursions. If similar results are observed in diabetes, nateglinide may produce a more physiological insulin secretory response with the potential for a reduced risk of postabsorptive hypoglycemia.