New Formulations of Stimulants: An Update for Clinicians

Abstract

In the last 15 years, there has been a marked increase in the number of available stimulant formulations with the emphasis on long-acting formulations, and the introduction of several novel delivery systems such as orally dissolving tablets, chewable tablets, extended-release liquid formulations, transdermal patches, and novel ''beaded'' technology. All of these formulations involve changes to the pharmaceutical delivery systems of the two existing compounds most commonly employed to treat attention-deficit/hyperactivity disorder (ADHD), amphetamine (AMP) and methylphenidate (MPH). In addition to these new formulations, our knowledge about the individual differences in response has advanced and contributes to a more nuanced approach to treatment. The clinician can now make increasingly informed choices about these formulations and more effectively individualize treatment in a way that had not been possible before. In the absence of reliable biomarkers that can predict individualized response to ADHD treatment, clinical knowledge about differences in MPH and AMP pharmacodynamics, pharmacokinetics, and metabolism can be utilized to personalize treatment and optimize response. Different properties of these new formulations (delivery modality, onset of action, duration of response, safety, and tolerability) will most likely weigh heavily into the clinician's choice of formulation. To manage the broad range of options that are now available, clinicians should familiarize themselves in each of these categories for both stimulant compounds. This review is meant to serve as an update and a guide to newer stimulant formulations and includes a brief review of ADHD and stimulant properties.

An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations

“…There is considerable variability in both the pharmacokinetics of stimulants across the day at an individual level, as well as in response [18,76,118,123]. Several factors potentially influence or contribute to the variability seen in individuals treated with stimulants, including drug specific factors (e.g.…”

“…Given the significant variability in the pharmacokinetics and response to stimulants, it can be concluded that there is no one treatment that is superior for all patients and underscores the importance of individualizing treatment by titrating the dose of each formulation for optimal effects in each patient while minimizing adverse events [18,76,118,123].…”

“…There are currently no reliable predictors of response to a particular stimulant [123]. While stimulants have long been recommended as first-line pharmacotherapy for ADHD, there are inconsistencies in the treatment recommendations in current guidelines [133].…”

“…Most guidelines and consensus statements recommend stimulants without identifying an agent of first choice nor offer any distinctions between MPH and AMP [2,11,13,14], whereas some recommend MPH over AMP for children [15,133]. Because AMP is thought to work through a different mechanism of action than MPH, a lack of response to one class of psychostimulant does not preclude response to another class [122,123]. Therefore, when the initial choice of stimulant fails to deliver an optimal response or exhibits intolerance, then the patient becomes a candidate for an alternate stimulant (i.e.…”

“…Interestingly, a recent systematic review and network metaanalysis on the comparative efficacy and tolerability of medications used for managing ADHD in children, adolescents and adults concluded that the preferred first pharmacological choice for the treatment of ADHD in children and adolescents is MPH, whereas AMP is preferred in adults [133]. Lastly, since isometric mixtures are not bioequivalent, pharmacological differences in the ratios of enantiomers may also contribute to clinical differences [123].…”