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Effect of Hepatic and Renal Impairment on the Pharmacokinetics of Dalcetrapib

Altered Distribution of the Active Thiol?

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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.

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Acknowledgments

The authors wish to thank B. Gujral and P. Reid for operational management of the studies. These studies were supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Third-party writing assistance for this manuscript was provided by Prime Healthcare Ltd and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Mary Phelan, Judith Anzures-Cabrera, David J. Carlile, Lucy Rowell and Darren Bentley are employees of Roche Products Ltd, Welwyn Garden City, UK, a subsidiary of F. Hoffmann-La Roche. Olaf Kuhlmann is an employee of F. Hoffmann-La Roche Ltd, Basel, Switzerland. Gerhard Arold is an employee of Pharmaceutical Research Associates International. Richard Robson is an employee of Christchurch Clinical Studies Trust.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Roche Products Ltd, Shire Park, Welwyn Garden City, UK

    Mary Phelan, David J. Carlile & Darren Bentley

  2. Non-Clinical Drug Safety, Pharma Research and Early Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland

    Olaf Kuhlmann

  3. Pharmaceutical Research Associates International, Berlin, Germany

    Gerhard Arold

  4. Christchurch Clinical Studies Trust, Christchurch, New Zealand

    Richard Robson

  5. Department of Biostatistics, Roche Products Ltd, Shire Park, Welwyn Garden City, AL7 1TW, UK

    Judith Anzures-Cabrera & Lucy Rowell

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  1. Mary Phelan
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Correspondence to Mary Phelan.

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Phelan, M., Anzures-Cabrera, J., Carlile, D.J. et al. Effect of Hepatic and Renal Impairment on the Pharmacokinetics of Dalcetrapib. Clin Pharmacokinet 52, 255–265 (2013). https://doi.org/10.1007/s40262-013-0035-z

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