Use of bile correction factors for allometric prediction of human pharmacokinetic parameters of torcetrapib, a facile cholesteryl ester transfer protein inhibitor.
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.
Mullangi
Ramesh
R
Jubilant Innovation, Industrial Estate, Yeshwanthpur, Bangalore, India.
Ahlawat
Preeti
P
Trivedi
Ravi K
RK
Srinivas
Nuggehally R
NR
D000465:Algorithms; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001646:Bile / Q000737:chemistry*; D001835:Body Weight / Q000502:physiology; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D000882:Haplorhini; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D015233:Models, Statistical; D011237:Predictive Value of Tests; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D013045:Species Specificity
D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D011804:Quinolines; C483909:torcetrapib