Clinical Pharmacokinetics

, Volume 52, Issue 4, pp 255–265

Effect of Hepatic and Renal Impairment on the Pharmacokinetics of Dalcetrapib

Altered Distribution of the Active Thiol?
  • Mary Phelan
  • Judith Anzures-Cabrera
  • David J. Carlile
  • Lucy Rowell
  • Olaf Kuhlmann
  • Gerhard Arold
  • Richard Robson
  • Darren Bentley
Original Research Article


Background and 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.


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/m2. 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, r2 = 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.

Supplementary material

40262_2013_35_MOESM1_ESM.pdf (53 kb)
Supplementary material 1 (PDF 53 kb)


  1. 1.
    Fruchart JC, Sacks F, Hermans MP, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008;102(10 Suppl):1K–34K.PubMedCrossRefGoogle Scholar
  2. 2.
    Gordon T, Castelli WP, Hjortland MC, et al. High density lipoprotein as a protective factor against coronary heart disease: the Framingham Study. Am J Med. 1977;62(5):707–14.PubMedCrossRefGoogle Scholar
  3. 3.
    Navab M, Reddym ST, Van Lenten BJ, et al. HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms. Nat Rev Cardiol. 2011;8(4):222–32.PubMedCrossRefGoogle Scholar
  4. 4.
    Farmer JA, Liao J. Evolving concepts of the role of high-density lipoprotein in protection from atherosclerosis. Curr Atheroscler Rep. 2011;13(2):107–14.PubMedCrossRefGoogle Scholar
  5. 5.
    Okamoto H, Yonemori F, Wakitani K, et al. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature. 2000;406:203–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Niesor EJ, Magg C, Ogawa N, et al. Modulating cholesteryl ester transfer protein activity maintains efficient pre-β-HDL formation and increases reverse cholesterol transport. J Lipid Res. 2010;51(12):3443–54.PubMedCrossRefGoogle Scholar
  7. 7.
    Stein EA, Stroes ES, Steiner G, et al. Safety and tolerability of dalcetrapib. Am J Cardiol. 2009;104(1):82–91.PubMedCrossRefGoogle Scholar
  8. 8.
    Stein EA, Roth EM, Rhyne JM, et al. Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial. Eur Heart J. 2010;31(4):480–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Ballantyne CM, Miller M, Niesor EJ, et al. Effect of dalcetrapib plus pravastatin on lipoprotein metabolism and high-density lipoprotein composition and function in dyslipidemic patients: results of a phase IIb dose-ranging study. Am Heart J. 2012;163(3):515–21.PubMedCrossRefGoogle Scholar
  10. 10.
    Schwartz GG, Olsson AG, Ballantyne CM, et al. Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J. 2009;158(6):896–901.PubMedCrossRefGoogle Scholar
  11. 11.
    Schwartz GG, Olsson AG, Abt M, et al.; dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367(22):2089–99.Google Scholar
  12. 12.
    Bentley D, Young AM, Rowell L, et al. Evidence of a drug-drug interaction linked to inhibition of ester hydrolysis by orlistat. J Cardiovasc Pharmacol. 2012;60(4):390–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Gross G, Tardio J, Kuhlmann O. Solubility and stability of dalcetrapib in vehicles and biological media. Int J Pharm. 2012;437(1–2):103–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Maugeais C, von der Mark E, Niesor EJ, et al. Plasma lipoprotein fraction distribution of the CETP modulator dalcetrapib and the relationship with pharmacodynamic effects [abstract no. P25 plus poster]. High-Density Lipoprotein Satellite Symposium; Mar 30–Apr 1 2012; Cairns.Google Scholar
  15. 15.
    Heinig K, Bucheli F, Kuhlmann O, et al. Determination of dalcetrapib by liquid chromatography-tandem mass spectrometry. J Pharm Biomed Anal. 2012;66:314–24.PubMedCrossRefGoogle Scholar
  16. 16.
    Ranalletta M, Bierilo KK, Chen Y, et al. Biochemical characterization of cholesteryl ester transfer protein inhibitors. J Lipid Res. 2010;51(9):2739–52.PubMedCrossRefGoogle Scholar
  17. 17.
    Kuhlmann O, Heinig K. Dalcetrapib pharmacokinetics and metabolism in the cynomolgus monkey. Xenobiotica. 2011;41(5):430–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Derks M, Busse-Reid R, Kuhlmann O, et al. [14C]-dalcetrapib ADME following a single oral dose in healthy male subjects [abstract]. Clin Pharmacol Ther. 2010;87(1 Suppl):S9–37.Google Scholar
  19. 19.
    Derks M, Fowler S, Kuhlmann O. A single-center, open-label, one-sequence study of dalcetrapib coadministered with ketoconazole, and an in vitro study of the S-methyl metabolite of dalcetrapib. Clin Ther. 2009;31(3):586–99.PubMedCrossRefGoogle Scholar
  20. 20.
    Aceves-Baldo P, Anzures-Cabrera J, Bentley D. In vivo evaluation of drug-drug interactions linked to UGT inhibition: the effect of probenecid on dalcetrapib pharmacokinetics. Int J Clin Pharmacol Ther. In Press.Google Scholar
  21. 21.
    Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, editor. The liver and portal hypertension. Philadelphia: W.B. Saunders; 1964. p. 50–64.Google Scholar
  22. 22.
    Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41.PubMedCrossRefGoogle Scholar
  24. 24.
    Hessheimer AJ, Forner A, Varela M, et al. Metabolic risk factors are a major comorbidity in patients with cirrhosis independent of the presence of hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 2010;22(10):1239–44.PubMedCrossRefGoogle Scholar
  25. 25.
    Targher G, Chonchol M, Pichiri I, et al. Risk of cardiovascular disease and chronic kidney disease in diabetic patients with non-alcoholic fatty liver disease: just a coincidence? J Endocrinol Invest. 2011;34(7):544–51.PubMedGoogle Scholar
  26. 26.
    Chronic Kidney Disease Prognosis Consortium, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375(9731):2073–81.CrossRefGoogle Scholar
  27. 27.
    Parikh NI, Hwang SJ, Larson MG, et al. Chronic kidney disease as a predictor of cardiovascular disease (from the Framingham Heart Study). Am J Cardiol. 2008;102(1):47–53.PubMedCrossRefGoogle Scholar
  28. 28.
    Kaysen GA. Lipid and lipoprotein metabolism in chronic kidney disease. J Ren Nutr. 2009;19(1):73–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Vaziri ND. Causes of dysregulation of lipid metabolism in chronic renal failure. Semin Dial. 2009;22(6):644–51.PubMedCrossRefGoogle Scholar
  30. 30.
    Vaziri ND, Navab M, Fogelman AM. HDL metabolism and activity in chronic kidney disease. Nat Rev Nephrol. 2010;6(5):287–96.PubMedCrossRefGoogle Scholar
  31. 31.
    Vaziri ND, Norris K. Lipid disorders and their relevance to outcomes in chronic kidney disease. Blood Purif. 2011;3(1–3):189–96.CrossRefGoogle Scholar
  32. 32.
    Delcò F, Tchambaz L, Schlienger R, et al. Dose adjustment in patients with liver disease. Drug Saf. 2005;28:529–45.PubMedCrossRefGoogle Scholar
  33. 33.
    Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol. 2008;64(12):1147–61.PubMedCrossRefGoogle Scholar
  34. 34.
    Zhang Y, Zhang L, Abraham S, et al. Assessment of the impact of renal impairment on systemic exposure of new molecular entities: evaluation of recent new drug applications. Clin Pharmacol Ther. 2009;85(3):305–11.PubMedCrossRefGoogle Scholar
  35. 35.
    Le Couteur DG, Fraser R, Hilmer S, et al. The hepatic sinusoid in aging and cirrhosis: effects on hepatic substrate disposition and drug clearance. Clin Pharmacokinet. 2005;44(2):187–200.PubMedCrossRefGoogle Scholar
  36. 36.
    Hoyumpa AM, Schenker S. Is glucuronidation truly preserved in patients with liver disease? Hepatology. 1991;13(4):786–95.PubMedCrossRefGoogle Scholar
  37. 37.
    Derks M, Abt M, Mwangi A, et al. Lack of effect of dalcetrapib on QT interval in healthy subjects following multiple dosing. Eur J Clin Pharmacol. 2010;66(8):775–83.PubMedCrossRefGoogle Scholar
  38. 38.
    Dreisbach AW, Lertora JJL. The effect of chronic renal failure on drug metabolism and transport. Expert Opin Drug Metab Toxicol. 2008;4(8):1065–74.PubMedCrossRefGoogle Scholar
  39. 39.
    Dreisbach AW. The influence of chronic renal failure on drug metabolism and transport. Clin Pharmacol Ther. 2009;86(5):553–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Derks M, Abt M, Parr G, et al. No clinically relevant drug-drug interactions when dalcetrapib is co-administered with atorvastatin. Expert Opin Investig Drugs. 2010;19(10):1135–45.PubMedCrossRefGoogle Scholar
  41. 41.
    Prakash M, Upadhya S, Prabhu R. Protein thiol oxidation and lipid peroxidation in patients with uraemia. Scand J Clin Lab Invest. 2004;64:599–604.PubMedCrossRefGoogle Scholar
  42. 42.
    Berezhkovskiy LM. On the influence of protein binding on pharmacological activity of drugs. J Pharm Sci. 2010;99(4):2153–65.PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Mary Phelan
    • 1
  • Judith Anzures-Cabrera
    • 5
  • David J. Carlile
    • 1
  • Lucy Rowell
    • 5
  • Olaf Kuhlmann
    • 2
  • Gerhard Arold
    • 3
  • Richard Robson
    • 4
  • Darren Bentley
    • 1
  1. 1.Department of Clinical Pharmacology, Roche Products LtdWelwyn Garden CityUK
  2. 2.Non-Clinical Drug Safety, Pharma Research and Early Development, F. Hoffmann-La Roche LtdBaselSwitzerland
  3. 3.Pharmaceutical Research Associates InternationalBerlinGermany
  4. 4.Christchurch Clinical Studies TrustChristchurchNew Zealand
  5. 5.Department of Biostatistics, Roche Products LtdWelwyn Garden CityUK

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