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

Abstract

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.

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/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.

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, 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.

Conclusion

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)

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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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