Drug Regimen Individualization for Attention‐Deficit/Hyperactivity Disorder: Guidance for Methylphenidate and Dexmethylphenidate Formulations

Abstract

In 2000, the first biphasic modified-release (MR) formulation of methylphenidate (MPH) was approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). An immediate-release (IR) MPH pulse (22% of the dose) facilitates rapid onset of stimulant action, while the remaining MR portion of the dose provides for day-long duration of efficacy. A wide array of oral MR-MPH products has subsequently been approved that also allows for once-daily dosing, though each product is characterized by distinctive exposure time courses. This review compares each member of the current MPH armamentarium to assist in the rational selection of a specific MPH regimen for the individualized treatment of patients with ADHD. The IR portion of biphasic MPH formulations now ranges from 15%, 20%, 22%, 25%, 30%, and 37% IR-MPH, as well as a 50% IR-MPH product whose distinctly pulsatile time course closely resembles that of the pre-century "gold standard" twice-daily IR-MPH regimen. Further, transdermal, suspension, and orally disintegrating tablet products are now available to overcome any solid dosage form swallowing difficulties. Most of these formulations are racemic, though in 2001, a chiral switch drug IR-dexmethylphenidate (dexMPH) was approved, followed by biphasic MR-dexMPH (50% IR) in 2005. New U.S. Food and Drug Administration (FDA) partial area under the curve (pAUC) bioavailability metrics have improved discrimination between specific generic MR-MPH products. This has resulted in two Orange Book MR-MPH products being recoded from "AB" (i.e., meets necessary bioequivalence requirements) to "BX" (i.e., insufficient data to confirm bioequivalence). The metabolic drug interaction between MPH and alcohol, which increases MPH bioavailability, potentiates euphoric effects, and heightens abuse liability, is discussed. This review concludes with brief considerations of pharmacogenomic predictors of ADHD first-line drug selection, carboxylesterase allelic variants influencing interindividual MPH metabolism, and novel MPH formulations in the regulatory pipeline. KEY WORDS methylphenidate, dexmethylphenidate, attention-deficit/hyperactivity disorder, pharmacokinetics, partial area under the curve, early exposure, relative bioavailability, carboxylesterase 1, bioequivalence.Estimates of attention-deficit/hyperactivity disorder (ADHD) global prevalence generally range from 5% to 7% in the pediatric population. 1,2 Recognition that ADHD often persists into adulthood has become well established, a

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

“…The initial rapid release of drug results in an ascending release profile, which is then followed by a subsequent, prolonged phase of drug delivery [21]. However, the distinct pharmacokinetic profiles of these ER formulations are heavily influenced by their varying drug delivery mechanisms, including the rate and timing of drug release throughout the day, and the magnitude of plasma concentrations achieved [19,[23][24][25]33,112]. Furthermore, the onset and duration of action have been shown to closely mirror formulation-specific drug release mechanisms and their resulting pharmacokinetic profiles [19,24,33,[112][113][114].…”

“…Immediate-release (IR) formulations of stimulants were first approved by the Food and Drug Administration (FDA) Over the past 20 years, the ever-expanding armamentarium of long-acting stimulant formulations has evolved to include varying drug release profiles, enantiomers and/or salts, dosage forms (e.g. capsules containing composite or mixed beads, disintegrating tablets, chewable tablets, patches, liquid suspensions), and prodrugs (summarized in Table 1 and discussed in Section 4) [19,20,[24][25][26]. While this tremendous diversity of available long-acting stimulant formulations may be overwhelming and increase the complexity of selecting the most appropriate therapy, it also affords clinicians the opportunity to individualize therapy specifically based on their patient's characteristics, clinical needs, and dosing preferences.…”

“…However, given their rapid absorption and metabolism, the therapeutic effects of IR stimulants typically wear off within a few hours, requiring twice-or thrice-daily dosing to achieve symptom control [19,20]. This presents a number of significant challenges for patients, including fluctuating peak and trough plasma concentrations that may increase the risk of adverse events or reduce efficacy; the inconvenience of multiple daily dosing, which may result in embarrassment, stigma, and lack of privacy, especially when administrating therapy during a school or work day; reduced treatment compliance; and the potential for diversion of these Schedule II drugs [17,[19][20][21][22][23][24]. Sustained-release (SR) formulations of MPH were initially developed to address these challenges.…”

Pharmacologic Issues in Treating Neurodevelopmental Disorders

“…The optimal choice among a myriad of methylphenidate products available for prescribing can be bewildering, which can result in empirical choices. Patrick et al 7 provide an in-depth presentation of the pharmaceutical aspects of methylphenidate and dexmethylphenidate products to aid in individualization of pharmacotherapy.…”

“…Two reviews are included that address specific issues related to the treatment of ADHD with psychostimulants, the drugs of choice for this disorder. 6,7 An area of concern for caregivers and patients is whether these drugs can adversely affect growth, principally height. Questions abound about the value of drug holidays to mitigate this potential effect, whether any effect on growth is temporary or permanent, and to what degree differences in any growth effect Conflict of interest: The authors have declared no conflicts of interest for this article.…”