NLA Poster - Is it Safe to Take a Weak CYP3A4 Inhibitor with Lomitapide?

Lorraine L. Janeczko, MPH

In a study of healthy participants, simultaneous dosing of the weak CYP3A4 inhibitor atorvastatin with lomitapide roughly doubled their lomitapide exposure and increased the incidence of adverse events (AEs). Alternating the doses of atorvastatin with lomitapide by 12 hours resulted in 1.3-fold increased lomitapide levels with no additional AEs. No clinically relevant lomitapide exposure change was found with ethinyl estradiol (EE)/norgestimate, according to results presented in a poster at the National Lipid Association Scientific Sessions, June 10-14, 2015, in Chicago, Illinois.1
Because the participants varied in their responses, the authors advised that patients be monitored individually when dosing lomitapide with these agents. If simultaneous dosing with a weak CYP3A4 inhibitor is necessary, reducing the lomitapide might be considered, followed by a cautious re-uptitration, according to safety and tolerability.
Lomitapide, a CYP3A4 substrate, is a microsomal triglyceride transfer protein inhibitor used to treat homozygous familial hypercholesterolemia (HoFH).
To investigate the effects of the weak CYP3A4 inhibitors atorvastatin and (EE)/norgestimate on lomitapide pharmacokinetics, lead study author Gina Patel, MPharm, PhD, of Covance Clinical Data Analysis and Reporting Organization, in Madison, Wisconsin, and colleagues investigated healthy participants in two phase 1, open-label, randomized trials.
In the first period, all participants received single-dose lomitapide (20 mg) in the evening on Day 1. In period 2, they received either atorvastatin (80 mg once daily; n=32) or EE/norgestimate (0.035 mg/0.25 mg once daily; n=32). Dosing was begun on Days 11 or 8, respectively, with evening dosing in group 1 and morning dosing in group 2. At steady state (Days 15 or 22, respectively) a single 20-mg dose of lomitapide was given, and the CYP3A4 inhibitor was continued for 6 more days. Blood was taken for testing for up to 168 hours post-lomitapide dose.
Atorvastatin and lomitapide given together led to a roughly 2-fold increase in lomitapide exposure, while the agents given 12 hours apart resulted in a 1.3-fold increase. EE/norgestimate and lomitapide given together and 12 hours apart resulted in a roughly 1.3-fold increase in lomitapide exposure.

About Homozygous Familial Hypercholesterolemia (HoFH)

Homozygous familial hypercholesterolemia (HoFH) is a rare, genetic lipid disorder that typically arises due to defects in low-density lipoprotein (LDL) receptor genes with eventual impaired or total loss of LDL receptor function and inability to remove LDL cholesterol (LDL-C) from the blood. As a result, LDL-C levels in patients with untreated HoFH can typically be extremely elevated, between 400 mg/dL and 1000 mg/dL.2
Patients with HoFH can develop atherosclerosis during their first decade of life, and they can be at high risk for cardiovascular problems and serious cardiac events as young as in their 20s.2


1. Patel G, Dutta S, King TA, et al. Evaluation of effects of the weak CYP3A4 inhibitors  atorvastatin and ethinyl estradiol/norgestimate on lomitapide pharmacokinetics in healthy subjects. Presented at: the National Lipid Association Scientific Sessions 2015; June 11-14, 2015; Chicago, IL. Abstract 148.
2. Aegerion Pharmaceuticals. Accessed June 13, 2015.
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