An Exploratory Analysis of the Performance of Methylphenidate Regimens Based on a PKPD Model of Dopamine and Norepinephrine Transporter Occupancy
Sara Soufsaf, Philippe Robaey, Fahima Nekka
Universiy of Montreal
Introduction:
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.
In a previous work, we have developed endpoints based on pharmacokinetic (PK) to compare the efficacy of various MPH treatments [1]. This algorithm was based on the supposition that the efficacy of some MPH regimens is closely correlated to its PK. This allowed us to use the MPH PK as a surrogate for its effect. Yet, it was observed that stable concentrations of MPH throughout the day were associated with lower efficacy compared to increasing concentrations of MPH. Indeed, an acute tolerance to MPH has been proposed to explain that there is a lower efficacy of MPH in the afternoon compared to the early hours post-dose, despite similar levels of plasma concentration [2].
It is important to work upstream and consider PD endpoints that characterize the time course of MPH effect and quantify its target binding (i.e., to DAT and NET). Indeed, this mechanistic approach allows an exploration of (i) each transporter’s involvement in the efficacy of MPH and (ii) an objective and mechanistic rationale for the acute tolerance to MPH upstream of behavioral effects which may be further confounded by environmental factors.
Objectives:
We propose a quantitative evaluation of the therapeutic performance of MPH regimen based on a PKPD framework of DAT and NET occupancy.
Methods:
We introduce an in silico framework composed of (i) a population pharmacokinetic model of MPH [3], (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 [1].
DAT occupancy data was digitized (n=152) and described with two Michaelis-Menten models: a direct Emax model and an indirect Emax model. The acute tolerance model assumes a time-dependent acute tolerance through a change of EC50 in function of time [4].
NET occupancy was described with a dose-PD model [5]. We used this integrative framework to simulate the performance of extended-release (18-99mg) and tid MPH regimens (25-40mg).
Results:
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 following 63mg of MPH. Higher doses of MPH are associated with PK or DAT occupancy curves which exceed the TB, which leads to a decrease in performance scores.
We observe that the smallest commercially available dose of Concerta is the only one which leads to a NET occupancy within the desired range despite very poor performance regarding DAT occupancy.
Conclusions:
Our analysis is consistent with the notion of clinical overdose and the therapeutic value of low doses for some ADHD patients [6]. As well, it 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.
References:
[1] Bonnefois G, Robaey P, Barrière O, et al. An Evaluation Approach for the Performance of Dosing Regimens in Attention-Deficit/Hyperactivity Disorder Treatment. Journal of Child and Adolescent Psychopharmacology 2017; 27: 320–331.
[2] Swanson J, Gupta S, Guinta D, et al. Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children. Clinical Pharmacology & Therapeutics 1999; 66: 295–305.
[3] Soufsaf S, Robaey P, Bonnefois G, et al. A Quantitative Comparison Approach for Methylphenidate Drug Regimens in Attention-Deficit/Hyperactivity Disorder Treatment. J Child Adolesc Psychopharmacol. Epub ahead of print 4 February 2019. DOI: 10.1089/cap.2018.0093.
[4] Kimko H, Gibiansky E, Gibiansky L, et al. Population pharmacodynamic modeling of various extended- release formulations of methylphenidate in children with attention deficit hyperactivity disorder via meta-analysis. J Pharmacokinet Pharmacodyn 2012; 16.
[5] Hannestad J, Gallezot J-D, Planeta-Wilson B, et al. Clinically relevant doses of methylphenidate significantly occupy norepinephrine transporters in humans in vivo. Biol Psychiatry 2010; 68: 854–860.
[6] Ling D, Balce K, Weiss M, et al. Effects of low-dose versus normal-dose psychostimulants on executive functions in children with attention-deficit / hyperactivity disorder. 2019. Epub ahead of print 25 June 2019. DOI: 10.13140/RG.2.2.13672.39681.
