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

Abstract

Introduction: Long-acting stimulant formulations are recommended as first-line pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD). Over the past 20 years, extended-release (ER) methylphenidate (MPH) and amphetamine (AMP) formulations have evolved to include varying drug delivery technologies, enantiomers/salts, and dosage forms. All formulations are characterized by a unique pharmacokinetic profile that is closely mirrored by pharmacodynamic response allowing clinicians to individualize therapy based on their patient's clinical needs and dosing preferences. Areas covered: This review provides an update on the pharmacokinetic properties of approved and investigational ER MPH and AMP formulations and highlights pharmacokinetic features that clinicians should consider when selecting a long-acting stimulant. Expert opinion: Since there are no reliable biomarkers that can predict individualized response to longacting stimulants, clinicians need to consider their distinctive pharmacokinetic properties, including the pharmacokinetic profile, rate and extent of absorption, variability, dose proportionality, bioequivalence, and potential for accumulation. Clinicians also need to understand that certain factors can contribute to increased variability in pharmacokinetics and potentially affect outcomes. Less invasive, highthroughput techniques and novel time-based scales are being developed to advance research on the pharmacokinetic-pharmacodynamic relationships of stimulants. Model-based pharmacokineticpharmacodynamic approaches can be applied to aid the development of novel formulations and individualize therapy with existing drugs. ARTICLE HISTORYfor the treatment of ADHD. 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. Unfortunately, they were not as effective as IR formulations and the reduced efficacy was attributed to acute tolerance due to a lack of a steep absorption phase and a flat (i.e. zero-order) drug delivery profile following peak levels [19,21,22]. Subsequently, an ascending (e.g. first-order) drug delivery profile was proposed to overcome or minimize this tachyphylaxis [21,22]. Based on this observation, several extended-release (ER) formulations of both MPH and AMP have since been developed with ascending plasma concentrations that mimic twice-or thrice-daily ad...

Methylphenidate for attention-deficit/hyperactivity disorder in adults: a narrative review

“…The early formulations introduced in the market in the 1950s included a mixture of both racemates (80% (d/l)-erythro and 20% (d/l)-threo) (Bartl et al 2017;Heal and Pierce 2006;Markowitz et al 2003a). As it became clear that the central stimulating effects of methylphenidate are associated with the activity of threo isomers administration, while erythro isomers cause some adverse side effects, the production of more purified preparations became the subject of interest (Childress et al 2019;Markowitz et al 2003a). Therefore, subsequent generations of the drug contained only the threo enantiomers in equal proportions between the d-(2R:2'R) and l-(2S:2'S) forms of the molecule (which is the case for the majority of the Markowitz et al 2003a) Fig.…”

A Post Hoc Comparison of Prior ADHD Medication Dose and Optimized Delayed-release and Extended-release Methylphenidate Dose in a Pivotal Phase III Trial

“…The dose conversion ratios between optimized DR/ER-MPH doses and prior stimulants were higher than what would be expected given the 73.9% bioavailability of DR/ER-MPH 22 (ie,~1.3 for racemic MPH formulations and~2.7 for D-enantiomer MPH formulations 19 ). This discrepancy likely occurs because MPH absorption after DR/ER-MPH dosing is predicted to be extended over a longer duration of time compared with other MPH formulations: extended evening absorption as a result of colonic release and absorption, and release earlier in the morning as a result of evening dosing and the delayed-release properties of DR/ER-MPH.…”

“…17,18 Transitioning between stimulants is complex, and each particular medication provides unique drug exposure in each individual patient. 19 For example, long-acting MPHs that provide longer windows of coverage will require more absolute amounts of the active substance than is contained in MPH formulations which provide shorter windows of coverage. 20 The prescribing information for DR/ER-MPH states that it cannot be substituted for other MPH products on a milligram-per-milligram basis and that an optimized dose of DR/ER-MPH should be established by titration.…”

A Pharmacokinetic Study of Methylphenidate Hydrochloride Multilayer Extended-Release Capsules (Aptensio XR®) in Preschool-Aged Children with Attention-Deficit/Hyperactivity Disorder

“…The mechanism of action of MPH in ADHD is not completely understood, but it is believed to block dopamine and norepinephrine reuptake into the presynaptic neuron and increase their release into the extraneuronal space [10]. The PK profile of MPH has been summarized [8,11,12]. IR MPH is rapidly absorbed and has a half-life of 3-4 h. The PK properties of MPH have been described as age-and dose-dependent [7,11].…”

“…The PK profile of MPH has been summarized [ 8 , 11 , 12 ]. IR MPH is rapidly absorbed and has a half-life of 3–4 h. The PK properties of MPH have been described as age- and dose-dependent [ 7 , 11 ]. IR MPH requires two- or three-times-a-day drug administration; this requirement has been associated with non-adherence, administration during time away from home, and on–off responses resulting from fluctuating drug concentrations [ 10 , 13 – 15 ].…”