Assessment of the persistence of anacetrapib and evacetrapib concentrations using two pharmacokinetic modeling approaches

Abstract

Anacetrapib, a cholesterol ester transfer protein (CETP) inhibitor, has been reported to have longer elimination half-life after longer treatment. Two pharmacokinetic model-based approaches were used to assess whether evacetrapib, another CETP inhibitor, could behave similarly. Using population pharmacokinetic (PopPK) modeling, evacetrapib and anacetrapib pharmacokinetics were characterized using available concentration-time data, and steady-state conditions were simulated. Published 2-compartment models for each compound were adapted to include a hypothetical third compartment representing a depot into which drug could partition. Physiologically based pharmacokinetic (PBPK) modeling was used to predict steady-state conditions and terminal half-life based on known physicochemical and dispositional properties. The PopPK model described the anacetrapib data well, showing a likely third compartment with estimated apparent volume of 40,700 L. Anacetrapib's estimated half-life for this compartment was 550 days. Simulations for evacetrapib using a hypothetical 3-compartment model, the third compartment being consistent with that of the anacetrapib model, produced predictions inconsistent with reported results, indicating that evacetrapib did not substantially accumulate into a large compartment. The PBPK simulations were consistent with PopPK results, predicting accumulation for anacetrapib (but not evacetrapib) followed by very slow elimination. Based on available data and known physicochemical properties, evacetrapib is not expected to accumulate substantially during long-term treatment.

Clinical Pharmacokinetics and Pharmacodynamics of Dalcetrapib

“…Anacetrapib showed a long t ½ in clinical studies, and in some patients, detectable plasma concentrations were observed up to 4 years after the end of treatment [ 21 ]. Population pharmacokinetic modeling of anacetrapib indicated a deep tissue compartment consistent with accumulation in adipose tissue, which was confirmed with human tissue biopsy [ 22 , 23 ]. Preliminary modeling of dalcetrapib concentrations obtained in nine clinical studies ranging from phase I to phase III (8466 samples from 2861 subjects) showed that a two-compartment model provided a good fit to the data, and the fit was not improved by adding a third compartment to simulate an adipose tissue depot (unpublished data).…”

CETP inhibitor evacetrapib enters mouse brain tissue

“…We previously found that hCETPtg mice have approximately 22% higher cholesterol content in their brains compared to wild type mouse brains 35 . The elevated cholesterol content in the brain and in the periphery of hCETPtg mice could differentially affect the distribution and elimination kinetics of the very lipophilic CETP inhibitors (evacetrapib has an octanol to water partition coefficient of logP 7.56) 41 . Due to these fundamental physiological differences, pharmacokinetic parameters of a CETP inhibitor should be assessed in hCETPtg mice rather than wild type mice.…”

CETP inhibitor evacetrapib enters mouse brain tissue

“…We previously found that hCETPtg mice have approximately 22% higher cholesterol content in their brains compared to wild-type mice brains ( Oestereich et al, 2022 ). The elevated cholesterol content in the brain and the periphery of hCETPtg mice could differentially affect the distribution and elimination kinetics of the very lipophilic CETP inhibitors (evacetrapib has an octanol to water partition coefficient of logP 7.56) ( Small et al, 2015 ). Due to these fundamental physiological differences, the pharmacokinetic parameters of a CETP inhibitor should be assessed in hCETPtg mice rather than wild-type mice.…”