title: Evaluation of the effects of the weak CYP3A inhibitors atorvastatin and ethinyl estradiol/norgestimate on lomitapide pharmacokinetics in healthy subjects.
abstract: Lomitapide is a microsomal triglyceride transfer protein inhibitor approved as an adjunctive treatment for adult patients with homozygous familial hypercholesterolemia. Lomitapide is extensively metabolized via cytochrome P450 3A (CYP3A) and is a weak CYP3A inhibitor. Two phase 1 open-label, randomized (1:1), 2-arm drug interaction studies in healthy subjects assessed the effects of atorvastatin and ethinyl estradiol (EE)/norgestimate, both weak CYP3A inhibitors, on lomitapide pharmacokinetics with staggered (separated by 12 hours) or simultaneous administration. All subjects received a single dose of lomitapide (20 mg) in the evening on day 1. Atorvastatin (80 mg once daily, n = 32) or EE/norgestimate (0.035/0.25 mg once daily, n = 32) dosing was initiated on days 11 or 8, respectively, with evening (arm 1) or morning (arm 2) dosing; at steady state (days 15 or 22), a single lomitapide dose was administered; CYP3A inhibitor dosing continued for 6 days. Blood samples for pharmacokinetic analysis were taken until 168 hours postdose. With atorvastatin, lomitapide exposure was increased by approximately 2-fold and 1.3-fold, respectively, with simultaneous and staggered administration, respectively. Simultaneous and staggered EE/norgestimate and lomitapide administration resulted in an approximately 1.3-fold increase in lomitapide exposure. Reductions in lomitapide dose may be required for some patients when administered concomitantly with a weak CYP3A inhibitor.
authors.affiliation: Covance Early Clinical Biometrics, Madison, WI, USA.
authors.forename: Gina
authors.initials: G
authors.lastname: Patel
authors.affiliation: Covance Clinical Research Unit, Inc., Dallas, TX, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: King
authors.affiliation: Covance Early Clinical Biometrics, Madison, WI, USA.
authors.forename: Santanu
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Covance Early Clinical Biometrics, Madison, WI, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Korb
authors.affiliation: SGS Exprimo NV, Mechelen, Belgium.
authors.forename: Janet R
authors.initials: JR
authors.lastname: Wade
authors.affiliation: Aegerion Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Foulds
authors.affiliation: Aegerion Pharmaceuticals, Inc., Cambridge, MA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Sumeray
mesh_terms: D000293:Adolescent; D000328:Adult; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000069059:Atorvastatin / Q000009:adverse effects / Q000494:pharmacology; D001562:Benzimidazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D003277:Contraceptives, Oral, Combined / Q000009:adverse effects / Q000494:pharmacology; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D004338:Drug Combinations; D004347:Drug Interactions; D004997:Ethinyl Estradiol / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009644:Norgestrel / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000924:Anticholesteremic Agents; C473731:BMS201038; D001562:Benzimidazoles; D003277:Contraceptives, Oral, Combined; D065692:Cytochrome P-450 CYP3A Inhibitors; D004338:Drug Combinations; C109079:norgestimate, ethinyl estradiol drug combination; D009644:Norgestrel; D004997:Ethinyl Estradiol; D000069059:Atorvastatin
keywords: cardiovascular; contraception; drug interactions; lipid metabolism; pharmacokinetics and drug metabolism