An Agonist–Antagonist Interaction Model for Prolactin Release Following Risperidone and Paliperidone Treatment

A mechanistic pharmacokinetic/pharmacodynamic model is presented, characterizing the time course of prolactin in healthy as well as schizophrenic subjects following the administration of various doses and formulations of the antipsychotic drugs risperidone and paliperidone. Prolactin concentrations from nine studies (1,462 subjects) were analyzed in NONMEM. A competitive agonist–antagonist interaction model described the competition between these drugs and dopamine for the D2 receptors that regulate prolactin release. Tolerance development was explained by a feedback loop with prolactin stimulating dopamine release, whereas models wherein tolerance is described in terms of depletion of a prolactin pool did not explain the data well. The diurnal prolactin rhythm was described by a two‐period cosine function. Baseline prolactin was health‐status dependent and higher in women than in men, although the drug‐induced release was less than proportional to baseline. This quantitative mechanism‐based model is the first to describe prolactin release in patients, and it confirms that paliperidone and risperidone have similar potencies for prolactin release.

[1]  R. Kahn.  Schizophrenia, an integrated view by Rasmus Fog, Jes Gerlach en Ralf Hemmingsen (editors), Munksgaard, Copenhagen, 1995 , 1995, European Neuropsychopharmacology.

[2]  J. Leysen,et al.  Risperidone: a novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity. , 1994, The Journal of clinical psychiatry.

[3]  Rajesh Pahwa,et al.  MECHANISM OF ACTION , 2019, Naturally Occurring Small Molecules for Disease and Cancer Treatment.

[4]  Mats O. Karlsson,et al.  Assessment of Actual Significance Levels for Covariate Effects in NONMEM , 2001, Journal of Pharmacokinetics and Pharmacodynamics.

[5]  R. Petty.  Prolactin and antipsychotic medications: mechanism of action , 1999, Schizophrenia Research.

[6]  M. Hammarlund-Udenaes,et al.  Prolactin release after remoxipride by an integrated pharmacokinetic-pharmacodynamic model with intra- and interindividual aspects. , 1995, The Journal of pharmacology and experimental therapeutics.

[7]  F. Maloof,et al.  Metabolic clearance and production rates of prolactin in man. , 1979, The Journal of clinical investigation.

[8]  V. Piotrovsky,et al.  Pharmacokinetic-pharmacodynamic modeling in the data analysis and interpretation of drug-induced QT/QTc prolongation , 2005, The AAPS Journal.

[9]  R. G. Wilson,et al.  Prolactin , 1973 .

[10]  E. Ludwig,et al.  Population Pharmacokinetics of Risperidone and 9-Hydroxyrisperidone in Patients with Acute Episodes Associated with Bipolar I Disorder , 2007, Journal of Pharmacokinetics and Pharmacodynamics.

[11]  Steven M. Pincus,et al.  Basal, pulsatile, entropic, and 24-hour rhythmic features of secondary hyperprolactinemia due to functional pituitary stalk disconnection mimic tumoral (primary) hyperprolactinemia. , 2001, The Journal of clinical endocrinology and metabolism.

[12]  H. Möller,et al.  Pharmacokinetic-pharmacodynamic modeling of tolerance to the prolactin-secreting effect of chlorprothixene after different modes of drug administration. , 1999, The Journal of pharmacology and experimental therapeutics.

[13]  G. Arana,et al.  Hyperprolactinaemia in Antipsychotic-Treated Patients , 1998 .

[14]  S. Kapur,et al.  The Differential Effects of Atypical Antipsychotics on Prolactin Elevation Are Explained by Their Differential Blood-Brain Disposition: A Pharmacological Analysis in Rats , 2002, Journal of Pharmacology and Experimental Therapeutics.

[15]  B. Zhu.  The competitive and noncompetitive antagonism of receptor-mediated drug actions in the presence of spare receptors. , 1993, Journal of pharmacological and toxicological methods.

[16]  B. Kinon,et al.  Prevalence of hyperprolactinemia in schizophrenic patients treated with conventional antipsychotic medications or risperidone 1 1 This work was sponsored by Eli Lilly and Company. , 2003, Psychoneuroendocrinology.

[17]  M. Karlsson,et al.  Population pharmacokinetic‐pharmacodynamic modeling of moxonidine using 24‐hour ambulatory blood pressure measurements , 1998, Clinical pharmacology and therapeutics.

[18]  A. Wieck,et al.  Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. , 2004, Drugs.

[19]  D. Copolov,et al.  Abnormal prolactin response to haloperidol challenge in men with schizophrenia. , 1987, The American journal of psychiatry.

[20]  M O Karlsson,et al.  Diagnosing Model Diagnostics , 2007, Clinical pharmacology and therapeutics.

[21]  M L Johnson,et al.  Twenty-four-hour rhythms in plasma concentrations of adenohypophyseal hormones are generated by distinct amplitude and/or frequency modulation of underlying pituitary secretory bursts. , 1990, The Journal of clinical endocrinology and metabolism.

[23]  Mathematical model forin vivo pharmacodynamics integrating fluctuation of the response: Application to the prolactin suppressant effect of the dopaminomimetic drug DCN 203–922 , 1991, Journal of Pharmacokinetics and Biopharmaceutics.

[24]  P. Bräunig,et al.  Hyperdopaminergia in schizophreniform psychosis: A chronobiological study , 1993, Psychiatry Research.

[25]  M. Weissman,et al.  The cross national epidemiology of obsessive compulsive disorder. The Cross National Collaborative Group. , 1994, The Journal of clinical psychiatry.

[26]  P. Bräunig,et al.  Circadian rhythm of tryptophan, serotonin, melatonin, and pituitary hormones in schizophrenia , 1994, Biological Psychiatry.

[27]  A. Peer,et al.  Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects , 1993, Clinical pharmacology and therapeutics.

[28]  G. Asnis,et al.  A preliminary study of sex-related differences in prolactin responses to dopamine blockade and insulin hypoglycemia and in penfluridol plasma levels in schizophrenic patients , 2004, Psychopharmacology.

[29]  M. Karlsson,et al.  Morphine-3-glucuronide has a minor effect on morphine antinociception. Pharmacodynamic modeling. , 1998, Journal of pharmaceutical sciences.

[30]  Lewis B. Sheiner,et al.  Building population pharmacokineticpharmacodynamic models. I. Models for covariate effects , 1992, Journal of Pharmacokinetics and Biopharmaceutics.

[31]  E. Lindström,et al.  Prolactin level during 5 years of risperidone treatment in patients with psychotic disorders , 2007, Acta psychiatrica Scandinavica.

[32]  E N Jonsson,et al.  Xpose--an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. , 1999, Computer methods and programs in biomedicine.

[33]  L. Kahn,et al.  Hyperprolactinemia and Schizophrenia: Mechanisms and Clinical Aspects , 2003, Journal of psychiatric practice.

[34]  David Gottlieb,et al.  Mechanism of Action , 2012, Antibiotics.

[35]  P. F. M. Janssen,et al.  Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding , 1996, Psychopharmacology.