The Art of Reconciliation

Modeling of prolactin response following dopamine D2 receptor antagonists in rats: can it be translated to clinical dosing?

“…7) could not explain the predicted prolactin response. If DAs 0 is 10 000 as has been done in preclinical and clinical publications till now (Friberg et al 2009b;Ma et al 2010;Petersson et al 2012Petersson et al , 2013, D 2 receptor occupancy by dopamine is nearly 100%, even in the presence of the drug, implying that D2 receptor occupancy by the antipsychotic drug is very low. If this parameter is taken to be 10.9, as estimated from rat data, predictions of RO were higher, but yet remained far below reported occupancy levels.…”

“…Two approaches were investigated to obtain the human KIs. Petersson and colleagues have shown that human in vitro experimental KI values for antipsychotics correlate well with corresponding values estimated in vivo (r 2 = 0.94, P < 0.001) for five different antipsychotics, using data from 16 clinical trials (Petersson et al 2013). In the first approach, these values were fixed to those from in vitro experimental human values (Taneja et al 2016b).…”

“…In other words, in the absence of drug, the concentration of free receptors available for interaction with the drug is extremely low, which seems unlikely from a physiological standpoint. Petersson and colleagues have shown that in vitro experimental human KI values are highly correlated with corresponding estimates from population data (Petersson et al 2013). On the other hand, Johnson and colleagues have proposed a scaling which normalizes estimated rat in vivo K d to in vitro KI values for rats and humans (Johnson et al 2016).…”

“…The translational AAI model failed to accurately predict RO and plasma prolactin. It is of translational value if an alternative approach is applied, wherein system-specific parameters are fixed based on published data and KIs derived from in vitro experimental information (Petersson et al 2013). Based on our findings, we speculate on possible improvements in the modeling approach for future research.…”

“…To the best of our knowledge, the interspecies scaling of prolactin response has been described only for remoxipride (Stevens et al 2012), whereas rat to human scaling has not been published for the AAI model. Given this background, the aim of this work was to evaluate the predictive performance of either model applying standard systems pharmacology interspecies scaling approaches (Mager et al 2009;Stevens et al 2012;Petersson et al 2013). We further examine the translatability of these PKPD models to predict pituitary dopamine receptor occupancy (D 2 RO) and plasma prolactin response at steady-state concentrations of PA and REM.…”