A. Taneja (1), A. Vermeulen (2), D. Huntjens (2), M. Danhof (3), E.C.M. De Lange (3), J.H. Proost (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: Treatment with D2 antagonists results in prolactin release, and thus prolactin is a biomarker of dopamine antagonism. We compare the model performance of two semi-mechanistic PKPD models, the pool model and the agonist-antagonist interaction model, to describe prolactin release following administration of risperidone (RI), paliperidone (PA) or remoxipride (REM) in rats. The hypothesis that potency differences exist for risperidone and paliperidone was evaluated and rat to human translations were conducted.
Methods: The models were fitted to single or multiple dose data on the 3 paradigm compounds. Different potencies (EC50 and KI) were estimated for RI and PA, as compared to a common potency. The pool model was modified to estimate RO50, or the receptor occupancy at half-maximal effect, a system specific parameter. This was done using model predicted and observed KI values. As peripheral D2 antagonism is responsible for prolactin release, free population plasma concentrations of the D2 antagonists were considered as the drivers of the pharmacodynamic (PD) response. Finally, we predicted the time course of plasma prolactin in humans following PA administration, using an inter-species scaling approach.
Results: Both models were able to describe the data and model performance was comparable. Potencies of RI and PA did not differ significantly. Estimated EC50 for RI and PA was 35.1(relative standard error 51%) and for REM it was 94.8 (31%) nM. KI values for these compounds were 14.6 (17%) and 165 (14%) nM respectively. RO50 was 28.7 (21%) %. System specific PD parameters were scaled using allometric principles, while RO50 was assumed to be species independent. Predicted human plasma prolactin profiles were comparable with observed and published findings. Tachyphylaxis due to depletion of the prolactin pool was predicted after the second dose.
Conclusions: The performance of both models was comparable in describing single and multiple dose data. Single dose typical human predictions with the pool model were in agreement with observed data.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
[2] 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
[3]Friberg LE, Vermeulen AM, Petersson KJ, Karlsson MO. Clin Pharmacol Ther 2009; 85(4): 409-17.
Reference: PAGE 24 (2015) Abstr 3413 [www.page-meeting.org/?abstract=3413]
Poster: Drug/Disease modeling - Endocrine