Preclinical evaluation of new drug-drug interactions of lomitapide: A proposal for novel mechanism of interaction associated with lipid metabolic changes.

Lomitapide, a microsomal triglyceride transfer protein inhibitor, is a lipid-lowering drug that inhibits chylomicron formation in enterocytes and very low-density lipoprotein (VLDL) formation in the liver. Previous studies have shown that very low-density lipoprotein and/or low-density lipoprotein (VLDL/LDL) can deliver certain drugs in addition to lipids. Thus, we hypothesized that serum concentrations of drugs that are more likely to be distributed to VLDL/LDL in the serum (referred to as "VLDL/LDL-philic drugs" in this paper) may be altered by co-administered lomitapide. To verify this interest, we administered VLDL/LDL-philic drugs along with lomitapide to mice. Repeated administration of lomitapide decreased the serum lipid levels and VLDL/LDL-philic drug concentrations, to 20% for amiodarone, to 52% for doxycycline, and to 62% for tetracycline. These decreases occurred concurrently with the accumulation of lipids and drugs in enterocytes. The enterocyte distribution coefficients, defined as the amount of drug in enterocytes divided by the serum drug concentration, were significantly increased by lomitapide treatment for all the VLDL/LDL-philic drugs tested. In addition, an acute absorption study showed that amiodarone absorption was reduced to less than 30% by lomitapide, accompanied by accumulation of amiodarone in enterocytes. Collectively, through a series of experiments, we revealed the association between drugs and VLDL/LDL, and their impact on pharmacokinetics. Our study suggested that lomitapide decreases serum concentrations of VLDL/LDL-philic drugs probably due to changes in their absorption kinetics, proposing novel drug-drug interactions associated with lipid metabolic changes.