Taneja A( 1), Vermeulen A (2), Huntjens D( 2), Danhof M( 3), De Lange ECM (3), Proost JH( 1)
(1) Division of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute of Pharmacy, University of Groningen, the Netherlands (2) Model Based Drug Development, Janssen Research & Development, Beerse, Belgium (3) Department of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, the Netherlands
Objectives:Schizophrenia is characterized by dopamine dysregulation. Treatment with D2 antagonists results in side effects including prolactin release, which manifests clinically as weight gain, gynaecomastia and decreased libido in males. In this project we evaluate mechanism-based PKPD models [1,2] which can describe the time course of prolactin (PRL) concentrations in plasma (PD) in rats following administration of D2 antagonists.
Methods:Plasma concentration profiles of risperidone and prolactin were obtained following single dose administration via oral (n=39) or subcutaneous (n=61) routes in male Sprague-dawley rats who received a dose of 0.01, 0.04, 0.16, 0.63 or 2.5 mg/kg or vehicle. Plasma concentrations of risperidone and its active metabolite paliperidone were simulated using a two-compartment model with sequential absorption [3]. A mechanistic PKPD pool model was used to describe the prolactin time course. This comprises of the following sub-models:
-A pool model describing prolactin synthesis, storage in lactotrophs, prolactin release into plasma and elimination from plasma.
-A drug effect component quantifying the effect of D2 antagonists on prolactin release.
Results: We obtained the following model parameter estimates: baseline prolactin level 3.59 ng/ml, rate constant for the release of prolactin from the lactotrophs 0.46 /h, rate constant for prolactin elimination from the plasma 4.84 /h. The drug effect was parameterised by using an Emax function. Our results indicate that peak plasma prolactin secretion induced by risperidone is greater than 250 ng/ml. An Emax and a linear function were tested to parameterise the positive feedback effects of prolactin. Model performance was slightly better with an Emax function.
Conclusions:Estimated values for baseline prolactin levels and rate constant for the release of prolactin were comparable to the values reported by Stevens et al (6.2 ng/ml and 0.6 /h, respectively). However, alternative parametrisation will need to be evaluated prior to confirming these results. In addition, the results suggest that, multiple dosing is necessary in order to describe homeostatic feedback mechanisms with single doses.
References:
[1] Stevens J, Ploeger BA, Hammarlund-Udenaes M, Osswald G, van der Graaf PH, Danhof M, de Lange EC. J Pharmacokinet Pharmacodyn 2012; 39(5): 463-77
[2] Friberg LE, Vermeulen AM, Petersson KJ, Karlsson MO. Clin Pharmacol Ther 2009; 85(4): 409-17
[3] Kozielska M, Johnson M, Pilla Reddy V, Vermeulen A, Li C, Grimwood S, de Greef R, Groothuis GM, Danhof M, Proost JH. Pharmacokinetic-Pharmacodynamic Modelling of the Dopamine D2 and 5HT2A receptor occupancy of risperidone and paliperidone in rats.PharmRes 2012: 29(7): 1932-48.
Reference: PAGE 23 () Abstr 3192 [www.page-meeting.org/?abstract=3192]
Poster: Drug/Disease modeling - CNS