Delving into the Latest Updates on Rocacetrapib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

CETP

Mechanism

CETP inhibitors(Cholesteryl ester transfer protein inhibitors)

Therapeutic Areas

Endocrinology and Metabolic Disease

Active Indication-

Inactive Indication

Dyslipidemias

Originator Organization

Chong Kun Dang Pharmaceutical Corp.

Active Organization-

Inactive Organization

Chong Kun Dang Pharmaceutical Corp.

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC31H34F7NO3

InChIKeyGBHPDJQHZADVAA-SOKVYYICSA-N

CAS Registry1402796-27-3

CKD-519, a potent cholesteryl ester transfer protein (CETP) inhibitor, is a clinical candidate being developed for the treatment of dyslipidemia. It is considered a Biopharmaceutical Classification System II compound with low solubility and high permeability. The objective of this study was to develop early formulations focusing on the dissolution rate of the compound to achieve dose-dependent exposure. High performance formulation strategies including solid dispersion (SD) and a self-microemulsifying drug delivery system (SMEDDS) were investigated and their in vivo and in vitro correlations were also evaluated in monkeys along with dose optimization in human volunteers. The SD granules were prepared in a fluid bed granulator using microcrystalline cellulose and mannitol as carriers. Poloxamer 407 and Eudragit E PO were each found to be a suitable solubilizing agent and polymer for the improvement of the CKD-519 dissolution rate. Pharmacokinetic studies in monkeys showed that the SD tablets exhibited better absorption than the SMEDDS in a dose-dependent manner from 1.5 mg to 100 mg. The mannitol-based SD tablet formulations were bioequivalent. However, pharmacokinetics studies in humans showed that the dose was saturable above 100 mg of CKD-519. This study was performed to determine how to develop early formulations for clinical studies and to identify rational formulation development strategies for CKD-519 to establish the pharmaceutical proof-of-concept in humans.

01 Feb 2018·Pharmacological ResearchQ2 · MEDICINE

Present therapeutic role of cholesteryl ester transfer protein inhibitors

Q2 · MEDICINE

Review

Author: Ferri, Nicola ; Sirtori, Cesare R ; Corsini, Alberto ; Ruscica, Massimiliano

Therapeutic interventions aimed at increasing high-density lipoprotein (HDL) levels in order to reduce the residual cardiovascular (CV) risk of optimally drug treated patients have not provided convincing results, so far. Transfer of cholesterol from extrahepatic tissues to the liver appears to be the major atheroprotective function of HDL, and an elevation of HDL levels could represent an effective strategy. Inhibition of the cholesteryl ester transfer protein (CETP), raising HDL-cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels, reduces low-density lipoprotein-cholesterol (LDL-C) and apoB levels, thus offering a promising approach. Despite the beneficial influence on cholesterol metabolism, off-target effects and lack of reduction in CV events and mortality (with torcetrapib, dalcetrapib and evacetrapib) highlighted the complex mechanism of CETP inhibition. After the failure of the above mentioned inhibitors in phase III clinical development, possibly due to the short duration of the trials masking benefit, the secondary prevention REVEAL trial has recently shown that the inhibitor anacetrapib significantly raised HDL-C (+104%), reduced LDL-C (-18%), with a protective effect on major coronary events (RR, 0.91; 95%CI, 0.85-0.97; p = 0.004). Whether LDL-C lowering fully accounts for the CV benefit or if HDL-C-rise is a crucial factor still needs to be determined, although the reduction of non-HDL (-18%) and Lp(a) (-25%), should be also taken into account. In spite of the positive results of the REVEAL Study, Merck decided not to proceed in asking regulatory approval for anacetrapib. Dalcetrapib (Dal-GenE study) and CKD-519 remain the two molecules within this area still in clinical development.

PharmaceuticsQ3 · MEDICINE

Quantitative Prediction of Human Pharmacokinetics and Pharmacodynamics of CKD519, a Potent Inhibitor of Cholesteryl Ester Transfer Protein (CETP)

Q3 · MEDICINE

ArticleOA

Author: Choi, Suein ; Jeon, Sangil ; Yim, Dong-Seok ; Han, Seunghoon

CKD519, a selective inhibitor of cholesteryl ester transfer protein(CETP), is undergoing development as an oral agent for the treatment of primary hypercholesterolemia and mixed hyperlipidemia. The aim of this study was to predict the appropriate efficacious dose of CKD519 for humans in terms of the inhibition of CETP activity by developing a CKD519 pharmacokinetic/pharmacodynamic (PK/PD) model based on data from preclinical studies. CKD519 was intravenously and orally administered to hamsters, rats, and monkeys for PK assessment. Animal PK models of all dose levels in each species were developed using mixed effect modeling analysis for exploration, and an interspecies model where allometric scaling was applied was developed based on the integrated animal PK data to predict the human PK profile. PD parameters and profile were predicted using in vitro potency and same-in-class drug information. The two-compartment first-order elimination model with Weibull-type absorption and bioavailability following the sigmoid Emax model was selected as the final PK model. The PK/PD model was developed by linking the interspecies PK model with the Emax model of the same-in-class drug. The predicted PK/PD profile and parameters were used to simulate the human PK/PD profiles for different dose levels, and based on the simulation result, the appropriate efficacious dose was estimated as 25 mg in a 60 kg human. However, there were some discrepancies between the predicted and observed human PK/PD profiles compared to the phase I clinical data. The huge difference between the observed and predicted bioavailability suggests that there is a hurdle in predicting the absorption parameter only from animal PK data.

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