Mechanism-based PK–PD model for the prolactin biological system response following an acute dopamine inhibition challenge: quantitative extrapolation to humans
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The aim of this investigation was to develop a mechanism-based pharmacokinetic–pharmacodynamic (PK–PD) model for the biological system prolactin response following a dopamine inhibition challenge using remoxipride as a paradigm compound. After assessment of baseline variation in prolactin concentrations, the prolactin response of remoxipride was measured following (1) single intravenous doses of 4, 8 and 16 mg/kg and (2) following double dosing of 3.8 mg/kg with different time intervals. The mechanistic PK–PD model consisted of: (i) a PK model for remoxipride concentrations in brain extracellular fluid; (ii) a pool model incorporating prolactin synthesis, storage in lactotrophs, release into- and elimination from plasma; (iii) a positive feedback component interconnecting prolactin plasma concentrations and prolactin synthesis; and (iv) a dopamine antagonism component interconnecting remoxipride brain extracellular fluid concentrations and stimulation of prolactin release. The most important findings were that the free brain concentration drives the prolactin release into plasma and that the positive feedback on prolactin synthesis in the lactotrophs, in contrast to the negative feedback in the previous models on the PK–PD correlation of remoxipride. An external validation was performed using a dataset obtained in rats following intranasal administration of 4, 8, or 16 mg/kg remoxipride. Following simulation of human remoxipride brain extracellular fluid concentrations, pharmacodynamic extrapolation from rat to humans was performed, using allometric scaling in combination with independent information on the values of biological system specific parameters as prior knowledge. The PK–PD model successfully predicted the system prolactin response in humans, indicating that positive feedback on prolactin synthesis and allometric scaling thereof could be a new feature in describing complex homeostatic mechanisms.
KeywordsPK–PD model Prolactin Remoxipride Translational
Pfizer Global Research and Development, Sandwich, England, United Kingdom financially supported this work.
- 4.Bagli M, Suverkrup R, Quadflieg R, Hoflich G, Kasper S, Moller HJ, Langer M, Barlage U, Rao ML (1999) Pharmacokinetic–pharmacodynamic modeling of tolerance to the prolactin-secreting effect of chlorprothixene after different modes of drug administration. J Pharmacol Exp Ther 291:547–554PubMedGoogle Scholar
- 17.Stevens J, Van den Berg D-J, De Ridder S, Niederlander HAG, Van der Graaf PH, Danhof M, 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. J Chromatogr B 878:969–975CrossRefGoogle Scholar
- 30.Burstein ES, Ma J, Wong S, Gao Y, Pham E, Knapp AE, Nash NR, Olsson R, Davis RE, Hacksell U, Weiner DM, Brann MR (2005) Intrinsic efficacy of antipsychotics at human d2, d3, and d4 dopamine receptors: identification of the clozapine metabolite n-desmethylclozapine as a d2/d3 partial agonist. J Pharmacol Exp Ther 315:1278–1287PubMedCrossRefGoogle Scholar
- 37.Van der Graaf PH, Van Schaick EA, Math-ot RA, Ijzerman AP, Danhof M (1997) Mechanism-based pharmacokinetic–pharmacodynamic modeling of the effects of N6-cyclopentyladenosine analogs on heart rate in rat: estimation of in vivo operational affinity and efficacy at adenosine A1 receptors. J Pharmacol Exp Ther 283:809–816Google Scholar
- 38.Visser SA, Wolters FL, Gubbens-Stibbe JM, Tukker E, Van der Graaf PH, Peletier LA, Danhof M (2003) Mechanism-based pharmacokinetic/pharmacodynamic modeling of the electroencephalogram effects of GABAA receptor modulators: in vitro–in vivo correlations. J Pharmacol Exp Ther 304:88–101PubMedCrossRefGoogle Scholar
- 39.Zuideveld KP, Van der Graaf PH, Newgreen D, Thurlow R, Petty N, Jordan P, Peletier LA, Danhof M (2004) Mechanism-based pharmacokinetic–pharmacodynamic modeling of 5-ht1a receptor agonists: estimation of in vivo affinity and intrinsic efficacy on body temperature in rats. J Pharmacol Exp Ther 308:1012–1020PubMedCrossRefGoogle Scholar