Journal of Pharmacokinetics and Pharmacodynamics

, Volume 39, Issue 5, pp 463–477 | Cite as

Mechanism-based PK–PD model for the prolactin biological system response following an acute dopamine inhibition challenge: quantitative extrapolation to humans

  • Jasper Stevens
  • Bart A. Ploeger
  • Margareta Hammarlund-Udenaes
  • Gunilla Osswald
  • Piet H. van der Graaf
  • Meindert Danhof
  • Elizabeth C. M. de Lange
Original Paper


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.


PK–PD model Prolactin Remoxipride Translational 



Pfizer Global Research and Development, Sandwich, England, United Kingdom financially supported this work.


  1. 1.
    Petty RG (1999) Prolactin and antipsychotic medications: mechanism of action. Schizophr Res 35(Suppl):S67–S73PubMedCrossRefGoogle Scholar
  2. 2.
    Movin-Osswald G, Hammarlund-Udenaes M (1995) Prolactin release after remoxipride by an integrated pharmacokinetic–pharmacodynamic model with intra- and interindividual aspects. J Pharmacol Exp Ther 274:921–927PubMedGoogle Scholar
  3. 3.
    Freeman ME, Kanyicska B, Lerant A, Nagy G (2000) Prolactin: structure, function, and regulation of secretion. Physiol Rev 80:1523–1631PubMedGoogle Scholar
  4. 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
  5. 5.
    Friberg LE, Vermeulen AM, Petersson KJF, Karlsson MO (2008) An agonist-antagonist interaction model for prolactin release following risperidone and paliperidone treatment. Clin Pharmacol Ther 85:409–417PubMedCrossRefGoogle Scholar
  6. 6.
    Ma G, Friberg LE, Movin-Osswald G, Karlsson MO (2010) Comparison of the agonist-antagonist interaction model and the pool model for the effect of remoxipride on prolactin. Br J Clin Pharmacol 70:815–824PubMedCrossRefGoogle Scholar
  7. 7.
    Danhof M, De Jongh J, De Lange EC, Della PO, Ploeger BA, Voskuyl RA (2007) Mechanism-based pharmacokinetic–pharmacodynamic modeling: biophase distribution, receptor theory, and dynamical systems analysis. Annu Rev Pharmacol Toxicol 47:357–400PubMedCrossRefGoogle Scholar
  8. 8.
    Ploeger BA, Van der Graaf PH, Danhof M (2009) Incorporating receptor theory in mechanism-based pharmacokinetic–pharmacodynamic (PK–PD) modeling. Drug Metab Pharmacokinet 24:3–15PubMedCrossRefGoogle Scholar
  9. 9.
    Gabrielsson J, Green AR (2009) Quantitative pharmacology or pharmacokinetic pharmacodynamic integration should be a vital component in integrative pharmacology. J Pharmacol Exp Ther 331:767–774PubMedCrossRefGoogle Scholar
  10. 10.
    Danhof M, De Lange EC, Della Pasqua OE, Ploeger BA, Voskuyl RA (2008) Mechanism-based pharmacokinetic–pharmacodynamic (PK–PD) modeling in translational drug research. Trends Pharmacol Sci 29:186–191PubMedCrossRefGoogle Scholar
  11. 11.
    De Lange EC, De Boer AG, Breimer DD (2000) Methodological issues in microdialysis sampling for pharmacokinetic studies. Adv Drug Deliv Rev 45:125–148PubMedCrossRefGoogle Scholar
  12. 12.
    Yassen A, Olofsen E, Kan J, Dahan A, Danhof M (2007) Animal-to-human extrapolation of the pharmacokinetic and pharmacodynamic properties of buprenorphine. Clin Pharmacokinet 46:433–447PubMedCrossRefGoogle Scholar
  13. 13.
    Zuideveld KP, Van der Graaf PH, Peletier LA, Danhof M (2007) Allometric scaling of pharmacodynamic responses: application to 5-ht1a receptor mediated responses from rat to man. Pharm Res 24:2031–2039PubMedCrossRefGoogle Scholar
  14. 14.
    Boxenbaum H (1982) Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics. J Pharmacokinet Biopharm 10:201–227PubMedGoogle Scholar
  15. 15.
    Stevens J, Ploeger BA, Van der Graaf PH, Danhof M, De Lange EC (2011) Systemic and direct nose-to-brain transport pharmacokinetic model for remoxipride after intravenous and intranasal administration. Drug Metab Dispos 39:2275–2282PubMedCrossRefGoogle Scholar
  16. 16.
    Stevens J, Suidgeest E, Van der Graaf PH, Danhof M, De Lange EC (2009) A new minimal-stress freely-moving rat model for preclinical studies on intranasal administration of CNS drugs. Pharm Res 26:1911–1917PubMedCrossRefGoogle Scholar
  17. 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
  18. 18.
    Gisleskog PO, Karlsson MO, Beal SL (2002) Use of prior information to stabilize a population data analysis. J Pharmacokinet Pharmacodyn 29:473–505PubMedCrossRefGoogle Scholar
  19. 19.
    Mohell N, Sallemark M, Rosqvist S, Malmberg A, Hogberg T, Jackson DM (1993) Binding characteristics of remoxipride and its metabolites to dopamine d2 and d3 receptors. Eur J Pharmacol 238:121–125PubMedCrossRefGoogle Scholar
  20. 20.
    Chi HJ, Shin SH (1978) The effect of exposure to ether on prolactin secretion and the half-life of endogenous prolactin in normal and castrated male rats. Neuroendocrinology 26:193–201PubMedCrossRefGoogle Scholar
  21. 21.
    Post TM, Freijer JI, Ploeger BA, Danhof M (2008) Extensions to the visual predictive check to facilitate model performance evaluation. J Pharmacokinet Pharmacodyn 35:185–202PubMedCrossRefGoogle Scholar
  22. 22.
    Abelo A, Eriksson UG, Karlsson MO, Larsson H, Gabrielsson J (2000) A turnover model of irreversible inhibition of gastric acid secretion by omeprazole in the dog. J Pharmacol Exp Ther 295:662–669PubMedGoogle Scholar
  23. 23.
    Ben Jonathan N, LaPensee CR, LaPensee EW (2008) What can we learn from rodents about prolactin in humans? Endocr Rev 29:1–41PubMedCrossRefGoogle Scholar
  24. 24.
    Phelps CJ (1986) Immunocytochemical analysis of prolactin cells in the adult rat adenohypophysis: distribution and quantitation relative to sex and strain. Am J Anat 176:233–242PubMedCrossRefGoogle Scholar
  25. 25.
    Dada MO, Campbell GT, Blake CA (1984) Pars distalis cell quantification in normal adult male and female rats. J Endocrinol 101:87–94PubMedCrossRefGoogle Scholar
  26. 26.
    Asa SL, Penz G, Kovacs K, Ezrin C (1982) Prolactin cells in the human pituitary. A quantitative immunocytochemical analysis. Arch Pathol Lab Med 106:360–363PubMedGoogle Scholar
  27. 27.
    Utama FE, Tran TH, Ryder A, LeBaron MJ, Parlow AF, Rui H (2009) Insensitivity of human prolactin receptors to nonhuman prolactins: relevance for experimental modeling of prolactin receptor-expressing human cells. Endocrinology 150:1782–1790PubMedCrossRefGoogle Scholar
  28. 28.
    Kohler C, Radesater AC, Karlsson-Boethius G, Bryske B, Widman M (1992) Regional distribution and in vivo binding of the atypical antipsychotic drug remoxipride. A biochemical and autoradiographic analysis in the rat brain. J Neural Transm Gen Sect 87:49–62PubMedCrossRefGoogle Scholar
  29. 29.
    Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998) Dopamine receptors: from structure to function. Physiol Rev 78:189–225PubMedGoogle Scholar
  30. 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
  31. 31.
    Perello M, Chacon F, Cardinali DP, Esquifino AI, Spinedi E (2006) Effect of social isolation on 24-h pattern of stress hormones and leptin in rats. Life Sci 78:1857–1862PubMedCrossRefGoogle Scholar
  32. 32.
    Featherstone K, White MR, Davis JR (2012) The prolactin gene: a paradigm of tissue-specific gene regulation with complex temporal transcription dynamics. J Neuroendocrinol 24:977–990PubMedCrossRefGoogle Scholar
  33. 33.
    Widman M, Nilsson LB, Bryske B, Lundstrom J (1993) Disposition of remoxipride in different species. Species differences in metabolism. Arzneimittelforschung 43:287–297PubMedGoogle Scholar
  34. 34.
    Farde L, Von Bahr C (1990) Distribution of remoxipride to the human brain and central d2-dopamine receptor binding examined in vivo by pet. Acta Psychiatr Scand Suppl 358:67–71PubMedCrossRefGoogle Scholar
  35. 35.
    Al-Fulaij MA, Ren Y, Beinborn M, Kopin AS (2007) Identification of amino acid determinants of dopamine 2 receptor synthetic agonist function. J Pharmacol Exp Ther 321:298–307PubMedCrossRefGoogle Scholar
  36. 36.
    Karabulut AK, Pratten MK (1998) Species-specificity of growth-promoting effects of prolactin during rat embryogenesis. J Anat 192(Pt 1):1–12PubMedCrossRefGoogle Scholar
  37. 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. 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. 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

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Jasper Stevens
    • 1
  • Bart A. Ploeger
    • 2
  • Margareta Hammarlund-Udenaes
    • 3
  • Gunilla Osswald
    • 4
  • Piet H. van der Graaf
    • 5
  • Meindert Danhof
    • 1
    • 2
  • Elizabeth C. M. de Lange
    • 1
  1. 1.Division of Pharmacology, Gorlaeus LaboratoriesLeiden-Amsterdam Center for Drug Research, Leiden UniversityLeidenThe Netherlands
  2. 2.LAP&P Consultants BVLeidenThe Netherlands
  3. 3.Department of Pharmaceutical BiosciencesUppsala UniversityUppsalaSweden
  4. 4.AstraZeneca R&DSödertäljeSweden
  5. 5.Pfizer, SandwichKentUK

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