Specific Populations

Hepatic Impairment

A single-dose, open-label study was conducted to eva luate the pharmacokinetics of 60 mg lomitapide in healthy volunteers with normal hepatic function compared with patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. In patients with moderate hepatic impairment, lomitapide AUC and Cmax were 164% and 361% higher, respectively, compared with healthy volunteers. In patients with mild hepatic impairment, lomitapide AUC and Cmax were 47% and 4% higher, respectively, compared with healthy volunteers. Lomitapide has not been studied in patients with severe hepatic impairment (Child-Pugh score 10-15) [see Dosage and Administration (2.6), Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.8)].

Renal Impairment

A single-dose, open-label study was conducted to eva luate the pharmacokinetics of 60 mg lomitapide in patients with end-stage renal disease receiving hemodialysis compared with healthy volunteers with normal renal function. Healthy volunteers had estimated creatinine clearance >80 mL/min by the Cockcroft-Gault equation. Compared with healthy volunteers, lomitapide AUC0-inf and Cmax were 40% and 50% higher, respectively, in patients with end-stage renal disease receiving hemodialysis. Effects of mild, moderate, and severe renal impairment as well as end-stage renal disease not yet on dialysis on lomitapide exposure have not been studied [see Dosage and Administration (2.5) and Use in Specific Populations (8.7)].

Drug Interactions

[see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.6), (5.7), (5.8), and Drug Interactions (7)].

In vitro Assessment of Drug Interactions

Lomitapide does not induce CYPs 1A2, 3A4, or 2B6. Lomitapide inhibits CYP3A4. Lomitapide does not inhibit CYPs 1A2, 2B6, 2C9, 2C19, 2D6, or 2E1. M1 and M3 do not induce CYPs 1A2, 3A4, or 2B6. M1 and M3 do not inhibit CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4. Lomitapide is not a P-gp substrate. Lomitapide inhibits P-gp but does not inhibit breast cancer resistance protein (BCRP).

Effects of other Drugs on Lomitapide

Table 5 summarizes the effect of coadministered drugs on lomitapide AUC and Cmax.

Table 5: Effect of Coadministered Drugs on Lomitapide Systemic Exposure  BID = twice daily; QD = once daily
↑ = increase
COADMINISTERED
DRUG DOSING OF
COADMINISTERED
DRUG DOSING OF
LOMITAPIDE RATIO OF LOMITAPIDE EXPOSURE
WITH/WITHOUT
COADMINISTERED DRUG
NO EFFECT = 1
    AUC Cmax
Contraindicated with lomitapide [see Contraindications (4) and Warnings and Precautions (5.6)]
Ketoconazole 200 mg BID for 9 days 60 mg QD   ↑ 27 ↑ 15
CYP3A4 Inhibitors

Lomitapide exposure increased 27-fold in the presence of ketoconazole, a strong CYP3A4 inhibitor. Thus, concomitant use of strong CYP3A4 inhibitors and lomitapide is contraindicated. The effect of moderate CYP3A4 inhibitors on lomitapide exposure has not been studied. However, moderate CYP3A4 inhibitors will likely increase lomitapide exposure significantly based on the results of concomitant use of strong and weak CYP3A4 inhibitors [see Drug Interactions (7