title: Effect of hepatic and renal impairment on the pharmacokinetics of dalcetrapib: altered distribution of the active thiol?
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Clinical Pharmacology, Roche Products Ltd, Shire Park, Welwyn Garden City AL7 1TW, UK. mary.phelan@roche.com
authors: Mary
authors: M
authors: Phelan
authors: Judith
authors: J
authors: Anzures-Cabrera
authors: David J
authors: DJ
authors: Carlile
authors: Lucy
authors: L
authors: Rowell
authors: Olaf
authors: O
authors: Kuhlmann
authors: Gerhard
authors: G
authors: Arold
authors: Richard
authors: R
authors: Robson
authors: Darren
authors: D
authors: Bentley
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000577:Amides; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004952:Esters; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D012044:Regression Analysis; D013438:Sulfhydryl Compounds / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000577:Amides; D000924:Anticholesteremic Agents; D004952:Esters; D013438:Sulfhydryl Compounds; C411602:dalcetrapib
references: Am J Cardiol. 2008 Jul 1;102(1):47-53
references: 18572034
references: Nature. 2000 Jul 13;406(6792):203-7
references: 10910363
references: Scand J Clin Lab Invest. 2004;64(6):599-604
references: 15370466
references: Clin Ther. 2009 Mar;31(3):586-99
references: 19393849
references: Semin Dial. 2009 Nov-Dec;22(6):644-51
references: 20017835
references: Eur J Gastroenterol Hepatol. 2010 Oct;22(10):1239-44
references: 20505515
references: Nat Rev Nephrol. 2010 May;6(5):287-96
references: 20308998
references: Eur J Clin Pharmacol. 2010 Aug;66(8):775-83
references: 20521033
references: Eur J Clin Pharmacol. 2008 Dec;64(12):1147-61
references: 18762933
references: Expert Opin Drug Metab Toxicol. 2008 Aug;4(8):1065-74
references: 18680441
references: J Endocrinol Invest. 2011 Jul-Aug;34(7):544-51
references: 21427524
references: Am Heart J. 2009 Dec;158(6):896-901.e3
references: 19958854
references: J Cardiovasc Pharmacol. 2012 Oct;60(4):390-6
references: 22820896
references: Am J Cardiol. 2009 Jul 1;104(1):82-91
references: 19576325
references: Nat Rev Cardiol. 2011 Apr;8(4):222-32
references: 21304474
references: Int J Clin Pharmacol Ther. 2013 Mar;51(3):215-8
references: 23357838
references: Lancet. 2010 Jun 12;375(9731):2073-81
references: 20483451
references: Xenobiotica. 2011 May;41(5):430-6
references: 21348578
references: Expert Opin Investig Drugs. 2010 Oct;19(10):1135-45
references: 20738227
references: Hepatology. 1991 Apr;13(4):786-95
references: 1901292
references: N Engl J Med. 2012 Nov 29;367(22):2089-99
references: 23126252
references: Am J Med. 1977 May;62(5):707-14
references: 193398
references: J Lipid Res. 2010 Sep;51(9):2739-52
references: 20458119
references: Blood Purif. 2011;31(1-3):189-96
references: 21228589
references: J Pharm Sci. 2010 Apr;99(4):2153-65
references: 19827100
references: J Lipid Res. 2010 Dec;51(12):3443-54
references: 20861162
references: Clin Pharmacokinet. 2005;44(2):187-200
references: 15656697
references: Clin Pharmacol Ther. 2009 Mar;85(3):305-11
references: 19020495
references: J Ren Nutr. 2009 Jan;19(1):73-7
references: 19121776
references: Nephron. 1976;16(1):31-41
references: 1244564
references: Clin Pharmacol Ther. 2009 Nov;86(5):553-6
references: 19776735
references: Drug Saf. 2005;28(6):529-45
references: 15924505
references: Br J Surg. 1973 Aug;60(8):646-9
references: 4541913
references: Eur Heart J. 2010 Feb;31(4):480-8
references: 20097702
references: Am Heart J. 2012 Mar;163(3):515-21, 521.e1-3
references: 22424025
references: Int J Pharm. 2012 Nov 1;437(1-2):103-9
references: 22884829
references: J Pharm Biomed Anal. 2012 Jul;66:314-24
references: 22541249
references: Curr Atheroscler Rep. 2011 Apr;13(2):107-14
references: 21380938
references: Am J Cardiol. 2008 Nov 17;102(10 Suppl):1K-34K
references: 19068318