ecovered in feces.
Pharmacokinetic Parameters:The pharmacokinetic parameters of repaglinide obtained from a single-dose, crossover study in healthy subjects and from a multiple-dose, parallel, dose-proportionality (0.5, 1, 2 and 4 mg) study in patients with type 2 diabetes are summarized in the following table:
*dosed preprandially with three mealsParameterPatients with type 2 diabetes*Dose 0.5 mg 1 mg 2 mg 4 mgAUC0-24 hr Mean(ng/mL*hr): 68.9154.4 125.8129.8 152.489.6 447.4211.3Dose 0.5 mg 1 mg 2 mg 4 mgCmax0-5 hr Mean(ng/mL): 9.810.2 18.39.1 26.013.0 65.830.1Dose 0.5 - 4 mgTmax0-5 hr Means (SD) 1.0 - 1.4 (0.3 - 0.5) hrDose 0.5 - 4 mgTMeans (Ind Range) 1.0 - 1.4 (0.4 - 8.0) hrParameterHealthy SubjectsCL based on i.v.3816 L/hrVss based on i.v.3112 LAbsBio569%CL= total body clearance Vss= volume of distribution at steady state AbsBio = absolute bioavailabilityThese data indicate that repaglinide did not accumulate in serum. Clearance of oral repaglinide did not change over the 0.5 - 4 mg dose range, indicating a linear relationship between dose and plasma drug levels.
Variability of Exposure:Repaglinide AUC after multiple doses of 0.25 to 4 mg with each meal varies over a wide range. The intra-individual and inter-individual coefficients of variation were 36% and 69%, respectively. AUC over the therapeutic dose range included 69 to 1005 ng/mL*hr, but AUC exposure up to 5417 ng/mL*hr was reached in dose escalation studies without apparent adverse consequences.
Special Populations
Geriatric:Healthy volunteers were treated with a regimen of 2 mg taken before each of 3 meals. There were no significant differences in repaglinide pharmacokinetics between the group of patients <65 years of age and a comparably sized group of patientsyears of age (See PRECAUTIONS,Geriatric Use).
Pediatric:No studies have been performed in pediatric patients.
Gender:
Race:No pharmacokinetic studies to assess the effects of race have been performed, but in a U.S. 1-year study in patients with type 2 diabetes, the blood glucose-lowering effect was comparable between Caucasians (n=297) and African-Americans (n=33). In a U.S. dose-response study, there was no apparent difference in exposure (AUC) between Caucasians (n=74) and Hispanics (n=33).
Drug-Drug Interactions
Drug interaction studies performed in healthy volunteers show that PRANDIN had no clinically relevant effect on the pharmacokinetic properties of digoxin, theophylline, or warfarin. Co-administration of cimetidine with PRANDIN did not significantly alter the absorption and disposition of repaglinide.
Additionally, the following drugs were studied in healthy volunteers with co-administration of PRANDIN. Listed below are the results:
CYP2C8 and CYP3A4 Inhibitors/Inducer
Gemfibrozil and Itraconazole: Co-administration of gemfibrozil (600 mg) and a single dose of 0.25 mg PRANDIN (after 3 days of twice-daily 600 mg gemfibrozil) resulted in an 8.1-fold higher repaglinide AUC and prolonged repaglinide half-life from 1.3 to 3.7 hr. Co-administration with itraconazole and a single dose of 0.25 mg PRANDIN (on the third day of a regimen of 200 mg initial dose, twice-daily 100 mg itraconazole) resulted in a 1.4-fold higher repaglinide AUC. Co-administration of both gemfibrozil and itraconazole with PRANDIN resulted in a 19-fold higher repaglinide AUC and prolonged repaglinide half-life to 6.1 hr. Plasma repaglinide concentration at 7 h increased 28.6-fold with gemfibrozil co-admin |
