Pharmacokinetic interactions of the microsomal triglyceride transfer protein inhibitor, lomitapide, with drugs commonly used in the management of hypercholesterolemia.

Study Objective: To characterize the effects of two doses (10 and 60 mg) of lomitapide—a microsomal triglyceride transfer protein inhibitor approved as adjunct treatment to lower low-density lipoprotein cholesterol levels in patients with homozygous familial hypercholesterolemia—on the pharmacokinetics of several lipid-lowering therapies: atorvastatin, simvastatin, rosuvastatin, fenofibrate, ezetimibe, and niacin.

Design: Two prospective open-label studies (study 1 and study 2).

Setting: Two clinical research units.

Subjects: A total of 130 healthy volunteers (114 subjects in study 1 and 16 subjects in study 2).

Intervention: In study 1, subjects were enrolled sequentially to one of the following eight open-label treatment arms (probe drug + lomitapide): atorvastatin 20 mg + lomitapide 10 mg, atorvastatin 20 mg + lomitapide 60 mg, simvastatin 20 mg + lomitapide 10 mg, rosuvastatin 20 mg + lomitapide 10 mg, rosuvastatin 20 mg + lomitapide 60 mg, fenofibrate 145 mg + lomitapide 10 mg, ezetimibe 10 mg + lomitapide 10 mg, and extended-release niacin 1000 mg + lomitapide 10 mg. Study 2 consisted of the ninth treatment arm: simvastatin 40 mg + lomitapide 60 mg. Subjects received one dose of the probe drug on the morning of day 1. On days 2–7, subjects took their dose of lomitapide once/day in the morning. On day 8, subjects received one dose of lomitapide simultaneously with the same probe drug they took on day 1. Subjects returned 1 week later (day 15) for a final visit to check safety laboratory parameters.

Measurements And Main Results: A full pharmacokinetic profile was performed for the probe drug on day 1 and day 8 (after 7 days of dosing with lomitapide [i.e., at steady state]). Pharmacokinetic parameters were calculated from the plasma concentration-time data for each day by using noncompartmental methods. Analysis of variance was applied to the ln-transformed maximum concentration (Cmax) and area under the plasma concentration-time curve from time 0–t (AUC0–t) values, and ratios of the means were compared for day 8 versus day 1. Lomitapide increased exposure to the statin medications. The percent least squares means ratios (LSMR%) (90% confidence intervals [CIs]) for AUC0–t of the statin medications with lomitapide at the 60 mg dose were as follows: 129 (115–144) for the sum of the active atorvastatin moieties, 168 (139–203) for simvastatin acid, and 132 (112–157) for rosuvastatin. The LSMR% (90% CI) for Cmax was 138 (120–160) for the sum of the active atorvastatin moieties, 157 (133–186) for simvastatin acid, and 104 (82–32) for rosuvastatin. The LSMRs were not appreciably altered for the other probe drugs.

Conclusion: This study shows that lomitapide is a weak inhibitor of CYP3A4 and increased the exposure of statin medications. Careful monitoring of adverse events of CYP3A4-metabolized statins should be used when initiating therapy with lomitapide.