The AAPS Journal

, Volume 15, Issue 2, pp 533–541 | Cite as

Predictions of In Vivo Prolactin Levels from In Vitro K i Values of D2 Receptor Antagonists Using an Agonist–Antagonist Interaction Model

  • Klas J. Petersson
  • An M. Vermeulen
  • Lena E. Friberg
Research Article


Prolactin elevation is a side effect of all currently available D2 receptor antagonists used in the treatment of schizophrenia. Prolactin elevation is the result of a direct antagonistic D2 effect blocking the tonic inhibition of prolactin release by dopamine. The aims of this work were to assess the correlation between in vitro estimates of D2 receptor affinity and pharmacokinetic–pharmacodynamic model-based estimates obtained from analysis of clinical data using an agonist–antagonist interaction (AAI) model and to assess the value of such a correlation in early prediction of full prolactin time profiles. A population model describing longitudinal prolactin data was fitted to clinical data from 16 clinical phases 1 and 3 trials including five different compounds. Pharmacokinetic data were modeled for each compound and the prolactin model was both fitted in per-compound fits as well as simultaneously to all prolactin data. Estimates of prolactin elevating potency were compared to corresponding in vitro values and their predictability was evaluated through model-based simulations. The model successfully described the prolactin time course for all compounds. Estimates derived from experimental preclinical data and the model fit of the clinical data were strongly correlated (p < 0.001), and simulations adequately predicted the prolactin elevation in five out of six compounds. The AAI model has the potential to be used in drug development to predict prolactin response for a given exposure of D2 antagonists using routinely produced preclinical data.

Key words

in vitroin vivo correlation pharmacodynamic scaling population modeling prolactin 



Klas Petersson would like to acknowledge Janssen Pharmaceutica N.V. for sponsorship of his PhD work. Part of the computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under Project p2011063


  1. 1.
    Kapur S, Remington G. Dopamine D(2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry. 2001;50(11):873–83.PubMedCrossRefGoogle Scholar
  2. 2.
    Biedermann F, Fleischhacker WW. Emerging drugs for schizophrenia. Expert Opin Emerg Drugs. 2011;16(2):271–82.PubMedCrossRefGoogle Scholar
  3. 3.
    Petty RG. Prolactin and antipsychotic medications: mechanism of action. Schizophr Res. 1999;35(Suppl):S67–73.PubMedCrossRefGoogle Scholar
  4. 4.
    Turrone P, Kapur S, Seeman MV, Flint AJ. Elevation of prolactin levels by atypical antipsychotics. Am J Psychiatry. 2002;159(1):133–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther. 1989;251(1):238–46.PubMedGoogle Scholar
  6. 6.
    Kapur S, Langlois X, Vinken P, Megens AA, De Coster R, Andrews JS. The differential effects of atypical antipsychotics on prolactin elevation are explained by their differential blood–brain disposition: a pharmacological analysis in rats. J Pharmacol Exp Ther. 2002;302(3):1129–34.PubMedCrossRefGoogle Scholar
  7. 7.
    Kapur S, Seeman P. Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?: a new hypothesis. Am J Psychiatry. 2001;158(3):360–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Langer G, Sachar EJ, Gruen PH, Halpern FS. Human prolactin responses to neuroleptic drugs correlate with antischizophrenic potency. Nature. 1977;266(5603):639–40.PubMedCrossRefGoogle Scholar
  9. 9.
    Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature. 1976;261(5562):717–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Bagli M, Suverkrup R, Quadflieg R, Hoflich G, Kasper S, Moller HJ, et al. Pharmacokinetic–pharmacodynamic modeling of tolerance to the prolactin-secreting effect of chlorprothixene after different modes of drug administration. J Pharmacol Exp Ther. 1999;291(2):547–54.PubMedGoogle Scholar
  11. 11.
    Friberg LE, Vermeulen AM, Petersson KJ, Karlsson MO. An agonist–antagonist interaction model for prolactin release following risperidone and paliperidone treatment. Clin Pharmacol Ther. 2009;85(4):409–17.PubMedCrossRefGoogle Scholar
  12. 12.
    Movin-Osswald G, Hammarlund-Udenaes M. Prolactin release after remoxipride by an integrated pharmacokinetic–pharmacodynamic model with intra- and interindividual aspects. J Pharmacol Exp Ther. 1995;274(2):921–7.PubMedGoogle Scholar
  13. 13.
    Ma G, Friberg LE, Movin-Osswald G, Karlsson MO. Comparison of the agonist–antagonist interaction model and the pool model for the effect of remoxipride on prolactin. Br J Clin Pharmacol. 2010;70(6):815–24.PubMedCrossRefGoogle Scholar
  14. 14.
    Te Beek ET, Moerland M, de Boer P, van Nueten L, de Kam ML, Burggraaf J, et al. Pharmacokinetics and central nervous system effects of the novel dopamine D2 receptor antagonist JNJ-37822681. J Psychopharmacol. 2011;26(8):1119–27.CrossRefGoogle Scholar
  15. 15.
    Mesens N, Steemans M, Hansen E, Verheyen GR, Van Goethem F, Van Gompel J. Screening for phospholipidosis induced by central nervous drugs: comparing the predictivity of an in vitro assay to high throughput in silico assays. Toxicol In Vitro. 2010;24(5):1417–25.PubMedCrossRefGoogle Scholar
  16. 16.
    Tresadern G, Bartolome JM, Macdonald GJ, Langlois X. Molecular properties affecting fast dissociation from the D2 receptor. Bioorg Med Chem. 2011;19(7):2231–41.PubMedCrossRefGoogle Scholar
  17. 17.
    Movin-Osswald G, Hammarlund-Udenaes M. Remoxipride: pharmacokinetics and effect on plasma prolactin. Br J Clin Pharmacol. 1991;32(3):355–60.PubMedCrossRefGoogle Scholar
  18. 18.
    Vermeulen A, Piotrovsky V, Ludwig EA. Population pharmacokinetics of risperidone and 9-hydroxyrisperidone in patients with acute episodes associated with bipolar I disorder. J Pharmacokinet Pharmacodyn. 2007;34(2):183–206.PubMedCrossRefGoogle Scholar
  19. 19.
    Lindbom L, Ribbing J, Jonsson EN. Perl-speaks-NONMEM (PsN)—a Perl module for NONMEM related programming. Comput Methods Prog Biomed. 2004;75(2):85–94.CrossRefGoogle Scholar
  20. 20.
    Jonsson EN, Karlsson MO. Xpose—an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Prog Biomed. 1999;58(1):51–64.CrossRefGoogle Scholar
  21. 21.
    R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2010.Google Scholar
  22. 22.
    Friberg LE, Sandstrom M, Karlsson MO. Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model. Invest New Drugs. 2010;28(6):744–53.PubMedCrossRefGoogle Scholar
  23. 23.
    Zuideveld KP, Van der Graaf PH, Peletier LA, Danhof M. Allometric scaling of pharmacodynamic responses: application to 5-Ht1A receptor mediated responses from rat to man. Pharm Res. 2007;24(11):2031–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Yassen A, Olofsen E, Kan J, Dahan A, Danhof M. Animal-to-human extrapolation of the pharmacokinetic and pharmacodynamic properties of buprenorphine. Clin Pharmacokinet. 2007;46(5):433–47.PubMedCrossRefGoogle Scholar
  25. 25.
    Lepist EI, Jusko WJ. Modeling and allometric scaling of s(+)-ketoprofen pharmacokinetics and pharmacodynamics: a retrospective analysis. J Vet Pharmacol Ther. 2004;27(4):211–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Raaflaub J. On the pharmacokinetics of chlorprothixene in man. Experientia. 1975;31(5):557–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Quitkin FM, editors. Current psychotherapeutic drugs. 2nd ed. Washington: American Psychiatric; 1998.Google Scholar
  28. 28.
    Seyffart G. Drug dosage in renal insufficiency. New York: Springer; 1991.CrossRefGoogle Scholar
  29. 29.
    Schmidt ME, Kent JM, Daly E, Janssens L, Van Osselaer N, Husken G, et al. A double-blind, randomized, placebo-controlled study with JNJ-37822681, a novel, highly selective, fast dissociating D(2) receptor antagonist in the treatment of acute exacerbation of schizophrenia. Eur Neuropsychopharmacol. 2012;22(10):721–33.PubMedCrossRefGoogle Scholar
  30. 30.
    Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl). 1996;124(1–2):57–73.CrossRefGoogle Scholar
  31. 31.
    Cooper DS, Ridgway EC, Kliman B, Kjellberg RN, Maloof F. Metabolic clearance and production rates of prolactin in man. J Clin Invest. 1979;64(6):1669–80.PubMedCrossRefGoogle Scholar
  32. 32.
    Rao ML, Gross G, Strebel B, Halaris A, Huber G, Braunig P, et al. Circadian rhythm of tryptophan, serotonin, melatonin, and pituitary hormones in schizophrenia. Biol Psychiatry. 1994;35(3):151–63.PubMedCrossRefGoogle Scholar
  33. 33.
    Rao ML, Gross G, Halaris A, Huber G, Marler M, Strebel B, et al. Hyperdopaminergia in schizophreniform psychosis: a chronobiological study. Psychiatry Res. 1993;47(2):187–203.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2013

Authors and Affiliations

  • Klas J. Petersson
    • 1
  • An M. Vermeulen
    • 2
  • Lena E. Friberg
    • 1
  1. 1.Department of Pharmaceutical BiosciencesUppsala UniversityUppsalaSweden
  2. 2.Division of Janssen PharmaceuticaJanssen Research & DevelopmentBeerseBelgium

Personalised recommendations