Klas J Petersson[1], Vijay Ivaturi[1], An M Vermeulen[2], Lena E Friberg[1]
[1] Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden [2] Advanced PKPD Modeling and Simulation, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium
Objectives: Prolactin elevation is a common side effect of compounds exhibiting antagonism at dopamine D2 –receptors. The time-course of prolactin can be described by a semi-mechanistic model [1] and the estimated potency of the prolactin elevating effect has been shown to correlate with the in vitro values of D2 –receptor affinity in humans on a compound level [2]. The aim of this work was to investigate the same correlation in rats and the potential use of rat data in bridging the in vitro and clinical data
Methods: Risperidone, olanzapine, remoxipride, haloperidol, JNJ-37822681 , JNJ-16157700 , JNJ-39269646 or vehicle were administered for two weeks to groups of 12 Sprague-Dawley rats; six males and six females. Six prolactin samples were taken on day 1 and day 14, and PK samples were collected at the same time points in satellite animals. PK models were developed for all compounds; these were subsequently used to drive a simultaneous fit of an agonist-antagonist interaction model [1] to the prolactin data from all compounds. The estimates of prolactin elevation potency were compared to in vitro values of affinity to rat D2-receptors as well as corresponding potency parameters obtained from human data.
Results: The agonist-antagonist model could adequately describe prolactin data also from rats. Turnover of prolactin in rats was estimated to 8 minutes which is similar to published values [3]. The estimate potency values correlated with in vitro values for rat receptor affinity ( R2 =0.67) if leaving out an outlier obtained from sparse data.
Conclusions: The AAI model could be applied across species. Estimates of prolactin elevation potency parameters correlated to a higher degree with in vitro values of rat D2-receptor affinity than corresponding model based potency estimates from human data. The correlation with in vitro values was weaker than found in human; this could be due to more uncertain estimates in rat because of less data.Estimates of rate constants in the model correponded to values predicted by scling using an exponent of -0.25.
References:
[1] 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 Apr;85(4):409-17
[2] Petersson KJ, Vermeulen AM, Friberg LE. Predictions of in vivo prolactin levels from in vitro Ki values of D2 receptor antagonists using an agonist-antagonist interaction model. PAGE 19 (2010) Abstr 1712 [www.page-meeting.org/?abstract=1712]
[3] Koch Y, Chow YF, Meites J. Metabolic clearance and secretion rates of prolactin in the rat. Endocrinology. 1971 Nov;89(5):1303-8.
Reference: PAGE 21 (2012) Abstr 2599 [www.page-meeting.org/?abstract=2599]
Poster: CNS