Lomitapide

Lomitapide is a selective inhibitor of microsomal transfer protein (MTP), an intracellular lipid-transfer protein that is found in the lumen of the endoplasmic reticulum and is responsible for binding and shuttling individual lipid molecules between membranes. MTP plays a key role in the assembly of apo B containing lipoproteins in the liver and intestines. Inhibition of MTP reduces lipoprotein secretion and circulating concentrations of lipoprotein-borne lipids including cholesterol and triglycerides.

Absorption

The absolute oral bioavailability of lomitapide is 7%. Absorption is not limited by penetration of the active substance across the intestinal barrier but is predominantly influenced by an extensive first pass effect. Peak plasma concentrations of lomitapide were reached 4-8 hours following oral dosing. Lomitapide pharmacokinetics is approximately dose-proportional for oral single doses in the therapeutic range. Doses higher than 60 mg suggest a trend toward nonlinearity and are not recommended.

Upon multiple dosing C_max and AUC increased in approximate proportion to lomitapide dose. C_max and AUC were increased following either a high-fat meal (77% and 58%, respectively) or low fat meal (70% and 28%, respectively). Accumulation of lomitapide in plasma was consistent with that predicted after a single dose following once daily oral dosing above 25 mg for up to 4 weeks. Inter-individual variability in lomitapide AUC was approximately 50%.

At steady state the accumulation of lomitapide was 2.7 at 25 mg and 3.9 at 50 mg.

Distribution

Following intravenous administration, the volume of distribution of lomitapide was high (mean = 1 200 litres) despite a high degree (> 99.8%) of binding to plasma protein. In animal studies lomitapide was highly concentrated (200-fold) in the liver.

Biotransformation

Lomitapide is extensively metabolised, predominantly by CYP3A4. CYP isoforms 2E1, 1A2, 2B6, 2C8, and 2C19 are involved to a lesser extent and isoforms 2D6 and 2C9 are not involved in the metabolism of lomitapide.

Elimination

Following administration of a radiolabeled oral solution dose to healthy subjects, 93% of the administered dose was recovered in urine and faeces. Approximately 33% of the radioactivity was excreted in urine as metabolites. The remainder was excreted in faeces, primarily as oxidised metabolites. The elimination half-life of lomitapide was approximately 29 hours.

Special populations

Data in the pivotal clinical study were analysed with respect to the impact of potential covariates on lomitapide exposure. Of the parameters examined (race, body mass index (BMI), gender, weight, age), only BMI could be classified as a potential covariate.

Age and gender

There was no clinically relevant effect of age (18-64 years) or gender on the pharmacokinetics of lomitapide. Lomitapide has not been investigated in patients aged 65 years or older.

Race

No dose adjustment is required for Caucasian or Latino patients. There is insufficient information to determine if lomitapide requires dose adjustment in other races. However, since the medicinal product is dosed in an escalating fashion according to individual patient safety and tolerability, no adjustment to the dosing regimen is recommended based on race.

Renal insufficiency

In the renal impairment population, lomitapide was only studied in patients with end-stage renal disease (ESRD). A pharmacokinetic study in patients with ESRD undergoing hemodialysis demonstrated a 36% increase in mean lomitapide plasma concentration compared to matched healthy controls. The terminal half-life of lomitapide was not affected.

Hepatic insufficiency

A single-dose, open-label study was conducted to evaluate 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 C_max were 164% and 361% higher, respectively, compared with healthy volunteers. In patients with mild hepatic impairment, lomitapide AUC and C_max 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).

Paediatric population

Lomitapide has not been investigated in children less than 18 years of age.

In repeat-dose oral toxicology studies in rodents and dogs, the principal drug-related findings were lipid accumulation in the small intestine and/or liver associated with decreases in serum cholesterol and/or triglyceride levels. These changes are secondary to the mechanism of action of lomitapide. Other liver-related changes in repeat-dose toxicity studies in rats and dogs included increased serum aminotransferases, subacute inflammation (rats only), and single-cell necrosis. In a 1 year repeat-dose study in dogs there were no microscopic changes in the liver although serum AST was minimally increased in females.

Pulmonary histiocytosis was observed in rodents. Decreased red blood cell parameters as well as poikilocytosis and/or anisocytosis were observed in dogs. Testicular toxicity was observed in dogs at 205 times the human exposure (AUC) at 60 mg in a 6-month study. No adverse effects on the testes were observed in a 1-year study in dogs at 64 times the human exposure at 60 mg.

In a dietary carcinogenicity study in mice, lomitapide was administered up to 104 weeks at doses ranging from 0.3 to 45 mg/kg/day. There were statistically significant increases in the incidences of liver adenoma and carcinoma at doses ≥1.5 mg/kg/day in males (≥2 times the human exposure at 60 mg daily based on AUC) and ≥7.5 mg/kg/day in females (≥9 times the human exposure at 60 mg based on AUC). Incidences of small intestinal carcinoma and/or combined adenoma and carcinoma (rare tumours in mice) were significantly increased at doses ≥15 mg/kg/day in males (≥26 times the human exposure at 60 mg based on AUC) and at 15 mg/kg/day in females (22 times the human exposure at 60 mg based on AUC).

In an oral carcinogenicity study in rats, lomitapide was administered up to 99 weeks at doses up to 7.5 mg/kg/day in males and 2.0 mg/kg/day in females. Focal hepatic fibrosis was observed in males and females and hepatic cystic degeneration was observed in males only. In high-dose males, an increased incidence of pancreatic acinar cell adenoma was observed at an exposure 6 times that in humans at 60 mg based on AUC.

Lomitapide was not mutagenic or genotoxic in a battery of in vitro and in vivo studies.

Lomitapide had no effect on reproductive function in female rats at doses up to 1 mg/kg or in male rats at doses up to 5 mg/kg. Systemic exposures to lomitapide at these doses were estimated to be 4 times (females) and 5 times (males) higher than the human exposure at 60 mg based on AUC.

Lomitapide was teratogenic in rats in the absence of maternal toxicity at an exposure (AUC) estimated to be twice that in humans at 60 mg. There was no evidence of embryofoetal toxicity in rabbits at 3 times the maximum recommended human dose (MRHD) of 60 mg based on body surface area. Embryofoetal toxicity was observed in rabbits in the absence of maternal toxicity at ≥6.5 times the MRHD. In ferrets, lomitapide was both maternally toxic and teratogenic at <1 times the MRHD.