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Use of bile correction factors for allometric prediction of human pharmacokinetic parameters of torcetrapib, a facile cholesteryl ester transfer protein inhibitor

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Summary

Torcetrapib was the lead candidate belonging to the class of cholesteryl ester transfer protein (CETP) inhibitor which was being developed for the management of cardiovascular risk factors by raising HDL. The availability of pharmacokinetic parameters (clearance: CL/F, volume of distribution: Vd/F, elimination rate constant: Kel and elimination half-life: t1/2) in mice, rats and monkeys, enabled the prediction of human parameter values using the well accepted tool of allometry. Although allometry work has been largely restricted to intravenous drugs, the present case of torcetrapib showed that allometry may be equally applicable to oral route. Simple allometry appeared to markedly inflate the human parameters for CL/F, Vd/F, Kel and t1/2. However, the application of bile correction factors provided allometric equations of 0.2486W0.877 (R2=0.9416), 1.4723W1.8263 (R2=0.8873), 0.1685W−095 (R2=0.828) and 4.1044W0.9493 (R2=0.9337) for CL/F, Vd/F, Kel, and t1/2, rendering a closer prediction of human parameter values. Accordingly, the predicted (observed) values of torcetrapib were 10.3 L/h (15.8 L/h), 3449 L (4810 L), 0.00298 h−1 (0.00328 h−1) and 211 h (231 h) for CL/F, Vd/F, Kel and t1/2, respectively. In summary, the data suggested that allometry tool with appropriate bile correction factors could be effectively used in a prospective manner for other orally administered CETP inhibitors.

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Author notes

  1. Nuggehally R. Srinivas

    Present address: Nektar Therapeutics (India) Pvt. Ltd, S.D Road, 500 003, Secunderabad, India

Authors and Affiliations

  1. Jubilant Innovation, Industrial Estate, Yeshwanthpur, Bangalore, India

    Ramesh Mullangi

  2. Clintec (International) India Ltd, India, Koramangala, Bangalore, India

    Preeti Ahlawat

  3. Department of Drug Metabolism and Pharmacokinetics, Discovery Research, Dr. Reddy’s Laboratories, Miyapur, Hyderabad, India

    Ravi K. Trivedi

  4. Integrated Drug Development, Suramus Biopharm, 77, 10th cross, 29th main, 560 078, J.P. Nagar, I Phase, Bangalore, India

    Nuggehally R. Srinivas

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Mullangi, R., Ahlawat, P., Trivedi, R.K. et al. Use of bile correction factors for allometric prediction of human pharmacokinetic parameters of torcetrapib, a facile cholesteryl ester transfer protein inhibitor. Eur. J. Drug Metabol. Pharmacokinet. 34, 57–63 (2009). https://doi.org/10.1007/BF03191385

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