An exploratory analysis of the performance of methylphenidate regimens based on a PKPD model of dopamine and norepinephrine transporter occupancy.

Methylphenidate (MPH) is a psychostimulant which inhibits the uptake of dopamine and norepinephrine transporters, DAT and NET, and is mostly used to treat Attention Deficit/Hyperactivity Disorder. The current dose optimization is done through titration, a cumbersome approach for patients. To assess the therapeutic performance of MPH regimens, we introduce an in silico framework composed of (i) a population pharmacokinetic model of MPH, (ii) a pharmacodynamic (PD) model of DAT and NET occupancy, (iii) a therapeutic box delimited by time and DAT occupancy, and (iv) a performance score computation. DAT occupancy data was digitized (n = 152) and described with Emax models. NET occupancy was described with a KPD model. We used this integrative framework to simulate the performance of extended-release (18-99 mg) and tid MPH regimens (25-40 mg). Early blood samples of MPH seem to lead to higher DAT occupancy, consistent with an acute tolerance observed in clinical rating scales. An Emax model with a time-dependent tolerance was fitted to available data to assess the observed clockwise hysteresis. Peak performance is observed at 63 mg. While our analysis does not deny the existence of an acute tolerance, data precision in terms of formulation and sampling times does not allow a definite confirmation of this phenomenon. This work justifies the need for a more systematic collection of DAT and NET occupancy data to further investigate the presence of acute tolerance and assess the impact of low MPH doses on its efficacy.