Evacetrapib: in vitro and clinical disposition, metabolism, excretion, and assessment of drug interaction potential with strong CYP3A and CYP2C8 inhibitors

Abstract

Evacetrapib is an investigational cholesteryl ester transfer protein inhibitor (CETPi) for reduction of risk of major adverse cardiovascular events in patients with high-risk vascular disease. Understanding evacetrapib disposition, metabolism, and the potential for drug–drug interactions (DDI) may help guide prescribing recommendations. In vitro, evacetrapib metabolism was investigated with a panel of human recombinant cytochromes P450 (CYP). The disposition, metabolism, and excretion of evacetrapib following a single 100-mg oral dose of 14C-evacetrapib were determined in healthy subjects, and the pharmacokinetics of evacetrapib were evaluated in the presence of strong CYP3A or CYP2C8 inhibitors. In vitro, CYP3A was responsible for about 90% of evacetrapib's CYP-associated clearance, while CYP2C8 accounted for about 10%. In the clinical disposition study, only evacetrapib and two minor metabolites circulated in plasma. Evacetrapib metabolism was extensive. A mean of 93.1% and 2.30% of the dose was excreted in feces and urine, respectively. In clinical DDI studies, the ratios of geometric least squares means for evacetrapib with/without the CYP3A inhibitor ketoconazole were 2.37 for area under the curve (AUC)(0–∞) and 1.94 for Cmax. There was no significant difference in evacetrapib AUC(0–τ) or Cmax with/without the CYP2C8 inhibitor gemfibrozil, with ratios of 0.996 and 1.02, respectively. Although in vitro results indicated that both CYP3A and CYP2C8 metabolized evacetrapib, clinical studies confirmed that evacetrapib is primarily metabolized by CYP3A. However, given the modest increase in evacetrapib exposure and robust clinical safety profile to date, there is a low likelihood of clinically relevant DDI with concomitant use of strong CYP3A or CYP2C8 inhibitors.

Effect of hepatic or renal impairment on the pharmacokinetics of evacetrapib

“…Evacetrapib is cleared primarily through CYP-mediated hepatic metabolism, with minor elimination through renal excretion [ 14 ]. As the intended patient population for CETP inhibitors may include patients with hepatic and renal impairment, it was important to ascertain whether evacetrapib could be safely prescribed to these populations without dose adjustment.…”

“…Evacetrapib is a potent and selective inhibitor of CETP that has demonstrated its ability to increase HDL-C and decrease LDL-C [ 10 – 13 ]. A human metabolism study in healthy subjects given a single oral dose of evacetrapib showed extensive hepatic metabolism of evacetrapib, identifying evacetrapib and two metabolites in plasma [ 14 ]. Most (93.1 %) of the administered dose was eliminated in the feces, while only 2.30 % of the dose was excreted in urine.…”

“…Most (93.1 %) of the administered dose was eliminated in the feces, while only 2.30 % of the dose was excreted in urine. In vitro data indicated that oxidative metabolism by cytochrome P450 (CYP) enzymes (predominately CYP3A and, to a lesser extent, CYP2C8) is primarily responsible for evacetrapib clearance [ 14 ]. Thus, hepatic impairment, but not renal impairment, could be expected to alter evacetrapib’s pharmacokinetic (PK) profile.…”

Impact of Increased GastricpHon the Pharmacokinetics of Evacetrapib in Healthy Subjects

“…Omeprazole inhibits gastric acid secretion and thereby increases the pH of the gastric environment, which may alter the absorption of drugs with pH‐dependent solubility . Omeprazole is a potent inhibitor of cytochrome P450 (CYP) 2C19, but there is no drug–drug interaction risk with evacetrapib because its clearance is mediated by CYP3A and CYP2C8, and not CYP2C19 . Oral dosing with omeprazole once/day achieves maximum suppression of gastric acid secretion within ~4 days of treatment.…”

“…11 Omeprazole is a potent inhibitor of cytochrome P450 (CYP) 2C19, but there is no drug-drug interaction risk with evacetrapib because its clearance is mediated by CYP3A and CYP2C8, and not CYP2C19. 12 Oral dosing with omeprazole once/ day achieves maximum suppression of gastric acid secretion within~4 days of treatment. After dosing with omeprazole 40 mg once/day for 7 days, median 24-hour gastric pH was increased in healthy subjects from 1.68 to 4.93, with the largest increases in gastric pH occurring 2-10 hours after the omeprazole dose.…”