Arthur J. Bergman

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.

Pharmacokinetics and Pharmacodynamic Effects of the Oral DPP-4 Inhibitor Sitagliptin in Middle-Aged Obese Subjects

Sitagliptin (MK‐0431) is an oral, potent, and selective dipeptidyl peptidase‐IV (DPP‐4) inhibitor developed for the treatment of type 2 diabetes. This multicenter, randomized, double‐blind, placebo‐controlled study examined the pharmacokinetic and pharmacodynamic effects of sitagliptin in obese subjects. Middle‐aged (45–63 years), nondiabetic, obese (body mass index: 30–40 kg/m2) men and women were randomized to sitagliptin 200 mg bid (n = 24) or placebo (n = 8) for 28 days. Steady‐state plasma concentrations of sitagliptin were achieved within 2 days of starting treatment, and >90% of the dose was excreted unchanged in urine. Sitagliptin treatment led to ∼90% inhibition of plasma DPP‐4 activity, increased active glucagon‐like peptide‐1 (GLP‐1) levels by 2.7‐fold (P < .001), and decreased post—oral glucose tolerance test glucose excursion by 35% (P < .050) compared to placebo. In nondiabetic obese subjects, treatment with sitagliptin 200 mg bid was generally well tolerated without associated hypoglycemia and led to maximal inhibition of plasma DPP‐4 activity, increased active GLP‐1, and reduced glycemic excursion.

Metabolism And Excretion of the Dipeptidyl Peptidase 4 Inhibitor [14C]Sitagliptin in Humans

The metabolism and excretion of [14C]sitagliptin, an orally active, potent and selective dipeptidyl peptidase 4 inhibitor, were investigated in humans after a single oral dose of 83 mg/193 μCi. Urine, feces, and plasma were collected at regular intervals for up to 7 days. The primary route of excretion of radioactivity was via the kidneys, with a mean value of 87% of the administered dose recovered in urine. Mean fecal excretion was 13% of the administered dose. Parent drug was the major radioactive component in plasma, urine, and feces, with only 16% of the dose excreted as metabolites (13% in urine and 3% in feces), indicating that sitagliptin was eliminated primarily by renal excretion. Approximately 74% of plasma AUC of total radioactivity was accounted for by parent drug. Six metabolites were detected at trace levels, each representing <1 to 7% of the radioactivity in plasma. These metabolites were the N-sulfate and N-carbamoyl glucuronic acid conjugates of parent drug, a mixture of hydroxylated derivatives, an ether glucuronide of a hydroxylated metabolite, and two metabolites formed by oxidative desaturation of the piperazine ring followed by cyclization. These metabolites were detected also in urine, at low levels. Metabolite profiles in feces were similar to those in urine and plasma, except that the glucuronides were not detected in feces. CYP3A4 was the major cytochrome P450 isozyme responsible for the limited oxidative metabolism of sitagliptin, with some minor contribution from CYP2C8.

Simvastatin Does Not Have a Clinically Significant Pharmacokinetic Interaction With Fenofibrate in Humans

Simvastatin and fenofibrate are both commonly used lipid‐regulating agents with distinct mechanisms of action, and their coadministration may be an attractive treatment for some patients with dyslipidemia. A 2‐period, randomized, open‐label, crossover study was conducted in 12 subjects to determine if fenofibrate and simvastatin are subject to a clinically relevant pharmacokinetic interaction at steady state. In treatment A, subjects received an 80‐mg simvastatin tablet in the morning for 7 days. In treatment B, subjects received a 160‐mg micronized fenofibrate capsule in the morning for 7 days, followed by a 160‐mg micronized fenofibrate capsule dosed together with an 80‐mg simvastatin tablet on days 8 to 14. Because food increases the bioavailability of fenofibrate, each dose was administered with food to maximize the exposure of fenofibric acid. The steady‐state pharmacokinetics (AUC0–24h, Cmax, and tmax) of active and total HMG‐CoA reductase inhibitors, simvastatin acid, and simvastatin were determined following simvastatin administration with and without fenofibrate. Also, fenofibric acid steady‐state pharmacokinetics were evaluated with and without simvastatin. The geometric mean ratios (GMRs) for AUC0–24h (80 mg simvastatin [SV] + 160 mg fenofibrate)/(80 mg simvastatin alone) and 90% confidence intervals (CIs) were 0.88 (0.80, 0.95) and 0.92 (0.82, 1.03) for active and total HMG‐CoA reductase inhibitors. The GMRs and 90% CIs for fenofibric acid (80 mg SV + 160 mg fenofibrate/160 mg fenofibrate alone) AUC0–24h and Cmax were 0.95 (0.88, 1.04) and 0.89 (0.77, 1.02), respectively. Because both the active inhibitor and fenofibric acid AUC GMR 90% confidence intervals fell within the prespecified bounds of (0.70, 1.43), no clinically significant pharmacokinetic drug interaction between fenofibrate and simvastatin was concluded in humans. The coadministration of simvastatin and fenofibrate in this study was well tolerated.

Tolerability and pharmacokinetics of metformin and the dipeptidyl peptidase-4 inhibitor sitagliptin when co-administered in patients with type 2 diabetes

ABSTRACT Objective: As part of the clinical development of sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of type 2 diabetes, the potential for pharmacokinetic interactions with other antihyperglycemic agents used in managing patients with type 2 diabetes are being carefully evaluated. The purposes of this study were to evaluate the tolerability of co-administered sitagliptin and metformin and effects of sitagliptin on metformin pharmacokinetics as well as metformin on sitagliptin pharmacokinetics under steady-state conditions. Methods: This placebo-controlled, multiple-dose, crossover study in patients with type 2 diabetes assessed the tolerability of co-administered sitagliptin (50u2009mg b.i.d.) with metformin (1000u2009mg b.i.d.). Patients received, in a randomized crossover manner, three treatments (each of 7 days duration): 50u2009mg sitagliptin twice daily and placebo to metformin twice daily; 1000u2009mg of metformin twice daily and placebo to sitagliptin twice daily; concomitant administration of 50u2009mg of sitagliptin twice daily and 1000u2009mg of metformin twice daily. Following dosing on Day 7 of each treatment period, these pharmacokinetic parameters were determined for plasma sitagliptin and metformin: area under the plasma concentrations–time curve over the dosing interval (AUC0–12 h), maximum observed plasma concentrations (Cmax), and time of occurrence of maximum observed plasma concentrations (Tmax). Renal clearance was also determined for sitagliptin. Results: In this study, no adverse experiences were reported by 11 of 13 patients. Two patients had adverse experiences, which were not related to study drugs as determined by the investigators. The mean metformin plasma concentration–time profiles were nearly identical with or without sitagliptin co-administration [metformin AUC0–12 h geometric mean ratio (GMR; [metformin + sitagliptin]/metformin)] was 1.02 (90% CI 0.95, 1.09). Similarly metformin administration did not alter the plasma sitagliptin pharmacokinetics [sitagliptin AUC0–12 h GMR ([sitagliptin + metformin]/sitagliptin)] was 1.02 (90% CI 0.97, 1.08) or renal clearance of sitagliptin. No efficacy measurements (glycosylated hemoglobin or fasting plasma glucose) were obtained during this study. Urinary pharmacokinetics for metformin were not determined due to the lack of effect of sitagliptin on plasma metformin pharmacokinetics. Conclusions: In this study, co-administration of sitagliptin and metformin was generally well tolerated in patients with type 2 diabetes and did not meaningfully alter the steady-state pharmacokinetics of either agent.

Pharmacokinetics of Aprepitant After Single and Multiple Oral Doses in Healthy Volunteers

Aprepitant is the first NK1 receptor antagonist approved for use with corticosteroids and 5HT3 receptor antagonists to prevent chemotherapy‐induced nausea and vomiting (CINV). The effective dose to prevent CINV is a 125‐mg capsule on day 1 followed by an 80‐mg capsule on days 2 and 3. Study 1 evaluated the bioavailability of the capsules and estimated the effect of food. The mean (95% confidence interval [CI]) bioavailabilities of 125‐mg and 80‐mg final market composition (FMC) capsules, as assessed by simultaneous administration of stable isotope‐labeled intravenous (IV) aprepitant (2 mg) and FMC capsules, were 0.59 (0.53, 0.65) and 0.67 (0.62, 0.73), respectively. The geometric mean (90% CI) area under the plasma concentration time curve (AUC) ratios (fed/fasted) were 1.2 (1.10, 1.30) and 1.09 (1.00, 1.18) for the 125‐mg and 80‐mg capsule, respectively, demonstrating that aprepitant can be administered independently of food. Study 2 defined the pharmacokinetics of aprepitant administered following the 3‐day regimen recommended to prevent CINV (125 mg/80 mg/80 mg). Consistent daily plasma exposures of aprepitant were obtained following this regimen, which was generally well tolerated.

Metabolism and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Humans

Anacetrapib is a novel cholesteryl ester transfer protein inhibitor being developed for the treatment of primary hypercholesterolemia and mixed dyslipidemia. The absorption, distribution, metabolism, and excretion of anacetrapib were investigated in an open-label study in which six healthy male subjects received a single oral dose of 150 mg and 165 μCi of [14C]anacetrapib. Plasma, urine, and fecal samples were collected at predetermined times for up to 14 days postdose and were analyzed for total radioactivity, the parent compound, and metabolites. The majority of the administered radioactivity (87%) was eliminated by fecal excretion, with negligible amounts present in urine (0.1%). The peak level of radioactivity in plasma (∼2 μM equivalents of [14C]anacetrapib) was achieved ∼4 h postdose. The parent compound was the major radioactive component (79–94% of total radioactivity) in both plasma and feces. Three oxidative metabolites, M1, M2, and M3, were detected in plasma and feces and were identified as the O-demethylated species (M1) and two secondary hydroxylated derivatives of M1 (M2 and M3). Each metabolite was detected at low levels, representing ≤14% of the radioactivity in plasma or fecal samples. In vitro data indicated that anacetrapib is metabolized mainly by CYP3A4 to form M1, M2, and M3. Overall, these data, along with those from other preclinical and clinical studies, indicate that anacetrapib probably exhibits a low-to-moderate degree of oral absorption in humans and the absorbed fraction of the dose is eliminated largely via CYP3A4-catalyzed oxidative metabolism, followed by excretion of metabolites by the biliary-fecal route.

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.