Pharmacokinetic Interactions of the Microsomal Triglyceride Transfer Protein Inhibitor, Lomitapide, with Drugs Commonly Used in the Management of Hypercholesterolemia

• Published in: Pharmacotherapy 2014-03, Vol.34 (3), p.227-239
• Main Authors: Tuteja, Sony, Duffy, Danielle, Dunbar, Richard L., Movva, Rajesh, Gadi, Ram, Bloedon, LeAnne T., Cuchel, Marina
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Anticholesteremic Agents - administration & dosage; Anticholesteremic Agents - pharmacokinetics; Benzimidazoles - administration & dosage; Benzimidazoles - pharmacokinetics; Biological and medical sciences; Carrier Proteins - antagonists & inhibitors; CYP3A4; Disease Management; Disorders of blood lipids. Hyperlipoproteinemia; Dose-Response Relationship, Drug; drug interaction; Drug Interactions - physiology; Drug Therapy, Combination; Female; Humans; Hypercholesterolemia - drug therapy; Hypercholesterolemia - metabolism; lomitapide; Male; Medical sciences; Metabolic diseases; Middle Aged; Pharmacology. Drug treatments; Prospective Studies; statins; Young Adult
• ISSN: 0277-0008; 1875-9114
• DOI: 10.1002/phar.1351

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 atorva