PII-72A pharmacokinetic model to document the interconversion between Paliperidone’s enantiomers

Abstract

BACKGROUND/AIMS Paliperidone is a mixture of two equally potent enantiomers. The proposed pharmacokinetic model aims at characterizing the pharmacokinetics of the two enantiomers of Paliperidone and their interconversion. METHODS In this single-dose, 5-period cross over study, 20 subjects were randomised to receive either a 30 min i.v. infusion of 1 mg Paliperidone, a 1 mg Immediate Release (IR) formulation or an 1 mg solution of the (+) or (−) enantiomer, a 3 mg Extended Release (ER) formulation of Paliperidone. RESULTS Plasma concentration-time profiles of each enantiomer were best described by a 2 compartment pharmacokinetic model, with a lag time after oral administration. The median volume of the peripheral compartment is much higher for the (−) enantiomer (192 L) compared to the (+) enantiomer (70.6 L). The intercompartment clearance of the (+) enantiomer is lower than for the (−) enantiomer, 78.8 L/h and 282 L/h. The elimination clearance of the (+) enantiomer is lower than the clearance of the (−) enantiomer, 1.41 and 8.15 L/h. The interconversion clearance (CLi) between both enantiomers is 7.90 L/h and independent of (+) to (−) or (−) to (+) interconversion. The bioavailability after administration of the IR was 121% and for ER formulation 28%. CONCLUSION With this study a pharmacokinetic model has been developed to describe the disposition of Paliperidone and to characterise the interconversion between the two enantiomers of Paliperidone. Clinical Pharmacology & Therapeutics (2005) 79, P55–P55; doi: 10.1016/j.clpt.2005.12.197