Evaluating serdexmethylphenidate and dexmethylphenidate capsules as a once-daily treatment option for ADHD.

INTRODUCTION: Attention deficit/hyperactivity disorder (ADHD) is a common behavioral disorder which is best treated through a combination of medication and behavioral therapy, with stimulant medications serving as a first-line treatment approach. Serdexmethylphenidate (SDX), a prodrug of dexmethylphenidate (d-MPH), a commonly utilized stimulant medication, has recently received approval and is marketed in the U.S.A. AREAS COVERED: This review summarizes peer-reviewed literature on SDX published between 2021-2023 and a review of data available from ClinicalTrials.gov. EXPERT OPINION: SDX represents a new option for treatment for ADHD. It is unique in its prodrug design and achieves a relatively extended duration of action in comparison to other stimulant formulations. Although the research is relatively limited thus far, early data suggests it to be a safe medication to consider with side effects being similar to other stimulant medications. Its prodrug design is useful in potentially serving as a deterrent to intentional parenteral abuse and its ability to be opened and sprinkled makes it an option for those individuals with ADHD who might be unable to swallow pills.

Safety and Tolerability of Serdexmethylphenidate/Dexmethylphenidate Capsules in Children with Attention-Deficit/Hyperactivity Disorder: A 12-Month, Open-Label Safety Study.

Objective: Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) is approved for the treatment of patients aged ≥6 years with attention-deficit/hyperactivity disorder (ADHD). A pivotal double-blind (DB) study of children aged 6-12 years with ADHD demonstrated efficacy for ADHD with good tolerability. In this study, we assessed the safety and tolerability of daily oral SDX/d-MPH for up to 1 year in children with ADHD. Methods: This was a dose-optimized, open-label safety study with SDX/d-MPH in children aged 6-12 years with ADHD that included subjects who successfully completed the DB study (rollover) and new subjects. The study consisted of a 30-day screening phase, a dose optimization phase for new subjects only, a 360-day treatment phase, and follow-up. Adverse events (AEs) were assessed from the first day of SDX/d-MPH administration to the end of the study. During the treatment phase, ADHD Rating Scale-5 (ADHD-RS-5) and Clinical Global Impressions-Severity (CGI-S) scale assessments were used to evaluate ADHD severity. Results: Of the 282 subjects enrolled (70 rollover; 212 new), 28 discontinued treatment in the dose optimization phase and 254 entered the treatment phase. By study completion, 127 had discontinued and 155 had completed the study. The treatment-phase safety population included all enrolled subjects who received ≥1 dose of study drug and had ≥1 postdose safety assessment. Of 238 subjects assessed in the treatment-phase safety population, 143 (60.1%) had ≥1 treatment-emergent adverse events (TEAEs), and 36 (15.1%), 95 (39.9%), and 12 (5.0%) had mild, moderate, or severe TEAEs, respectively. The most common TEAEs were decreased appetite (18.5%), upper respiratory tract infection (9.7%), nasopharyngitis (8.0%), decreased weight (7.6%), and irritability (6.7%). There were no clinically meaningful trends in electrocardiograms, cardiac events, or blood pressure events, and none led to discontinuation. Two subjects had eight serious AEs that were unrelated to treatment. There were overall reductions in ADHD symptoms and severity as assessed by ADHD-RS-5 and CGI-S during the treatment phase. Conclusions: In this 1-year study, SDX/d-MPH was found to be safe and well tolerated and comparable with other methylphenidate products, with no unexpected safety findings. SDX/d-MPH also showed sustained efficacy during the 1-year treatment period. ClinicalTrials.gov identifier: NCT03460652.

Short-Term Vision-Related Ocular Side Effects of Treatment with Dexmethylphenidate for Attention-Deficit/Hyperactivity Disorder.

Objective: To evaluate the short-term effect of dexmethylphenidate (D-MPH) on visual acuity (VA), pupil size, anterior chamber depth, and accommodation-convergence reflex in children treated with D-MPH for attention-deficit/hyperactivity disorder (ADHD). Method: Prospective cohort study including 15 patients aged 8-16 (11.58 ± 2.39) treated with D-MPH for ADHD. Patients were questioned for subjective complaints such as blurred vision and photosensitivity. An ophthalmic evaluation was performed twice; before and 1.5 hours after D-MPH administration. The examination included evaluation of best corrected visual acuity at distance and near, accommodation range, convergence range, 3D vision test (stereopsis), and anterior segment optical coherence tomography. Results: A significant association between change in pupil diameter and D-MPH treatment dose was demonstrated (p = 0.01). In addition, a positive correlation between complaints about blurred vision and pupil's size change was found (p < 0.05). There were no significant changes in VA, convergence range, stereopsis, accommodation range, or anterior chamber measures. Conclusions: Our findings provide support for the effect of stimulants on pupil diameter in a dose-dependent manner. No clinically significant differences in visual functions were found 1.5 hours after consumption of D-MPH. Institutional review board clinical trial refference no. 0122-17-TLV.

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

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.

Acute and Long-Term Cardiovascular Effects of Stimulant, Guanfacine, and Combination Therapy for Attention-Deficit/Hyperactivity Disorder.

OBJECTIVES: This study examines cardiovascular (CV) effects of guanfacine immediate-release (GUAN-IR), dexmethylphenidate extended-release (DMPH), and their combination (COMB) during acute and long-term treatment of youth with attention-deficit/hyperactivity disorder. METHODS: Two hundred seven participants aged 7-14 years enrolled in an 8-week double-blind randomized trial of GUAN-IR (1-3 milligrams (mg)/day), DMPH (5-20 mg/day), or COMB with fixed-flexible dosing and titrated to optimal behavioral response. Heart rate, systolic blood pressure (BP), diastolic BP, and electrocardiograms were assessed at baseline, end of blinded optimization, and over a 1-year open-label maintenance phase. RESULTS: During acute titration, GUAN-IR decreased heart rate, systolic BP, and diastolic BP; DMPH increased heart rate, systolic BP, diastolic BP, and corrected QT (QTc) interval; COMB increased diastolic BP, but had no effects on heart rate, systolic BP, or QTc. During maintenance, GUAN-IR-associated decreases in heart rate and DMPH-associated increases in systolic BP returned to baseline values. Other variables across the three groups remained unchanged from the end of blinded titration. There were no discontinuations due to CV adverse events. CONCLUSION: GUAN-IR, DMPH, and COMB were well tolerated and safe. Expected changes in CV parameters during acute titration were seen in GUAN-IR and DMPH groups, with COMB values falling intermediately between the two other treatment groups. No serious CV events occurred in any participant. GUAN-IR- and DMPH-associated CV changes generally returned to baseline with sustained therapy. These data suggest that COMB treatment might attenuate long-term CV effects of GUAN-IR and stimulant monotherapy, possibly reducing risk of the small but statistically significant changes associated with either single treatment. Clinicaltrials.gov Identifier: NCT00429273.

Methylphenidate and dexmethylphenidate formulations for children with attention-deficit/hyperactivity disorder.

PURPOSE: Current literature on the safety and efficacy of various intermediate- and long-acting preparations of methylphenidate and dexmethylphenidate for pediatric attention-deficit/hyperactivity disorder (ADHD) is reviewed. SUMMARY: The efficacy of methylphenidate in controlling ADHD symptoms is firmly established. Given the drug's relatively short half-life in pediatric patients (about 2.5 hours), a number of intermediate- and long-acting products have been developed; these extended-release methylphenidate products provide the same efficacy as immediate-release (IR) formulations, with the convenience of less frequent dosing. Intermediate-acting methylphenidate preparations have effects lasting as long as 8 hours, but peak concentrations are not attained for up to 5 hours, and many patients may require twice-daily dosing. Long-acting methylphenidate products developed to address these challenges include a controlled-release tablet and bimodal-delivery capsules containing mixtures of IR and extended-release beads (durations of effect, 8-12 hours). Options for patients with difficulty swallowing tablets or capsules include a once-daily transdermal delivery system and a once-daily liquid formulation. Dexmethylphenidate (the more pharmacologically active d-isomer of racemic methylphenidate) can provide efficacy comparable to that of IR methylphenidate at half the dose; an extended-release form of dexmethylphenidate can provide less fluctuation in peak and trough concentrations than the IR form. Methylphenidate and dexmethylphenidate products in capsule form can be opened and sprinkled on applesauce. CONCLUSION: The various formulations of IR and intermediate- and extended-release methylphenidate and dexmethylphenidate can be useful options in satisfying patients' individual needs in the management of ADHD. All are equally efficacious in controlling ADHD symptoms.

Extended-release dexmethylphenidate 30 mg/d versus 20 mg/d: duration of attention, behavior, and performance benefits in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: This study aimed to compare the effects of dexmethylphenidate (D-MPH) extended-release (ER) 30 mg and D-MPH-ER 20 mg on attention, behavior, and performance in children with attention-deficit/hyperactivity disorder. METHODS: In a randomized, double-blind, 3-period-by-3-treatment, crossover study, children aged 6 to 12 years with attention-deficit/hyperactivity disorder stabilized on methylphenidate (40-60 mg/d) or D-MPH (20-30 mg/d) received D-MPH-ER 20 mg/d, 30 mg/d, and placebo for 7 days each (final dose of each treatment period administered in a laboratory classroom). Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Combined (Attention and Deportment) rating scale and Permanent Product Measure of Performance (PERMP) math test assessments were conducted at baseline and 3, 6, 9, 10, 11, and 12 hours postdose. RESULTS: A total of 165 children (94 boys; mean age, 9.6 years) were randomized (162 included in intent-to-treat analyses). Significant improvements were noted for D-MPH-ER 30 mg over D-MPH-ER 20 mg at various late time points on the SKAMP scales (Combined scores at 9, 10, 11, and 12 hours postdose; Attention scores at 10, 11, and 12 hours postdose; deportment scores at 9 and 12 hours postdose). The PERMP math test-attempted and -correct scores (change from predose) were significantly higher with D-MPH-ER 30 mg than with D-MPH-ER 20 mg at 10, 11, and 12 hours postdose. Both D-MPH-ER doses were superior to placebo at all time points. CONCLUSIONS: D-MPH-ER 30 mg was superior to D-MPH-ER 20 mg at later time points in the day, suggesting that higher doses of D-MPH-ER may be more effective later in the day.