Torcetrapib
Adding a bile correction factor sharpens allometric prediction of human pharmacokinetic parameters for orally dosed torcetrapib (Eur J Drug Metab Pharmacokinet 2009)
Original title: Use of bile correction factors for allometric prediction of human pharmacokinetic parameters of torcetrapib, a facile cholesteryl ester transfer protein inhibitor
Using pharmacokinetic parameters (clearance, volume of distribution, elimination rate constant, and half-life) measured in mice, rats, and monkeys, researchers predicted human pharmacokinetic values for torcetrapib using allometric scaling, a technique previously used mainly for intravenous drugs. Simple allometry markedly overpredicted the human parameters, but applying bile correction factors produced allometric equations with strong fits (R-squared ranging from 0.828 to 0.9416) that yielded much closer predictions. The corrected predicted (observed) values were 10.3 L/h (15.8 L/h) for clearance, 3449 L (4810 L) for volume of distribution, 0.00298 per hour (0.00328 per hour) for elimination rate constant, and 211 hours (231 hours) for half-life, demonstrating that allometry with bile correction factors can be applied prospectively to orally administered CETP inhibitors.
Original abstract
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: K(el) and elimination half-life: t(l/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, K(el), and t(1/2). However, the application of bile correction factors provided allometric equations of 0.2486W(0.877) (R2 = 0.9416), 1.4723W(1.8263) (R2 = 0.8873), 0.1685W(-095) (R2 = 0.828) and 4.1044W(0.493) (R2 = 0.9337) for CL/F, Vd/F, K(el) and t(1/2), 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, K(el) and t(1/2), 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.