John F. Paolini

Ezetimibe: A Review of its Metabolism, Pharmacokinetics and Drug Interactions

Ezetimibe is the first lipid-lowering drug that inhibits intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients. Following oral administration, ezetimibe is rapidly absorbed and extensively metabolised (>80%) to the pharmacologically active ezetimibe-glucuronide. Total ezetimibe (sum of parent ezetimibe plus ezetimibe-glucuronide) concentrations reach a maximum 1-2 hours post-administration, followed by enterohepatic recycling and slow elimination. The estimated terminal half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours. Consistent with the elimination half-life of ezetimibe, an approximate 2-fold accumulation is observed upon repeated once-daily administration. The recommended dose of ezetimibe 10 mg/day can be administered in the morning or evening without regard to food. There are no clinically significant effects of age, sex or race on ezetimibe pharmacokinetics and no dosage adjustment is necessary in patients with mild hepatic impairment or mild-to-severe renal insufficiency. The major metabolic pathway for ezetimibe consists of glucuronidation of the 4-hydroxyphenyl group by uridine 5-diphosphate-glucuronosyltransferase isoenzymes to form ezetimibe-glucuronide in the intestine and liver. Approximately 78% of the dose is excreted in the faeces predominantly as ezetimibe, with the balance found in the urine mainly as ezetimibe-glucuronide. Overall, ezetimibe has a favourable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between ezetimibe and a variety of drugs commonly used in patients with hypercholesterolaemia. Ezetimibe does not have significant effects on plasma levels of HMG-CoA reductase inhibitors commonly known as statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), fibric acid derivatives (gemfibrozil, fenofibrate), digoxin, glipizide, warfarin and triphasic oral contraceptives (ethinylestradiol and levonorgestrel). Concomitant administration of food, antacids, cimetidine or statins had no significant effect on ezetimibe bioavailability. Although coadministration with gemfibrozil and fenofibrate increased the bioavailability of ezetimibe, the clinical significance is thought to be minor considering the relatively flat dose-response curve of ezetimibe and the lack of dose-related increase in adverse events. In contrast, coadministration with the bile acid binding agent colestyramine significantly decreased ezetimibe oral bioavailability (based on area under the plasma concentration-time curve of total ezetimibe). Hence, ezetimibe and colestyramine should be administered several hours apart to avoid attenuating the efficacy of ezetimibe. Finally, higher ezetimibe exposures were observed in patients receiving concomitant ciclosporin, and ezetimibe caused a small but statistically significant effect on plasma levels of ciclosporin. Because treatment experience in patients receiving ciclosporin is limited, physicians are advised to exercise caution when initiating ezetimibe in the setting of ciclosporin coadministration, and to carefully monitor ciclosporin levels.

Interaction of Single-Dose Ezetimibe and Steady-State Cyclosporine in Renal Transplant Patients

This open‐label, single‐period study evaluated the single‐dose pharmacokinetics of ezetimibe (EZE) 10 mg in the setting of steady‐state cyclosporine (CyA) dosing in renal transplant patients. A single 10‐mg dose of EZE was coadministered with the morning dose of CyA (75–150 mg twice a day). Total EZE (sum of unconjugated, parent EZE and EZE‐glucuronide; EZE‐total) AUC0‐last and Cmax were compared to values derived from a prespecified database of healthy volunteers. Geometric mean ratios (90% CIs) for (EZE + CyA)/EZE alone for EZE‐total AUC(0‐last) and Cmax were 3.41 (2.55, 4.56) and 3.91 (3.13, 4.89), respectively. Compared to healthy controls, EZE‐total AUC(0‐last) was 3.4‐fold higher in transplant patients receiving CyA; similar exposure levels were seen in a prior multiple‐dose study in which EZE 50 mg was administered to healthy volunteers without dose‐related toxicity. Because the long‐term safety implications of both higher EZE exposures and undetermined effect on CyA are not yet understood, the clinical significance of this interaction is unknown.

Effects of Ezetimibe on Cyclosporine Pharmacokinetics in Healthy Subjects

This single‐center, open‐label, 2‐period crossover study investigated the effects of multiple‐dose ezetimibe (EZE) on a single dose of cyclosporine (CyA). Healthy subjects received 2 treatments in random order with a 14‐day washout: (1) CyA 100 mg alone and (2) EZE 20 mg for 7 days with CyA 100 mg coadministered on day 7; EZE 20 mg alone was administered on day 8. AUC(0‐last) and Cmax geometric mean ratios (90% confidence interval) for ([CyA + EZE]/CyA alone) were 1.15 (1.07, 1.25) and 1.10 (0.97, 1.26), respectively. Tmax (∼1.3 hours) was similar with and without EZE (P >.200). Mean CyA exposure slightly increased (∼15%) with multiple‐dose EZE 20 mg; however, this value was contained within (0.80, 1.25). The implications for chronic EZE dosing within the usual clinical paradigm of chronic CyA dosing have not been established; caution is recommended when using these agents concomitantly. CyA concentrations should be monitored in patients receiving EZE and CyA.