Population Pharmacokinetic-Pharmacodynamic Modeling of a Novel Methylphenidate Extended-Release Orally Disintegrating Tablet in Pediatric Patients With Attention-Deficit/Hyperactivity Disorder

Teuscher, Nathan S.; Sikes, Carolyn; McMahen, Russ; Engelking, Dorothy

doi:10.1097/jcp.0000000000000944

Cited by 6 publications

(6 citation statements)

References 20 publications

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“…Modeling can also be used with existing long-acting stimulant formulations to inform the dose titration process or make predictions about the relative clinical benefit of formulations that have not been studied in head-to-head trials. Currently, when starting or switching to a new long-acting stimulant, clinicians advise patients to initiate therapy on a low dose and then titrate the dose up until symptom control is achieved without affecting tolerability [141]. However, dose titration can be a time-consuming process that leaves patients at subtherapeutic levels until an optimal dose is determined.…”

Section: Expert Opinionmentioning

confidence: 99%

“…Additionally, when switching from one formulation to another, clinicians are faced with the challenge of determining how to provide comparable coverage quickly without a lapse in response [123]. To date, two separate studies sought to develop the population pharmacokinetic-pharmacodynamic models for MLR-MPH and MPH XR-ODT to simulate pharmacodynamic responses for a range of body weights and doses, with the goal of facilitating the dose titration process by predicting an optimal dose for these formulations based on patient body weight [141,142]. Furthermore, another study sought to develop a pharmacokinetic-pharmacodynamic model for DR/ER-MPH and compare its clinical benefit to four other ER MPH formulations using the previously described model developed by Gomeni and colleagues for formulations with dual release characteristics [143].…”

Section: Expert Opinionmentioning

confidence: 99%

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

Childress

Komolova²,

Sallee³

2019

Expert Opinion on Drug Metabolism & Toxicology

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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...

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Section: Expert Opinionmentioning

confidence: 99%

Section: Expert Opinionmentioning

confidence: 99%

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

Childress

Komolova²,

Sallee³

2019

Expert Opinion on Drug Metabolism & Toxicology

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“…For instance, the relationship between systemic methylphenidate concentrations and efficacy in children and adolescents with Attention-Deficit Hyperactivity Disorder was frequently reported, but might be of questionable relevance. Among 160 children and adolescents across three reasonably reported and executed trials, a higher methylphenidate concentration was associated with improved performance, though different instruments were used across the studies [58][59][60]. Most studies judged of lower quality reported similar findings, with one exception [85]; however, the length of the follow-up period was unclear in this work, thus the relationship might have been underestimated.…”

Section: Considering the Relevance Of A Drug Concentration-effect Relmentioning

confidence: 81%

“…Relationships may concern the mother compound, metabolite, or both. side-effects relationship was found for three (venlafaxine [51], desipramine [56], ziprasidone [57]), and a relationship with both efficacy and side-effects for two (methylphenidate [19,[58][59][60], imipramine [61][62][63]). The indications for use of these drugs included major depression, conduct disorder, bipolar disorder, attention-deficit disorder with or without hyperactivity and Tourette syndrome or chronic tic disorder (Table 3).…”

Section: Quality Assessmentmentioning

confidence: 99%

“…The indications for use of these drugs included major depression, conduct disorder, bipolar disorder, attention-deficit disorder with or without hyperactivity and Tourette syndrome or chronic tic disorder (Table 3). In seven of the studies meeting all quality criteria, therapeutic reference ranges or concentrations for optimal treatment were reported [52][53][54][55][60][61][62]. The 47 studies that did not meet all quality criteria involved 20 psychotropic drugs, for which concentration-effect relationships were reported for 13.…”

Section: Quality Assessmentmentioning

confidence: 99%

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Psychotropic drug concentrations and clinical outcomes in children and adolescents: a systematic review

Kloosterboer

Vierhout

Stojanova

et al. 2020

Expert Opinion on Drug Safety

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Introduction: The use of psychotropic drugs in children and adolescents is widespread but associated with suboptimal treatment effects. Therapeutic drug monitoring (TDM) can improve safety of psychotropic drugs in children and adolescents but is not routinely performed. A major reason is that the relationship between drug concentrations and effects is not well known. Areas covered: This systematic review evaluated studies assessing the relationship between psychotropic drug concentrations and clinical outcomes in children and adolescents, including antipsychotics, psychostimulants, alpha-agonists, antidepressants, and mood-stabilizers. PRISMA guidelines were used and a quality assessment of the retrieved studies was performed. Sixty-seven eligible studies involving 24 psychotropic drugs were identified from 9,298 records. The findings were generally heterogeneous and the majority of all retrieved studies were not of sufficient quality. For 11 psychotropic drugs, a relationship between drug concentrations and side-effects and/or effectiveness was evidenced in reasonably reported and executed studies, but these findings were barely replicated. Expert opinion: In order to better support routine TDM in child-and adolescent psychiatry, future work must improve in aspects of study design, execution and reporting to demonstrate drug concentrationeffect relationships. The quality criteria proposed in this work can guide future TDM research. Systematic review protocol and registration PROSPERO CRD42018084159 ARTICLE HISTORY

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Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD)

Storebø

Storm

Ribeiro

et al. 2023

Cochrane Database of Systematic Reviews

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Population Pharmacokinetic-Pharmacodynamic Modeling of a Novel Methylphenidate Extended-Release Orally Disintegrating Tablet in Pediatric Patients With Attention-Deficit/Hyperactivity Disorder

Abstract: This model may help facilitate the dose-titration process by identifying an effective MPH XR-ODT target dose.

Cited by 6 publications

References 20 publications

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

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

Psychotropic drug concentrations and clinical outcomes in children and adolescents: a systematic review

Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD)

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