-
The Primary Care Companion For CNS... 2011To review the efficacy, safety, and abuse liability of approved treatments in adults with attention-deficit/hyperactivity disorder (ADHD), with a focus on once-daily...
OBJECTIVE
To review the efficacy, safety, and abuse liability of approved treatments in adults with attention-deficit/hyperactivity disorder (ADHD), with a focus on once-daily medications.
DATA SOURCES
PubMed was searched for relevant studies/reviews in English from 2002 to 2011 on adult ADHD treatments.
STUDY SELECTION
Keywords used in the search were ADHD, adults, and treatment. Limits included only clinical trials, meta-analyses, randomized controlled trials, and reviews including adults (aged ≥ 19 years).
DATA EXTRACTION
Selection criteria returned 471 publications. Retrieved studies were excluded if they primarily focused on children, treatments not indicated for ADHD, or ADHD and comorbid conditions.
DATA SYNTHESIS
An epidemiologic survey revealed that 10.9% of adults identified with ADHD had received treatment during the prior 12 months. Treatments for ADHD in adults include pharmacologic and nonpharmacologic options. US Food and Drug Administration-approved long-acting stimulants and a nonstimulant with proven efficacy and safety profiles have been developed and include osmotic-release oral system methylphenidate hydrochloride (OROS-methylphenidate), extended-release dexmethylphenidate hydrochloride, mixed amphetamine salts extended release (MAS-XR), the nonstimulant atomoxetine hydrochloride, and the prodrug lisdexamfetamine dimesylate. Long-acting stimulants differ in formulation characteristics used to achieve extended release, with OROS-methylphenidate employing an osmotic-release technology, extended-release dexmethylphenidate hydrochloride and MAS-XR using pH-dependent beads, and lisdexamfetamine dimesylate using prodrug technology. These features variably affect pharmacokinetic characteristics, duration of action, and abuse liability. While all long-acting medications have varied pharmacokinetic features, mechanism of action, and duration of effect, all are generally efficacious and safety profiles are similar.
CONCLUSION
Approved long-acting treatments in adults with ADHD were effective in improving symptoms and were generally well tolerated.
PubMed: 22454805
DOI: 10.4088/PCC.11r01168 -
Frontiers in Psychiatry 2024To evaluate treatment responder rate using the Attention-Deficit/Hyperactivity Disorder Rating Scale-5 (ADHD-RS-5) score based on optimized dose level of...
OBJECTIVE
To evaluate treatment responder rate using the Attention-Deficit/Hyperactivity Disorder Rating Scale-5 (ADHD-RS-5) score based on optimized dose level of serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) and changes in ADHD severity in children (aged 6-12 years) with ADHD.
METHODS
During a 21-day dose-optimization phase, 155 patients initiated treatment with 39.2/7.8 mg SDX/d-MPH in the first week and then were titrated to an optimum dose; 5 patients were downtitrated to 26.1/5.2 mg, 76 were uptitrated to 52.3/10.4 mg, and 69 remained at 39.2/7.8 mg during the following 2 weeks. Responder threshold values were 30% and 50% based on the percent change from baseline (day 0) to days 7, 14, and 21 in the ADHD-RS-5 score. The Conners 3rd Edition-Parent score was used to assess weekly changes in ADHD severity during the dose-optimization and treatment phases.
RESULTS
Of the 5 subjects whose dose was optimized at 26.1/5.2 mg, ≥80% across all days had ≥50% responder rate. Of the 69 subjects whose dose was optimized at 39.2/7.8 mg, 81.2% had ≥50% responder rate by day 21. Of the 76 subjects whose dose was optimized to 52.3/10.4 mg, 72.4% had ≥50% responder rate by day 21. Changes in ADHD severity, based on mean Conners 3rd Edition-Parent scores, improved from baseline at each visit during dose optimization for each subscale. At the dose-optimization phase, Conners 3rd Edition-Parent scores improved from baseline for SDX/d-MPH in all subscales.
CONCLUSION
A high percentage of subjects were responders upon reaching their final optimized dose. SDX/d-MPH demonstrated significant reductions in ADHD severity in children based on the Conners 3rd Edition-Parent scores. Determining the optimal dosage of SDX/d-MPH and its effect on ADHD severity could enable the development of a more clinically relevant treatment regimen in children with ADHD.
PubMed: 38566957
DOI: 10.3389/fpsyt.2024.1310483 -
Drugs in R&D Mar 2013α2-Adrenoceptor agonists are used adjunctively to psychostimulants in treating attention-deficit/hyperactivity disorder (ADHD) when psychostimulants alone do not... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
α2-Adrenoceptor agonists are used adjunctively to psychostimulants in treating attention-deficit/hyperactivity disorder (ADHD) when psychostimulants alone do not sufficiently reduce symptoms. However, data on the pharmacokinetic profiles and safety of combination treatments in ADHD are needed.
OBJECTIVE
The primary objective of this study was to evaluate the pharmacokinetic profiles of guanfacine extended release (GXR) and methylphenidate hydrochloride (MPH) extended release, alone and in combination.
STUDY DESIGN
This was an open-label, randomized, three-period crossover, drug-drug interaction study.
SETTING
The study was conducted at a single clinical research center.
PARTICIPANTS
Thirty-eight healthy adults were randomized in this study.
INTERVENTIONS
Subjects were administered single oral doses of GXR (Intuniv(®); Shire Development LLC, Wayne, PA, USA) 4 mg, MPH (Concerta(®); McNeil Pediatrics, Titusville, NJ, USA) 36 mg, or GXR and MPH combined.
MAIN OUTCOME MEASURES
Guanfacine, dexmethylphenidate (d-MPH), and l-methylphenidate (l-MPH) levels were measured with blood samples collected predose and up to 72 h postdose. Safety evaluations included treatment-emergent adverse events (TEAEs), vital signs, and electrocardiograms (ECGs).
RESULTS
Thirty-five subjects completed the study. Analyses of the 90 % confidence intervals (CIs) for the geometric mean ratios of the maximum plasma concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUC∞) values for guanfacine and d-MPH following administration of GXR or MPH alone or combined met strict bioequivalence criteria (90 % CIs within the interval of 0.80-1.25). Overall, combining GXR and MPH did not alter the pharmacokinetic parameters of either medication. Sixteen subjects (42.1 %) had at least one TEAE. The most commonly reported TEAEs included headache and dizziness following GXR, MPH, and GXR and MPH combined. Two subjects had clinically significant abnormalities in ECG results following coadministration: both events were mild and resolved the same day.
CONCLUSIONS
In this short-term, open-label study of healthy adults, coadministration of GXR and MPH did not result in significant pharmacokinetic drug-drug interactions. No unique TEAEs were observed with coadministration of GXR and MPH compared with either treatment alone.
Topics: Adrenergic alpha-2 Receptor Agonists; Adult; Central Nervous System Stimulants; Cross-Over Studies; Delayed-Action Preparations; Drug Interactions; Drug Therapy, Combination; Female; Guanfacine; Humans; Male; Methylphenidate; Young Adult
PubMed: 23519656
DOI: 10.1007/s40268-013-0009-5 -
Journal of Child and Adolescent... Dec 2016This study examines cardiovascular (CV) effects of guanfacine immediate-release (GUAN-IR), dexmethylphenidate extended-release (DMPH), and their combination (COMB)... (Comparative Study)
Comparative Study Randomized Controlled Trial
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.
Topics: Adolescent; Adrenergic alpha-2 Receptor Agonists; Attention Deficit Disorder with Hyperactivity; Blood Pressure; Central Nervous System Stimulants; Child; Delayed-Action Preparations; Dexmethylphenidate Hydrochloride; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Electrocardiography; Female; Guanfacine; Heart Rate; Humans; Male; Time Factors
PubMed: 27483130
DOI: 10.1089/cap.2015.0264 -
Journal of Clinical Psychopharmacology Aug 2015The potentiation of positive subjective responses to immediate-release dexmethylphenidate (d-MPH) or dl-methylphenidate (dl-MPH) by ethanol was investigated over the... (Comparative Study)
Comparative Study Randomized Controlled Trial
The potentiation of positive subjective responses to immediate-release dexmethylphenidate (d-MPH) or dl-methylphenidate (dl-MPH) by ethanol was investigated over the time course of maximal drug exposure after a single dose. In a 4-way, randomized, crossover study design, 12 men and 12 women normal volunteers received d-MPH (0.15 mg/kg) or dl-MPH (0.3 mg/kg) with or without ethanol (0.6 g/kg). Serial visual analog scales were used as surrogates for drug abuse liability ("high," "good," "like," "stimulated," and "any drug effect"). Combining pure d-MPH with ethanol significantly (P < 0.005) increased the area under the effect curves (AUC(0-5.25h)) of all 5 subscales. The dl-MPH-ethanol combination significantly (P < 0.05) increased these AUCs with the exception of like (P = 0.08). Effects of the pure d-MPH-ethanol combination exhibited delayed potentiation relative to dl-MPH-ethanol. A pharmacokinetic interaction between the l-isomer of dl-MPH and ethanol has previously been shown to increase early exposure to d-MPH. Administration of the pure isomer d-MPH precludes this absorption phase pharmacokinetic interaction with ethanol. This notwithstanding, the pure d-MPH-ethanol combination resulted in comparable, if not greater, cumulative stimulant potentiation than the dl-MPH-ethanol combination. These findings provide evidence of a pharmacodynamic component to d-MPH-ethanol synergistic interactions and carry implications for the rational drug individualization in the treatment of attention-deficit/hyperactivity disorder.
Topics: Affect; Central Nervous System Stimulants; Cross-Over Studies; Dexmethylphenidate Hydrochloride; Drug Synergism; Ethanol; Female; Humans; Male; Methylphenidate
PubMed: 26075488
DOI: 10.1097/JCP.0000000000000348 -
Neuropsychiatric Disease and Treatment Dec 2006Attention-deficit/hyperactivity disorder (ADHD) affects a large number of children. For decades, the stimulants have been the mainstay of pharmacological treatment for...
Attention-deficit/hyperactivity disorder (ADHD) affects a large number of children. For decades, the stimulants have been the mainstay of pharmacological treatment for ADHD. Dexmethylphenidate (d-MPH), the d-isomer of the traditional racemic mixtures of d,l-threo-(R,R)-MPH, was recently introduced as another potential option in the stimulant class of medications. This paper reviews and summarizes the available research literature on d-MPH regarding pharmacodynamic, pharmacokinetic, chemical structure, receptor binding, toxicology, and clinical perspectives. d-MPH potentially may offer some advantages in the realms of absorption and duration of action compared with its racemic counterpart. The differences in pharmacokinetics and clinical implications of the immediate-release and extended-release forms of d-MPH are also compared and contrasted.
PubMed: 19412495
DOI: 10.2147/nedt.2006.2.4.467 -
Journal of Child and Adolescent... Jun 2014This study seeks to determine if variation in the dopamine transporter gene (SLC6A3/DAT1) moderates the dose-response effects of long-acting dexmethylphenidate (D-MPH)... (Comparative Study)
Comparative Study Randomized Controlled Trial
OBJECTIVES
This study seeks to determine if variation in the dopamine transporter gene (SLC6A3/DAT1) moderates the dose-response effects of long-acting dexmethylphenidate (D-MPH) and mixed amphetamine salts (MAS) in children with attention-deficit/hyperactivity disorder (ADHD).
METHODS
Fifty-six children and adolescents (mean age=11.7±2.2) participated in a double-blind, two period crossover, dose-response study with a randomized placebo week in each 4 week drug period. Each period consisted of sequential week-long exposures to three dose levels (10, 20, 25-30 mg, depending upon weight) of D-MPH or MAS.
RESULTS
Doses of 10-20 mg of either D-MPH or MAS had little to no effect on hyperactivity-impulsivity and total ADHD symptom scores in subjects with the 9/9 genotype; this was in contrast to the dose-response curves of subjects with either the 10/10 or 10/9 genotype.
CONCLUSIONS
ADHD youth with the 9/9 genotype may require higher stimulant doses to achieve adequate symptom control.
Topics: Adolescent; Amphetamines; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Cross-Over Studies; Dexmethylphenidate Hydrochloride; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; Double-Blind Method; Female; Genotype; Humans; Male
PubMed: 24813374
DOI: 10.1089/cap.2013.0102 -
Journal of Medical Economics Oct 2013To compare therapy augmentation and deviation rates from the recommended once-daily dosing regimen in Attention Deficit Hyperactivity Disorder (ADHD) patients initiated...
Comparison of therapy augmentation and deviation rates from the recommended once-daily dosing regimen between LDX and commonly prescribed long-acting stimulants for the treatment of ADHD in youth and adults.
OBJECTIVE
To compare therapy augmentation and deviation rates from the recommended once-daily dosing regimen in Attention Deficit Hyperactivity Disorder (ADHD) patients initiated on lisdexamfetamine (LDX) vs other once-daily Food and Drug Administration (FDA) approved stimulants.
METHODS
ADHD patients initiated on a long-acting ADHD stimulant medication (index medication) in/after 2007 were selected from a large U.S. administrative claims database. Patients were required to be persistent for ≥90 days and continuously enrolled in their healthcare plan for ≥12 months following treatment initiation date. Based on age and previous treatment status, patients were classified into treatment-naïve children and adolescents (6-17 years old), previously treated children and adolescents, treatment-naïve adults (≥18 years old), and previously treated adults. Furthermore, patients were classified into four mutually exclusive treatment groups, based on index medication: lisdexamfetamine (LDX), osmotic release methylphenidate hydrochloride long-acting (OROS MPH), other methylphenidate/dexmethylphenidate long-acting (MPH LA), and amphetamine/dextroamphetamine long-acting (AMPH LA). The average daily consumption was measured as the quantity of index medication supplied in the 12-month study period divided by the total number of days of supply. Therapy augmentation was defined as the use of another ADHD medication concomitantly with the index medication for ≥28 consecutive days. Therapy augmentation and deviation rates from the recommended once-daily dosing regimen were compared between treatment groups using multivariate logistic regression models.
RESULTS
Compared to the other treatment groups, LDX patients were less likely to augment with another ADHD medication (range odds ratios [OR]; 1.28-3.30) and to deviate from the recommended once-daily dosing regimen (range OR; 1.73-4.55), except for previously treated adult patients, where therapy augmentation differences were not statistically significant when compared to OROS MPH and MPH LA patients.
LIMITATION
This study did not control for ADHD severity.
CONCLUSION
Overall, compared to LDX-treated patients, patients initiated on other ADHD medications were equally or more likely to have a therapy augmentation and more likely to deviate from the recommended once-daily dosing regimen.
Topics: Adolescent; Adult; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Delayed-Action Preparations; Dextroamphetamine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Insurance Claim Review; Lisdexamfetamine Dimesylate; Male; Retrospective Studies; United States; Young Adult
PubMed: 23937642
DOI: 10.3111/13696998.2013.832258 -
The American Journal of Managed Care Mar 2014A "chiral switch" occurs in the pharmaceutical market when a drug made up of 2 enantiomer forms is replaced with a purified single-enantiomer version, often in the...
OBJECTIVES
A "chiral switch" occurs in the pharmaceutical market when a drug made up of 2 enantiomer forms is replaced with a purified single-enantiomer version, often in the context of a patent expiration. We studied the prevalence of chiral switching in the United States over the past decade, including trends in use of, and expenditures on, these products in Medicaid.
STUDY DESIGN
Retrospective analysis.
METHODS
We used US Adopted Names prefixes (lev/levo/ar/es/dex/dextro) to identify all single-enantiomer drugs approved from 2001 to 2011. From publicly available US Food and Drug Administration (FDA) approval documents, we extracted the characteristics of the pivotal premarket trials for the single enantiomers. Specifically, we evaluated whether the single enantiomer was directly compared with the precursor racemic drug and whether there was evidence of superior efficacy. We used quarterly drug expenditure data from each state Medicaid program to chart trends in use of, and spending on, the single-enantiomer products and their racemic precursors during the study period.
RESULTS
From 2001 to 2011, the FDA approved 9 single-enantiomer products: dexlansoprazole, levoleucovorin, levocetirizine, armodafinil, arformoterol, eszopiclone, escitalopram, dexmethylphenidate, and esomeprazole. Of those 9 drugs, 3 had at least 1 pre-approval randomized trial that included the racemic precursor as a direct comparator, but there was no evidence of superiority of the single enantiomer over the racemic at comparable doses. Between 2001 and 2011, US Medicaid programs spent approximately $6.3 billion on these 9 single-enantiomer drugs.
CONCLUSIONS
Recently approved single-enantiomer drugs showed no evidence of superior efficacy over the older racemic precursors in the pivotal trials leading to their approval, and in a majority of cases, they were not directly compared.
Topics: Antidotes; Azabicyclo Compounds; Benzhydryl Compounds; Bronchodilator Agents; Central Nervous System Stimulants; Cetirizine; Dexlansoprazole; Dexmethylphenidate Hydrochloride; Drug Approval; Drug Prescriptions; Drugs, Generic; Esomeprazole; Eszopiclone; Ethanolamines; Formoterol Fumarate; Histamine H1 Antagonists, Non-Sedating; Humans; Hypnotics and Sedatives; Levoleucovorin; Medicaid; Modafinil; Patents as Topic; Piperazines; Proton Pump Inhibitors; Retrospective Studies; Stereoisomerism; United States; United States Food and Drug Administration; Wakefulness-Promoting Agents
PubMed: 24773330
DOI: No ID Found -
Drug Metabolism and Disposition: the... Jan 2013Enantioselective hydrolysis of oral racemic methylphenidate (dl-MPH) by carboxylesterase 1 (CES1) limits the absolute bioavailability of the pharmacologically active... (Comparative Study)
Comparative Study
Enantioselective hydrolysis of oral racemic methylphenidate (dl-MPH) by carboxylesterase 1 (CES1) limits the absolute bioavailability of the pharmacologically active d-MPH isomer to approximately 30% and that of the inactive l-MPH to only 1-2%. Coadministration of dl-MPH with ethanol results in elevated d-MPH plasma concentrations accompanied by CES1-mediated enantioselective transesterification of l-MPH to l-ethylphenidate (EPH). The present study tested the hypothesis that administration of the pure isomer dexmethylphenidate (d-MPH) will overcome the influence of ethanol on d-MPH absorption by eliminating competitive CES1-mediated presystemic metabolism of l-MPH to l-EPH. Twenty-four healthy volunteers received dl-MPH (0.3 mg/kg) or d-MPH (0.15 mg/kg), with or without ethanol (0.6 g/kg). During the absorption phase of dl-MPH, concomitant ethanol significantly elevated d-MPH plasma concentrations (44-99%; P < 0.005). Furthermore, immediately following the ethanol drink the subjective effects of "high," "good," "like," "stimulated," and overall "effect" were significantly potentiated (P ≤ 0.01). Plasma l-EPH concentrations exceeded those of l-MPH. Ethanol combined with pure d-MPH did not elevate plasma d-MPH concentrations during the absorption phase, and the ethanol-induced potentiation of subjective effects was delayed relative to dl-MPH-ethanol. These findings are consistent with l-MPH competitively inhibiting presystemic CES1 metabolism of d-MPH. Ethanol increased the d-MPH area under the curve (AUC)(0-inf) by 21% following dl-MPH (P < 0.001) and 14% for d-MPH (P = 0.001). In men receiving d-MPH-ethanol, the d-MPH absorption partial AUC(0.5-2 hours) was 2.1 times greater and the time to maximum concentration (T(max)) occurred 1.1 hours earlier than in women, consistent with an increased rate of d-MPH absorption reducing hepatic extraction. More rapid absorption of d-MPH carries implications for increased abuse liability.
Topics: Adult; Area Under Curve; Carboxylesterase; Dexmethylphenidate Hydrochloride; Esterification; Ethanol; Female; Hemodynamics; Humans; Male; Methylphenidate; Stereoisomerism; Young Adult
PubMed: 23104969
DOI: 10.1124/dmd.112.048595