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Understanding the delivery technology used in ADHD stimulant medications can help to individualize treatment

Published online by Cambridge University Press:  13 February 2025

Andrew J. Cutler Open the ORCID record for Andrew J. Cutler [Opens in a new window]  and
Jacob Hanaie
Andrew J. Cutler*
Affiliation:
Chief Medical Officer, Neuroscience Education Institute, Carlsbad, CA, USA Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA
Jacob Hanaie
Affiliation:
Department of Psychiatry, Kedren Community Mental Health, Los Angeles, CA, USA
*
Corresponding author: Andrew J. Cutler; Email: [email protected]
Rights & Permissions [Opens in a new window]

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a highly heterogeneous disorder for which treatment personalization is essential. Stimulant medications are the first-line option for ADHD management due to their high efficacy. While the choice of stimulant is limited to methylphenidate or amphetamine, there are numerous formulation options each associated with different potential benefits and restrictions. The goal is to deliver a stimulant medication that provides an even, continuous control of symptoms tailored to the patient’s symptoms and lifestyle. This article reviews the technologies used to deliver stimulants and the impact their characteristics have on the pharmacokinetic profiles, dosing regimens, and flexibility of the medication. The aim was to help clinicians in their treatment decision-making process and provide patients with effective and individualized management of their ADHD symptoms.

Keywords

ADHDdelivery technologyindividualized treatmentstimulant medicationsextended release
Type
Review
Information
CNS Spectrums , Volume 30 , Issue 1 , 2025 , e30
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.
Copyright
© The Author(s), 2025. Published by Cambridge University Press

Clinical implications

  1. 1. A universal approach to treat attention-deficit/hyperactivity disorder (ADHD) is unlikely to be optimal for all patients due to the heterogeneity in etiology, neurobiology, symptoms, impairment, comorbidities, and disease course.

  2. 2. There are a limited number of therapeutic categories of medication to treat this highly variable condition; and the technology used to deliver stimulants, the first-line medical management option, becomes more relevant as clinicians look to personalize treatment.

  3. 3. The most desired features of stimulant medication are a quick onset of efficacy, a long and consistent duration, minimal interactions with concomitant medications or food, reduced abusability, and a smooth pharmacokinetic curve without a sharp peak or an abrupt offset.

  4. 4. ADHD delivery technologies impact the pharmacokinetic profile by altering the timing of drug release and the plasma concentrations achieved over the course of the day, which influence the clinical onset and duration as well as tolerability of the medication.

  5. 5. This review discusses the benefits and restrictions of the various stimulant delivery technologies to help guide healthcare providers in their ADHD treatment choices.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity.1 Since ADHD is heterogeneous in etiology, neurobiology, symptoms, impairment, comorbidities, and disease course,Reference Faraone, Bellgrove and Brikell2 a universal approach to treat ADHD is unlikely to be optimal for all patients. Considerations that impact treatment decisions include the patient’s response to current or previous medication, the onset and duration of coverage for which symptom relief is required, concomitant medications and their effects on the patient and/or other medications, present comorbidities, patient preference, and the likelihood of adherence to different formulations.Reference Mechler, Banaschewski, Hohmann and Häge3, Reference Cutler and Mattingly4 With the substantial neurobiological and clinical variability associated with ADHD and the limited number of therapeutic categories of medication available for treatment, the technology involved in the delivery of these medications becomes more relevant for their effective utilization.

This article focuses on the delivery technologies typically used in stimulant medications for ADHD, as stimulants are the first-line treatment option in ADHD management due to their high efficacy.Reference Faraone, Bellgrove and Brikell2 Amphetamine (AMP) and methylphenidate (MPH) are the two types of stimulants approved in the United States (US) to treat ADHD. Both are short-acting, and different formulations contain one of the isomers or a racemic mixture.Reference Childress5 As ADHD symptoms and impairments often persist all day long beyond work or school hours, there has been an evolution in extended-release (ER) technologies to provide all-day coverage, and several formulations of long-acting stimulants have received approval in recent years. It is important to understand the characteristics of the technologies used, their clinical relevance, and the resulting impact on treatment outcomes. This article presents the technologies and formulations that were developed in response to the evolving needs and understanding of the ADHD disease state, highlighting the advantages and limitations of these solutions.

New formulations possess unique advantages to accomplish the common goals of a stimulant—to provide a quick onset of efficacy, a long and consistent duration, minimal interactions with medications or food, reduced abusability, and a smooth pharmacokinetic (PK) curve, avoiding a sharp peak or an abrupt offset. In 2019, the US Food and Drug Administration (FDA) issued a Guidance for Industry on developing stimulants for ADHD, which stated that stimulants have a strong concentration–response relationship for efficacy and safety.6 This refers to the relationship between the PK (plasma level, or the movement of drugs in the body) and pharmacodynamics (PD; clinical effect) of the drug. ADHD delivery technologies impact the PK profile by influencing the timing of drug release and the plasma concentrations achieved over the course of the day, which in turn translate into the clinical onset and duration as well as tolerability of the medication.Reference Childress, Komolova and Sallee7 Additionally, there are PK characteristics that should be considered when translation to efficacy is the goal,6 for example, one should not just consider threshold levels but ascension to the threshold as an important part of the efficacy story.6 Due to different properties, some formulations have demonstrated undesirable inter- and intraindividual variability in clinical effects,Reference Ermer, Adeyi and Pucci8 and therefore, stimulants have to be individualized for optimal efficacy and tolerability. Notably, the metabolism of both methylphenidate and amphetamine may differ between individuals due to genetic variability in the enzymes that metabolize themReference Ermer, Adeyi and Pucci8 and/or dopaminergic tone or response.Reference Volkow and Swanson9

An increased understanding of the technologies used in stimulant medications can assist clinicians in tailoring ADHD treatment to patients’ needs. The following review covers the evolution of long-acting stimulant formulations and the various technologies involved, with a discussion based on the authors’ clinical experience in using the different technologies to guide treatment individualization and optimization for their patients.

Development of delivery technologies

The first stimulant medications to treat ADHD were immediate-release (IR) formulations of amphetamine or methylphenidate. However, due to the short duration of action, patients required multiple doses each day. This has led to poor adherenceReference Ahmed and Aslani10, Reference Christensen, Sasané, Hodgkins, Harley and Tetali11 and significant fluctuations in medication levels in the blood over the course of the day, which can manifest clinically as side effects at the peak plasma level, a rapid decrease in efficacy, or a rebound or “crash” syndrome (cognitive impairment, irritability, emotional lability, etc.) due to sharp decline in plasma level.Reference Childress, Komolova and Sallee7 Early technologies were developed to mimic twice-a-day (BID) dosing, which was the standard at the time. It was subsequently realized that a smoother PK curve with a broader peak and a gradual descent in plasma levels was preferable.

Osmotic release

One of the first technologies developed to extend therapeutic duration was osmotic release, including OROS® (osmotic-controlled release oral system) used in Concerta® and Osmodex® used in Relexxii®. Osmotic delivery systems utilize both an overcoat of IR methylphenidate that is absorbed immediately to provide an early onset of efficacy and an ER component dependent on osmotic pressure. Tablets have multiple chambers that either contain medication or serve as an inert “push” compartment. As medication travels through the gastrointestinal (GI) tract, water is absorbed by an osmotic membrane in the “push” chamber, causing it to swell and push the medication out of the tablet through a small laser-drilled hole.12 This technology successfully extended the duration of efficacy, allowing for once-daily dosing. However, at the time of development, a tachyphylaxis phenomenon was noted during the day, which may or may not have been clinically relevant, resulting in an attempt to provide ascending plasma levels from the first to the second peak.Reference Swanson13 Utilizing two asymmetric release points is one of the several limitations that persist with osmotic delivery,12 which could result in undesirable variability in plasma medication levels throughout the day. In fact, the OROS® technology was designed to deliver 22% of the total methylphenidate via the IR coating and 78% via osmotic delivery.12 As there is a close relationship between the PKs of a stimulant and its clinical effect,6 this could result in delay and variability in efficacy throughout the day.

Additionally, the controlled-release tablet does not deform—it must be swallowed whole and cannot be given to patients with severe GI narrowing.12

Multiple beads

Beaded technologies emerged as an alternative ER delivery system. Beaded systems using multiple different beads in one capsule often leverage the changing pH throughout the GI system to direct the release of medication at distinct locations to give IR and ER. The first iteration of ER medication utilizing this technology, Diffucaps® used in Metadate CD® (currently only available as a generic, methylphenidate HCl ER tablet), allowed for once-daily dosing.14 In this medication, 30% of the methylphenidate is delivered with the IR bead, and 70% is delivered by the ER bead.14 However, like the PK curve seen with BID IR dosing and osmotic release, this long-acting formulation continued to show peaks and troughs in blood levels across the day.14 The Microtrol™ technologyReference Sallee and Smirnoff15 used in Adderall XR®16 similarly delivers mixed amphetamine salts using two populations of beads.Reference Childress, Komolova and Sallee7 The first is an IR bead designed to release medication in the stomach (pH 1.5–3.5), and the second is an ER bead that releases in the small intestine (at pH 5.5).Reference Childress, Komolova and Sallee7, Reference Sallee and Smirnoff15 Unlike Diffucaps®, the Microtrol™ technology delivers mixed amphetamine salts in an equal 50:50 split of IR and ER between the two beads, which provides a smoother PK curve. However, clinicians found the duration of efficacy to be too short for some patients, particularly adults, leading to the development of another formulation used in Mydayis®. This medication adds a third bead that releases medication even more distally in the intestine (at pH 7), thus potentially extending the efficacy to up to 16 hours.17 Amphetamine is delivered in an equal percentage of ⅓:⅓:⅓ between the three beads.Reference Strawn, Dobson and Giles18 Another technology, the spheroidal oral drug absorption system (SODAS®), is used in Focalin XR® and Ritalin LA®. SODAS® also uses two populations of IR and ER beads with an equal 50:50 split in methylphenidate delivery.19, 20 Please refer to Table 1 and Figure 1 for specific compositions of the technologies mentioned.

Table 1. Overview of drug delivery technologies and the brands that use those technologies to provide extended-release formulations of stimulant medications for the treatment of ADHD. The PK parameters are those that are easily available from the prescribing information (PI) of each product

Note: All products can be taken with or without food unless as described in clinical considerations column; the impact of high-fat meals on Cmax and/or Tmax for methylphenidates is due to variability associated with the active drug combined with the technology.

Abbreviations: A, adults; AD, adolescents; ADHD, attention-deficit/hyperactivity disorder; AE, adverse event; AMP, amphetamine; C, children; Cmax, peak plasma concentration; CR, controlled release; DR, delayed release; d-MPH, dexmethylphenidate; ER, extended release; Fe, fed; Fa, fasted; GI, gastrointestinal; IR, immediate release; LDX, lisdexamfetamine; MAS, mixed amphetamine salts; MLR, multilayer release; MPH, methylphenidate; ODT, orally disintegrating tablet; OROS, osmotic-controlled release oral system; PK, pharmacokinetic; PPI, proton pump inhibitor; SDX, serdexmethylphenidate; SODAS, spheroidal oral drug absorption system; T½, terminal half-life; Tmax, time to peak plasma concentration.

*Take whole or sprinkled on applesauce without chewing.

Figure 1. A summary of the ER/DR technologies available for stimulant medications in ADHD. ADHD, attention-deficit/hyperactivity disorder; CR, controlled release; d-MPH, dexmethylphenidate; DR, delayed release; ER, extended release; GI, gastrointestinal; IR, immediate release; LDX, lisdexamfetamine; MLR, multilayer release; OROS, osmotic-controlled release oral system; PK, pharmacokinetic; SDX, serdexmethylphenidate; SODAS, spheroidal oral drug absorption system.

Multilayer beads

Other beaded systems use one population of beads with multiple functional layers. Examples of this multilayer-release (MLR) bead technology include Aptensio XR™ and Adhansia XR®. Duration of clinical efficacy was improved between the development of Aptensio XR™ and Adhansia XR®. In Adhansia XR®, the technology of the second release layer was changed to release medication even more gradually to extend the duration of efficacy for adolescents and adults.

Another multilayered technology is DELEXIS®, used in Jornay PM®. DELEXIS® consists of a single population of two-layer microbeads with delayed-release (DR) and ER layers around a drug-loaded core, allowing for evening dosing with onset of efficacy the following morning. In healthy adults, a single 100 mg oral dose given in the evening showed an initial time lag of 10 hours.32 As the bead traverses the GI tract, increasing wettability leads to the breakdown of the hard outer DR layer overnight, forming pores that expose the underlying ER layer to GI fluids. The increased wetting of this soluble ER layer causes it to slowly dissolve, allowing for gradual diffusion of the medication from the core into the intestinal lumen, where it is absorbed.Reference Zhang, DeSousa, Sallee, Lickrish and Incledon30, 31 Since colonic absorption is less efficient than that in other regions of the GI tract, it contributes to a smooth rise in plasma medication levels during release, as well as a broad peak concentration and a subsequent gradual descent in plasma levels.Reference Steingard, Taskiran, Connor, Markowitz and Stein57, Reference Incledon, Incledon and Gomeni60 This technology is associated with considerable intraindividual consistency in the time from ingestion to clinical effect.

While the evolution of beaded technologies has allowed for smoother PK curves, extended clinical duration, and flexibility around the time of dosing, the biggest limitation for most of them lies in the potential for factors that influence pH (diet, medications) and GI transit time, thereby altering the release profile.

Transdermal delivery

A desire for flexible daily dosing and an alternative to oral formulations led to the development of transdermal delivery systems. The DOT Matrix® used in Daytrana® (methylphenidate) and Xelstrym™ (amphetamine) allows patients to adjust medication duration by simply changing the wear time, providing a potentially shortened duration when the patch is peeled off early (although MPH concentrations are reported to decline in a biexponential manner, likely due to continued distribution of MPH from the skin after patch removal). It also provides visual verification of adherence.34 This technology offers an option for patients who cannot or prefer not to swallow pills, commonly seen in children or patients with co-occurring autism spectrum disorder.Reference Mattingly, Wilson, Ugarte and Glaser61 While transdermal delivery addresses several patient needs, it is limited by a delayed onset of efficacy, dermal side effects such as skin irritation, and increased rate and extent of absorption when applied to inflamed skin.33, 34

Prodrug

Prodrug technology represented a significant advancement in stimulant formulations. A prodrug is an active medication covalently bound to an inactive moiety, which renders the prodrug inactive until it is cleaved by an endogenous enzyme to release the active medication. This gradual process results in a slow release of the medication.38 The LAT® prodrug technology first used in Vyvanse®, or lisdexamfetamine (LDX, a molecule of lysine attached to dextroamphetamine), requires absorption in the large intestine and subsequent cleavage of the lysine group in red blood cells to release the medication. Of note, its package insert reports inter-subject variability of 25% or less,38 and there could be variation in clinical effect based upon variations of absorption and conversion of LDX.6 To overcome this delay in clinical onset of effect,Reference Wigal, Brams and Gasior62 Azstarys® also has an IR component (dexmethylphenidate) to provide an early onset of efficacy while preserving a smooth extended duration of release.39 The prodrug delivery system results in a gradual increase in plasma amphetamine levels, a characteristic believed to confer properties of reduced abuse potential.Reference Volkow and Swanson9 Two studies have demonstrated that Vyvanse®, at FDA-approved doses, does not elicit high “likeability” scores from patients with a history of stimulant abuse compared to responses to IR d-AMP.Reference Jasinski and Krishnan63, Reference Jasinski and Krishnan64 While the serdexmethylphenidate prodrug component of Azstarys® showed decreased potential for abuse and by itself is a C-IV drug,Reference Shram, Setnik and Webster65 the combination with IR dexmethylphenidate renders Azstarys® a C-II drug, like other stimulants.

Ion-exchange resins

Individual differences in metabolism of amphetamine and methylphenidateReference Markowitz and Patrick66–Reference Dinis-Oliveira68 can mediate the duration of clinical efficacy when the medication is released as a bolus, characteristic of beaded and osmotic pump technologies. Ion-exchange resins are formed by dissolving methylphenidate or amphetamine salt. The base drug (a positively charged cation) is separated from the negatively charged anion salt molecule and bound to a negatively charged resin particle. Ion-exchange technology allowed for the development of ER formulations such as liquids, oral dissolving tablets (ODTs), and chewables for patients who cannot or prefer not to swallow pills. While providing a smooth PK profile, fast onset (via IR components), and extended duration (via ER components), microparticle technologies used in Adzenys XR-ODT® and Cotempla XR-ODT® rely on the changing pH throughout the GI tract to mediate medication release.Reference Trofimiuk, Wasilewska and Winnicka69 Therefore, similar to beaded technologies, drug release can be altered by diet- and medication-induced changes to gut pH.

LiquiXR® is an advanced ion-exchange and diffusion technology used in Dyanavel XR®, Quillivant XR®, and QuilliChew ER® that addresses this shortcoming by utilizing pH-independent processes. Each dose contains a mixture of ER and IR particles. ER particles are coated with a protective layer that does not dissolve as the medication moves throughout the GI tract. Instead, positively charged ions endogenous to the gut diffuse through the coating and dislodge medication molecules, which then diffuse through the coating into the GI cavity where the medication is absorbed. The coating thickness around particles varies, resulting in numerous release points rather than a bolus-style release; this is reflected in a smooth rise in plasma medication levels and a gradual decline at the end of the day.47–50 Thinner coatings provide a shorter diffusion distance and release molecules of medication sooner in the day, whereas thicker coatings require a longer diffusion path and therefore release the medication later. This unique combination of diffusion coating thicknesses across ER particles achieves a smooth, continuous extended release of the medication, while uncoated particles provide immediate medication release for a fast clinical onset.Reference Cutler, Childress and Pardo70, Reference Childress, Kando, King, Pardo and Herman71 The drugs that use LiquiXR® technology are among the few branded products still on the market, so access may be limited by their potential expense.

The variety of delivery technologies and progressive sophistication within each class of delivery systems have improved many aspects of the clinical profile of stimulants. Cumulatively, delivery system advancements have provided medication options with early onset and extended duration of efficacy, improved tolerability via decreased fluctuations in plasma levels, allowed flexibility for dose adjustments, provided non-oral formulation options, reduced abuse potential, and limited variability of therapeutic response from individual differences in pH or metabolism. Each delivery system addresses a unique set of challenges faced by patients while carrying its own limitations. It is, therefore, important for clinicians to consider these factors to optimize patient outcomes.

Discussion

Understanding the technologies used in different ADHD stimulants will better equip clinicians to customize ADHD treatment according to patient needs and preferences (Figure 2). Provided are some examples that demonstrate how various technologies meet patient need.

Figure 2. A summary of clinical considerations for ADHD stimulant treatment, based on the characteristics of the different technologies. ADHD, attention-deficit/hyperactivity disorder; OROS, osmotic-controlled release oral system; SODAS, spheroidal oral drug absorption system.

Some patients may prefer flexibility in dose adjustments or administration. Flexible dosing may be appreciated during initial titration in patients who require small adjustments due to sensitive tolerability or for those anticipating different duration needs. Formulations with ease of adjustment include liquid formulations that allow small dose adjustments, scored tablets which can be halved, and transdermal patches which can be removed early to shorten the duration of exposure. For flexibility of administration, patients who cannot or prefer not to swallow pills can take formulations that are liquid, chewable, sprinkled, orally disintegrated, or transdermal through a patch.

Certain technologies used in ADHD medications require consistency in administration and might not be suitable for all patients. For example, medications that have a delayed onset—including the osmotic delivery system, transdermal patch, and LDX prodrug—may require advanced planning. In the case of the DELEXIS® multilayer bead, if the patient wakes in the morning and realizes that they have missed the dose the night before, they cannot take it until the next scheduled time. Furthermore, patients may need to time their meals for certain medications as food (based on fat content or acidity) can alter drug release in some formulations. Other concerns include the need to avoid coadministration of certain medications or agents that would alter gut pH; for the latter, patients may benefit from medications that release independently of pH.

The timing of medication release differs with the ADHD delivery technologies. Patients may have individual needs for therapeutic onset based on their lifestyle or preferences. For example, the LDX prodrug,38 osmotic release,12, 22 and transdermal patch33, 34 technologies have a delayed drug release and subsequent delay in providing efficacy.6 If a patient commutes to school or works shortly after waking and taking medication, they may prefer an alternative formulation with a more rapid effect. Moreover, patients may have different needs when it comes to the duration of effect, which can also be matched to appropriate formulations and delivery technologies, for example, adjusting the timing of effect to reduce appetite suppression around mealtimes or choosing ER formulations with a shorter duration of efficacy might suit younger patients or those with shorter school or work days. The proportion of IR and ER components used in different technologies is an important consideration when selecting medication for a desired onset and duration. For example, osmotic release has a higher proportion of ER, whereas Microtrol™ beaded technology uses a 50/50 split of IR and ER components.

Some patients report that they like feeling their medication start working, while many prefer a smooth on and off. Technologies to smooth the PK peaks include the 2-layer microbead (DELEXIS®), in which the delayed absorption in the colon translates into less pronounced peaks than those relying on absorption earlier along the GI tract, and LiquiXR®, which contains numerous particles with variable coating thicknesses to consistently deliver the active drug. Other patients may prefer the release of medications in boluses, perhaps to regain appetite during parts of the day when plasma levels dip. Formulations with a smoother PK curve, and especially with a slower decline in plasma levels, may contribute to a more gradual offset of efficacy and lower risk of rebound and crash. Furthermore, immediate-release formulations can be used as needed or as supplementation to an ER or transdermal formulation to extend the duration of action.

Conclusion

Medications, particularly stimulants due to their significant efficacy, are an important component in the management of ADHD. Numerous variables need to be considered when evaluating the optimal choice to treat ADHD patients. The technology of stimulant formulations has evolved over time, as has our understanding on how ADHD stimulants should be administered—from early formulations which mimicked multiple IR dosing daily, with or without an ascending peak, to the current goal of providing a smooth, consistent level of stimulant release for the duration of the dose, with rapid onset and gradual offset of action.

The key outcome in the management of ADHD is the level of symptom control during a dosing period. Since plasma levels of ADHD stimulants translate into clinical effect, different drug delivery technologies can affect the concentration of stimulant in the blood and impact how well the medication controls symptoms. The timing of medication release by delivery technologies as well as the proportion of IR and ER components determine the resulting onset and duration of efficacy. Furthermore, the nature of drug release, as distinct boluses or a continuous pattern, results in distinct patterns of plasma levels and thus symptom control over the day. Technologies that rely on certain factors for drug release, such as pH, can be affected by external factors including medications or diet, and these interactions can have clinical consequences.

The management of ADHD requires numerous considerations to match the clinical needs, lifestyle, and social circumstances of each patient.Reference Cutler and Mattingly4 The different formulation technologies of stimulants present clinicians with a wide range of options from which the most appropriate treatment—based on symptom presentation, dosing interval, route of administration, concomitant medications, patient preferences, and lifestyle—can be selected. Ultimately, cost and access dictate many of our treatment choices, but for most patients, the newer formulations with more desirable PK profiles that provide a faster onset, smoother PK curve, longer duration, and more gradual decrease at the end of the day (less crash/rebound) are desirable.

Acknowledgments

Editorial support was provided by Highfield Communication, Oxford, United Kingdom, sponsored by Tris Pharma, Inc., Monmouth Junction, New Jersey, USA.

Author contribution

Conceptualization: J.H., A.J.C.; Visualization: J.H., A.J.C.; Writing – original draft: J.H., A.J.C.; Writing – review & editing: J.H., A.J.C.; Formal analysis: A.J.C.; Supervision: A.J.C.

Competing interest

Dr Cutler has acted as a consultant at Advisory Boards for AbbVie, Acadia, Alfasigma, Alkermes, Anavex Life Sciences, Axsome, Biogen, Biohaven, BioXcel, Boehringer Ingelheim, Brii Biosciences, Bristol Myers Squibb, Cerevel, Chase Therapeutics, Cognitive Research, Corium, Delpor, Evolution Research Group, 4M Therapeutics, Intra-Cellular Therapies, Ironshore Pharmaceuticals, Janssen/J&J, Jazz Pharma, Karuna, LivoNova, Lundbeck, Luye Pharma, Maplight Therapeutics, MedAvante-ProPhase, Mentavi, Neumora, Neurocrine, Neuroscience Education Institute, NeuroSigma, Noven, Otsuka, PaxMedica, PureTech Health, Relmada, Reviva, Sage Therapeutics, Sumitomo Pharma America, Sunovion, Supernus, Teva, Thynk, Tris Pharma, Vanda Pharmaceuticals, VistaGen, and VivoSense. He is a Speaker Bureau member for AbbVie, Acadia, Alfasigma, Alkermes, Axsome, BioXcel, Corium, Intra-Cellular Therapies, Ironshore Pharmaceuticals, Janssen/J&J, Lundbeck, Neurocrine, Noven, Otsuka, Sunovion, Supernus, Teva, Tris Pharma, and Vanda Pharmaceuticals. He holds stock options for 4M Therapeutics and Relmada. He is a member of the Data Safety Monitoring Board for Alar Pharma, COMPASS Pathways, Freedom Biosciences, and Pain Therapeutics.

Dr Hanaie has acted as a consultant at Advisory Boards for AbbVie, Alkermes, Biogen, BioXcel, Bristol Myers Squibb, Intra-Cellular Therapies, and Sunovion. He has also been a member of Speaker Bureaux for AbbVie, Alkermes, BioXcel, Intra-Cellular Therapies, Sunovion, and Teva.

Funding

Editorial support was funded by Tris Pharma, Inc., Monmouth Junction, New Jersey, USA.

References

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR). 5th ed. 2022.Google Scholar
Faraone, SV, Bellgrove, MA, Brikell, I, et al.Attention-deficit/hyperactivity disorder. Nat Rev Dis Primers. 2024;10(1): 11. doi:10.1038/s41572-024-00495-0Google Scholar
Mechler, K, Banaschewski, T, Hohmann, S, Häge, A.Evidence-based pharmacological treatment options for ADHD in children and adolescents. Pharmacol Ther. 2022;230:107940. doi:10.1016/j.pharmthera.2021.107940Google Scholar
Cutler, AJ, Mattingly, GW. Beyond the pill: new medication delivery options for ADHD. CNS Spectr. 2017;22(6):463–474. doi:10.1017/s1092852916000936Google Scholar
Childress, AC. Novel formulations of ADHD medications: stimulant selection and management. Focus (Am Psychiatr Publ). 2021;19:31–38. doi: 10.1176/appi.focus.20200032.Google Scholar
U.S. Food & Drug Administration. Attention Deficit Hyperactivity Disorder: Developing Stimulant Drugs for Treatment Guidance for Industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/attention-deficit-hyperactivity-disorder-developing-stimulant-drugs-treatment-guidance-industry.Google Scholar
Childress, AC, Komolova, M, Sallee, FR. An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations. Expert Opin Drug Metab Toxicol. 2019;15(11):937–974. doi:10.1080/17425255.2019.1675636Google Scholar
Ermer, JC, Adeyi, BA, Pucci, ML. Pharmacokinetic variability of long-acting stimulants in the treatment of children and adults with attention-deficit hyperactivity disorder. CNS Drugs. 2010;24(12):1009–1025. doi:10.2165/11539410-000000000-00000Google Scholar
Volkow, ND, Swanson, JM. Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD. Am J Psychiatry. 2003;160(11):1909–1918. doi:10.1176/appi.ajp.160.11.1909Google Scholar
Ahmed, R, Aslani, P.Attention-deficit/hyperactivity disorder: an update on medication adherence and persistence in children, adolescents and adults. Expert Rev Pharmacoecon Outcomes Res. 2013;13(6):791–815. doi:10.1586/14737167.2013.841544Google Scholar
Christensen, L, Sasané, R, Hodgkins, P, Harley, C, Tetali, S.Pharmacological treatment patterns among patients with attention-deficit/hyperactivity disorder: retrospective claims-based analysis of a managed care population. Curr Med Res Opin. 2010;26(4):977–989. doi:10.1185/03007991003673617Google Scholar
U.S. Food & Drug Administration. CONCERTA Prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021121s049lbl.pdfGoogle Scholar
Swanson, JM. Long-acting stimulants: development and dosing. Can Child Adolesc Psychiatr Rev. 2005;14(Supplement 1):4–9.Google Scholar
U.S. Food & Drug Administration. METADATE CD Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021259s034lbl.pdf.Google Scholar
Sallee, FR, Smirnoff, AV. Adderall XR: long acting stimulant for single daily dosing. Expert Rev Neurother. 2004;4(6):927–934. doi:10.1586/14737175.4.6.927Google Scholar
U.S. Food & Drug Administration. ADDERALL XR Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021303s038lbl.pdf.Google Scholar
U.S. Food & Drug Administration. MYDAYIS Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/022063s005lbl.pdf.Google Scholar
Strawn, JR, Dobson, ET, Giles, LL. Primary pediatric care psychopharmacology: focus on medications for ADHD, depression, and anxiety. Curr Probl Pediatr Adolesc Health Care. 2017;47(1):3–14. doi:10.1016/j.cppeds.2016.11.008Google Scholar
U.S. Food & Drug Administration. FOCALIN XR Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021802s038s041lbl.pdf.Google Scholar
U.S. Food & Drug Administration. RITALIN LA Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021284s042s046lbl.pdf.Google Scholar
Carter, NJ, Keating, GM. OROS hydromorphone prolonged release: a review of its use in the management of chronic, moderate to severe pain. CNS Drugs. 2010;24(4):337–361. doi:10.2165/11202580-000000000-00000Google Scholar
U.S. Food & Drug Administration. RELEXXII Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216117s001lbl.pdf.Google Scholar
Jain, D, Raturi, R, Jain, V, Bansal, P, Singh, R.Recent technologies in pulsatile drug delivery systems. Biomatter. 2011;1(1):57–65. doi:10.4161/biom.1.1.17717Google Scholar
Patel, RR, Patel, JK. Novel technologies of oral controlled release drug delivery system. SRP. 2010;1(2):128–132. doi:10.4103/0975-8453.75054Google Scholar
Nugent, SG, Kumar, D, Rampton, DS, Evans, DF. Intestinal luminal pH in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugs. Gut. 2001;48(4):571–577. doi:10.1136/gut.48.4.571Google Scholar
Childress, AC, Brams, MN, Cutler, AJ, Donnelly, GAE, Bhaskar, S.Efficacy and safety of multilayer, extended-release methylphenidate (PRC-063) in children 6-12 years of age with attention-deficit/hyperactivity disorder: a laboratory classroom study. J Child Adolesc Psychopharmacol. 2020;30(10):580–589. doi:10.1089/cap.2020.0109Google Scholar
Katzman, MA, Mattingly, G, Klassen, LJ, Cataldo, MJ, Donnelly, GAE. Randomized controlled crossover trials of the pharmacokinetics of PRC-063, a novel multilayer extended-release formulation of methylphenidate, in healthy adults. J Clin Psychopharmacol. 2020;40(6):579–587. doi:10.1097/jcp.0000000000001277Google Scholar
U.S. Food & Drug Administration. APTENSIO XR Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/205831s008lbl.pdf.Google Scholar
U.S. Food & Drug Administration. ADHANSIA XR Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212038s002lbl.pdf.Google Scholar
Zhang, F, DeSousa, NJ, Sallee, FR, Lickrish, D, Incledon, B. Mechanism of action of DELEXIS®, a novel, oral, colonic-targeted drug delivery platform. presented at: College of Psychiatric and Neurologic Pharmacists (CPNP) Virtual Conference; 2020.Google Scholar
Highland Therapeutics. Next-generation drug delivery targets early-morning release. 2016. https://www.nature.com/articles/d43747-020-00123-2.pdfGoogle Scholar
U.S. Food & Drug Administration. JORNAY PM Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/209311s010lbl.pdfGoogle Scholar
U.S. Food & Drug Administration. DAYTRANA Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021514s036lbl.pdf.Google Scholar
U.S. Food & Drug Administration. XELSTRYM Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215401s008lbl.pdf.Google Scholar
Markovic, M, Ben-Shabat, S, Dahan, A.Prodrugs for improved drug delivery: lessons learned from recently developed and marketed products. Pharmaceutics. 2020;12(11):1031. doi:10.3390/pharmaceutics12111031Google Scholar
Ermer, JC, Pennick, M, Frick, G.Lisdexamfetamine dimesylate: prodrug delivery, amphetamine exposure and duration of efficacy. Clin Drug Investig. 2016;36(5):341–356. doi:10.1007/s40261-015-0354-yGoogle Scholar
Sharman, J, Pennick, M.Lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells. Neuropsychiatr Dis Treat. 2014;10:2275–2280. doi:10.2147/NDT.S70382Google Scholar
U.S. Food & Drug Administration. VYVANSE Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021977s050,208510s007lbl.pdf.Google Scholar
Center for Drug Evaluation and Research. Multi-discipline review (Azstarys). https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/212994s004lbl.pdfGoogle Scholar
Braeckman, R, Guenther, S, Mickle, TC, Barrett, AC, Smith, A, Oh, C.Dose proportionality and steady-state pharmacokinetics of serdexmethylphenidate/dexmethylphenidate, a novel prodrug combination to treat attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2022;32(5):288–295. doi:10.1089/cap.2022.0015Google Scholar
U.S. Food & Drug Administration. AZSTARYS Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/212994s007lbl.pdf.Google Scholar
Mattingly, GW, Young, JL. A clinician’s guide for navigating the world of attention-deficit hyperactivity disorder medications. CNS Spectr. 2021;26(2):104–114. doi:10.1017/S1092852921000146Google Scholar
U.S. Food & Drug Administration. COTEMPLA XR-ODT Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/205489s012lbl.pdf.Google Scholar
U.S. Food & Drug Administration. ADZENYS XR-ODT Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/204326s011lbl.pdf.Google Scholar
U.S. Food & Drug Administration. ADZENYS ER Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/204325s003lbl.pdf.Google Scholar
Pardo, A, King, TR, Rafla, E, Kando, JC. Assessing palatability of a new amphetamine extended-release tablet formulation for the treatment of ADHD. Drug Des Devel Ther. 2021;15:2979–2985. doi:10.2147/dddt.S309378Google Scholar
Tris Pharma. Technologies. https://www.trispharma.com/our-focus/technology-platform/Google Scholar
U.S. Food & Drug Administration. QUILLIVANT XR Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/202100Orig1s023lbl.pdf.Google Scholar
U.S. Food & Drug Administration. QUILLICHEW ER Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/207960orig1s016lbl.pdf.Google Scholar
U.S. Food & Drug Administration. DYANAVEL XR Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/208147s016,210526s008lbl.pdf.Google Scholar
Adare Pharma Solutions. Diffucaps®. https://adarepharmasolutions.com/technologies/diffucaps/.Google Scholar
Adjei, A, Teuscher, NS, Kupper, RJ, et al.Single-dose pharmacokinetics of methylphenidate extended-release multiple layer beads administered as intact capsule or sprinkles versus methylphenidate immediate-release tablets (Ritalin®) in healthy adult volunteers. J Child Adolesc Psychopharmacol. 2014;24(10):570–578. doi:10.1089/cap.2013.0135Google Scholar
Buck, ML. Improving compliance with medication regimens. Pediatr Pharmacother.; 1997;3:8. https://med.virginia.edu/pediatrics/wp-content/uploads/sites/237/2015/12/199708.pdfGoogle Scholar
Connor, DF, Steingard, RJ. New formulations of stimulants for attention-deficit hyperactivity disorder: therapeutic potential. CNS Drugs. 2004;18(14):1011–1030. doi:10.2165/00023210-200418140-00005Google Scholar
Moodley, K, Pillay, V, Choonara, YE, et al.Oral drug delivery systems comprising altered geometric configurations for controlled drug delivery. Int J Mol Sci. 2012;13(1):18–43. doi:10.3390/ijms13010018Google Scholar
Siddiqui, MA. SODAS® (Spheroidal Oral Drug Absorption System). Pharmaceutical Research. https://pharmaceuticalresearch.wordpress.com/2012/07/05/sodas-spheroidal-oral-drug-absorption-system/.Google Scholar
Steingard, R, Taskiran, S, Connor, DF, Markowitz, JS, Stein, MA. New formulations of stimulants: an update for clinicians. J Child Adolesc Psychopharmacol. 2019;29(5):324–339. doi:10.1089/cap.2019.0043Google Scholar
Mydayis. https://www.mydayis-pro.com/mechanism-of-delivery.Google Scholar
KemPharm. KemPharm’s LAT Platform. https://www.youtube.com/watch?v=doWMh263hOg.Google Scholar
Incledon, B, Incledon, C, Gomeni, R, et al.Effect of colonic absorption on the pharmacokinetic properties of delayed-release and extended-release methylphenidate: in vivo, in vitro, and modeling evaluations. Clin Pharmacol Drug Dev. 2022;11(8):966–975. doi:10.1002/cpdd.1089Google Scholar
Mattingly, GW, Wilson, J, Ugarte, L, Glaser, P.Individualization of attention-deficit/hyperactivity disorder treatment: pharmacotherapy considerations by age and co-occurring conditions. CNS Spectr. 2021;26(3):202–221. doi:10.1017/s1092852919001822Google Scholar
Wigal, T, Brams, M, Gasior, M, et al.Randomized, double-blind, placebo-controlled, crossover study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder: novel findings using a simulated adult workplace environment design. Behav Brain Funct. 2010;6:34. doi: 10.1186/1744-9081-6-34.Google Scholar
Jasinski, DR, Krishnan, S.Human pharmacology of intravenous lisdexamfetamine dimesylate: abuse liability in adult stimulant abusers. J Psychopharmacol. 2009;23(4):410–418. doi:10.1177/0269881108093841Google Scholar
Jasinski, DR, Krishnan, S.Abuse liability and safety of oral lisdexamfetamine dimesylate in individuals with a history of stimulant abuse. J Psychopharmacol. 2009;23(4):419–427. doi:10.1177/0269881109103113Google Scholar
Shram, MJ, Setnik, B, Webster, L, et al.Oral, intranasal, and intravenous abuse potential of serdexmethylphenidate, a novel prodrug of d-methylphenidate. Curr Med Res Opin. 2022;38(7):1237–1250. doi:10.1080/03007995.2022.2076474Google Scholar
Markowitz, JS, Patrick, KS. The clinical pharmacokinetics of amphetamines utilized in the treatment of attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2017;27(8):678–689. doi:10.1089/cap.2017.0071Google Scholar
Zhu, HJ, Patrick, KS, Yuan, HJ, et al.Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis. Am J Hum Genet. 2008;82(6):1241–1248. doi:10.1016/j.ajhg.2008.04.015Google Scholar
Dinis-Oliveira, RJ. Metabolomics of methylphenidate and ethylphenidate: implications in pharmacological and toxicological effects. Eur J Drug Metab Pharmacokinet. 2017;42(1):11–16. doi:10.1007/s13318-016-0362-1Google Scholar
Trofimiuk, M, Wasilewska, K, Winnicka, K.How to modify drug release in paediatric dosage forms? Novel technologies and modern approaches with regard to children’s population. Int J Mol Sci. 2019;20(13):3200. doi:10.3390/ijms20133200Google Scholar
Cutler, AJ, Childress, AC, Pardo, A, et al.Randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy and safety of amphetamine extended-release tablets in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2022;83(5):22m14438. doi:10.4088/JCP.22m14438Google Scholar
Childress, AC, Kando, JC, King, TR, Pardo, A, Herman, BK. Early-onset efficacy and safety pilot study of amphetamine extended-release oral suspension in the treatment of children with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2019;29(1):2–8. doi:10.1089/cap.2018.0078Google Scholar
Figure 0

Table 1. Overview of drug delivery technologies and the brands that use those technologies to provide extended-release formulations of stimulant medications for the treatment of ADHD. The PK parameters are those that are easily available from the prescribing information (PI) of each product

Figure 1

Figure 1. A summary of the ER/DR technologies available for stimulant medications in ADHD. ADHD, attention-deficit/hyperactivity disorder; CR, controlled release; d-MPH, dexmethylphenidate; DR, delayed release; ER, extended release; GI, gastrointestinal; IR, immediate release; LDX, lisdexamfetamine; MLR, multilayer release; OROS, osmotic-controlled release oral system; PK, pharmacokinetic; SDX, serdexmethylphenidate; SODAS, spheroidal oral drug absorption system.

Figure 2

Figure 2. A summary of clinical considerations for ADHD stimulant treatment, based on the characteristics of the different technologies. ADHD, attention-deficit/hyperactivity disorder; OROS, osmotic-controlled release oral system; SODAS, spheroidal oral drug absorption system.