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.

Drug–Drug Interactions between Atorvastatin and Dronedarone Mediated by Monomeric CYP3A4

“…Both drugs are metabolized by CYP3A4 (37, 40–44) as shown in Figure 1, and both are involved in drug-drug interactions (36–39, 41). Importantly, the highly lever-aged effects of Multaq interactions with multiple cardiac ion channels(45) make interaction with other commonly prescribed medications, such as Lipitor, extremely relevant.…”

“…To extend this previously developed approach to pharmacologically important systems, we used a combination of experimental and computational methods to conduct a detailed investigation of the metabolism of atorvastatin (a cholesterol-lowering drug, Lipitor) and dronedarone (an antiarrythmic drug, Multaq) (Figure ). Both drugs are metabolized by CYP3A4 − as shown in Figure , and both are involved in drug–drug interactions. − , Importantly, the highly leveraged effects of interactions of Multaq with multiple cardiac ion channels make interaction with other commonly prescribed medications, such as Lipitor, extremely relevant. To understand the mechanism of CYP3A4 metabolism of these compounds, we measured the rates of steady-state metabolism of both drugs separately and in mixtures.…”

Interaction and potential mechanisms between atorvastatin and voriconazole, agents used to treat dyslipidemia and fungal infections

“…Cytochrome P450 3A4 (CYP3A4) is found in approximately 30% of all hepatic metabolic enzymes in ordinary people, and it is involved in the metabolism of approximately 50% of therapeutic drugs in clinical treatment (Patel et al, 2016). If the activity of CYP3A4 is inhibited, the levels of a concomitantly administered drug in plasma will increase, and the incidence of adverse reactions will increase significantly in clinical settings (Neuvonen, 2010).…”

Pharmacokinetic interaction between fimasartan and atorvastatin in healthy male volunteers

“…When atorvastatin is administered with fimasartan, it is expected that the activity of CYP3A4 would be weakly inhibited and the first-pass effect of fimasartan would be reduced, thus increasing systemic exposure to fimasartan. As the inhibitory effect of atorvastatin is weak (defined by the US Food and Drug Administration guidelines as increasing the AUC of sensitive index substrates from >1.25- to <2-fold), 32 the extent of drug interaction with fimasartan was also expected to be weak. We were able to confirm this in our study, whereby the AUC τ,ss of fimasartan increased by only 1.35-fold after the coadministration with atorvastatin.…”