Gemfibrozil and Pioglitazone: Interaction Details

a) Concomitant use of pioglitazone and gemfibrozil did not result in an increased risk of severe hypoglycemia resulting in emergency department treatment or hospitalization during the first 30 days compared with pioglitazone and pravastatin, though the risk was significantly increased during the first 180 days (adjusted HR, 1.6; 95% CI, 1.32 to 1.93) in a propensity-score adjusted analysis (n=11,531). The risk of severe hypoglycemia increased monotonically with time during later months of concomitant use, with the highest risk of 2.6-fold noted during days 120 to 180. The mechanism for this interaction may be more complex than CYP2C8 inhibition by fibrates and may include a pharmacodynamic interaction involving the impact of fibrates on glucose. Patients received a thiazolidinedione (rosiglitazone or pioglitazone) and an antihyperlipidemic (atorvastatin, fenofibrate, fluvastatin, gemfibrozil, lovastatin, pravastatin, rosuvastatin, or simvastatin) during the study. Pravastatin served as the reference exposure as it is a negligible inhibitor of CYP450 isoenzymes and would not be expected to interact ².

b) The pioglitazone AUC increased 3.2-fold and the t(1/2) increased 2.7 fold when coadministered with gemfibrozil in a randomized, placebo-controlled, 4-phase crossover study. Healthy, male volunteers (N=12) were randomized to placebo or gemfibrozil 600 mg twice daily orally for 4 days. On day 3, a single dose of pioglitazone 15 mg orally was administered. After a 4-week washout, volunteers received the alternate of placebo or gemfibrozil. The mean AUC (0 to infinity) of pioglitazone was 5.25 mg x hours (hr)/L (+/- 2.33 mg x hr/L) for the placebo phase and 16.91 mg x hr/L (+/- 5.47 mg x hr/L) for the gemfibrozil phase. The mean t(1/2) of pioglitazone was 8.3 hours (+/- 2.2 hours) for the placebo phase and 22.7 hours (+/- 7.6 hours) for the gemfibrozil phase. The AUCs (0 to 48 hr) of the pioglitazone metabolites (M-III and M-IV) were significantly decreased during the gemfibrozil phase compared with the placebo phase ³.

c) The AUC of pioglitazone increased 3.4-fold, and the t(1/2) of pioglitazone and its metabolites approximately doubled when coadministered with gemfibrozil in a randomized, 2-phase, crossover study. Healthy, male volunteers (N=10) were randomized to placebo or gemfibrozil 600 mg twice daily orally for a week. On day 4, a single dose of pioglitazone 30 mg orally was administered. After a 2-week washout, volunteers received the alternate of placebo or gemfibrozil. The mean AUC (0 to infinity) of pioglitazone was 11.1 mcg x hours (hr)/mL (range, 8.3 to 13.8 mcg x hr/mL) for the placebo phase and 37.5 mcg x hr/mL (range, 30.5 to 44.5 mcg x hr/mL) for the gemfibrozil phase. The mean t(1/2) of pioglitazone was 6.5 hours (range, 5.1 to 7.6 hours) for the placebo phase and 15.1 hours (range, 13.4 to 17.1 hours) for the gemfibrozil phase. The AUCs of the pioglitazone metabolites (M-III and M-IV) were not significantly different between the placebo and gemfibrozil phase. The half-lives for M-III and M-IV increased from 25.6 hours and 24.6 hours, respectively, for the placebo phase to 50 hours and 44 hours, respectively, for the gemfibrozil phase ⁴.