dalcetrapib and Kidney-Diseases

High-density lipoprotein cholesterol (HDL-C) contains dozens of apoproteins that participate in normal cholesterol metabolism with a reliance on renal catabolism for clearance from the body. The plasma pool of HDL-C has been an excellent inverse predictor of cardiovascular events. However, when HDL-C concentrations have been manipulated with the use of niacin, fibric acid derivatives, and cholesteryl ester transferase protein inhibitors, there has been no improvement in outcomes in patients where the low-density lipoprotein cholesterol has been well treated with statins. Apolipoprotein L1 (APOL1) is one of the minor apoproteins of HDL-C, newly discovered in 1997. Circulating APOL1 is a 43-kDa protein mainly found in the HDL3 subfraction. In patients with chronic kidney disease (CKD), mutant forms of APOL1 have been associated with rapidly progressive CKD and end-stage renal disease (ESRD). Because mutant forms of APOL1 are more prevalent in African Americans compared to Caucasians, it may explain some of the racial disparities seen in the pool of patients with ESRD in the United States. Thus, HDL-C is an important lipoprotein carrying apoproteins that play roles in vascular and kidney disease.

Topics: Amides; Apolipoprotein A-I; Benzodiazepines; Black or African American; Cholesterol Ester Transfer Proteins; Cholesterol Esters; Cholesterol, HDL; Cholesterol, LDL; Cohort Studies; Esters; Heart Diseases; Humans; Hyperlipoproteinemias; Kidney Diseases; Liver; Niacin; Observational Studies as Topic; Oxazolidinones; Prospective Studies; Quinolines; Randomized Controlled Trials as Topic; Risk; Sulfhydryl Compounds; Triglycerides; White People

Dalcetrapib, a cholesteryl ester transfer protein (CETP) modulator, is a thioester pro-drug that is rapidly hydrolysed to generate a pharmacologically active thiol. The thiol covalently binds to plasma proteins as mixed disulfides, extensively distributes into plasma lipoprotein fractions, and is principally cleared by metabolism, including extensive first-pass metabolism. Here we report two studies assessing the effects of hepatic and renal impairment on the pharmacokinetics of the thiol and its primary metabolites.. Adults with hepatic or renal impairment and healthy controls were recruited in two separate non-randomized, open-label studies. Eligible subjects were aged 18-70 years (hepatic impairment study) or 18-75 years (renal impairment study) with a body mass index 18-40 kg/m(2). Healthy controls were matched by age, bodyweight and sex. Each participant received a single 600 mg oral dose of dalcetrapib. Plasma and urine sampling was performed up to 3-4 days post-dalcetrapib administration for analysis of the pharmacokinetics of the thiol and its primary S-methyl and S-glucuronide metabolites. In the renal impairment study, CETP activity and mass, and lipid profiles were also assessed.. Twenty-eight subjects were enrolled in the hepatic impairment study (mild or moderate hepatic impairment, n = 8 in each group; controls, n = 12). Thirty-five subjects participated in the renal impairment study (mild, moderate or severe renal impairment, n = 8 in each group; controls, n = 11). In patients with moderate hepatic impairment, the area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) for thiol exposure was increased 34 % (geometric mean ratio [GMR] 1.34, 90 % CI 1.02-1.76), compared with matched controls. Regression analysis revealed a weak inverse relationship between thiol exposure and creatinine clearance (p = 0.0137, r(2) = 17.1 %). In patients with moderate or severe renal impairment, thiol exposures were 62 % (AUC(∞) GMR 1.62, 90 % CI 0.81-3.27) and 81 % (AUC(∞) GMR 1.81, 90 % CI 1.21-2.71) higher, respectively, than matched controls. Exposures of the S-glucuronide and S-methyl metabolites were also higher in hepatic and renal impairment groups. In the renal impairment study, CETP activity was decreased following administration of dalcetrapib, with no clear differences between groups.. Hepatic and renal impairment both altered dalcetrapib pharmacokinetics and increased thiol exposure, with the extent of the effect dependent on the severity of impairment. The effect of renal impairment may be linked to altered distribution of the thiol, which illustrates the importance of assessing distribution to understand the causes and consequences of altered pharmacokinetics of thiol drugs in patient populations.

Topics: Adolescent; Adult; Aged; Amides; Anticholesteremic Agents; Esters; Female; Humans; Kidney Diseases; Liver Diseases; Male; Metabolic Clearance Rate; Middle Aged; Regression Analysis; Sulfhydryl Compounds; Tissue Distribution; Young Adult