Mechanism-based PK-PD model of remoxipride with rat-to-human extrapolation: characterizing remoxipride target site PK and systems homeostatic feedback
Jasper Stevens (1), Bart Ploeger (2), Piet H van der Graaf (3), Meindert Danhof (1), Elizabeth C.M. de Lange (1)
(1) Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands; (2) LAP&P Consultants BV, Leiden, The Netherlands; (3) Pfizer, Sandwich, Kent, United Kingdom
Objectives: In animals, measurement of biomarkers at the target site of dopaminergic drugs can be easier obtained when compared to man. Pop PKPD approaches allows distinction between drug and system-specific properties that determine time course of effect to ultimately predict human PKPD relationships. In this study the time course of prolactin (PRL) concentrations in plasma (PD) in rats was characterized as a function of the PK of remoxipride (REM) in plasma and brainECF. This PKPD relationship was extrapolated to and compared to actual plasma PKPD data in human.
Methods: In male rats, plasma and brainECF PK profiles of REM together with PRL concs (PD) in plasma, were obtained after 30-min IV infusion of 4/8/16 mg/kg REM [1,2]. Also, plasma PRL concs were obtained after two subsequent 30 min IV infusions (3.8 mg/kg REM). PK and PD were investigated by NLME (NONMEM VI.2, ADVAN 9). A bootstrap procedure was used to derive the uncertainty in the parameter estimates of the final model, followed by a visual predictive check (VPC). The VPCs were performed by simulating 1000 replications of the PKPD model and a simulation dataset. Clinical REM data on plasma REM and PRL concs (8 healthy male subjects, two consecutive IV doses (data from M. Hammarlund-Udenaes) . A 2-comp PK model was developed and, by applying the compartmental PK ratio of the rat model, translated into a 3-comp model to predict brainECF concs in human. For the PKPD model in human, allometric scaling and independent information on the values of drug- and system specific parameters were used as prior knowledge .
Results: In rats, AUC's in plasma and brainECF showed linear REM PK. A 4-comp PK model, consisting of a central (plasma) compartment, a peripheral compartment, a brainECF and an absorption compartment, best described the PK data. Inclusion of brain elimination significantly improved the model. A precursor-pool model with REM brainECF conc-relationship (Emax) on PRL release, and a positive feedback of plasma PRL concs on the rate of prolactin synthesis in brain lactotrophs (Emax), best described the PD. In humans, the translated 3-comp model accurately predicted the clinical REM plasma PK data, as well as all PRL plasma profiles.
Conclusions: The structure of the preclinical derived MB PKPD model is adequate in describing PRL release in rats and human. Positive feedback on PRL synthesis could be a new feature in describing complex homeostatic feedback mechanisms.
 Stevens J, Suidgeest E, van der Graaf PH, Danhof M, and de Lange EC (2009) A new minimal-stress freely-moving rat model for preclinical studies on intranasal administration of CNS drugs. Pharm Res 26:1911-1917.
 Stevens J, van den Berg D-J, de Ridder S, Niederländer HAG, van der Graaf PH, Danhof M, and de Lange ECM (2010) Online solid phase extraction with liquid chromatography-tandem mass spectrometry to analyze remoxipride in small plasma-, brain homogenate-, and brain microdialysate samples. Journal of Chromatography B 878:969-975.
 Movin-Osswald G and Hammarlund-Udenaes M (1995) Prolactin release after remoxipride by an integrated pharmacokinetic-pharmacodynamic model with intra- and interindividual aspects. J Pharmacol Exp Ther 274:921-927.