Methylphenidate for Treating ADHD: A Naturalistic Clinical Study of Methylphenidate Blood Concentrations in Children and Adults With Optimized Dosage

Chermá, Maria D.; Josefsson, Martin; Rydberg, Irene; Woxler, Per; Trygg, Tomas; Hollertz, Olle; Gustafsson, Per A.

doi:10.1007/s13318-016-0346-1

Cited by 11 publications

(12 citation statements)

References 36 publications

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“…In our study, we found a slightly lower correlation between methylphenidate concentrations in oral fluid and plasma (r = 0.61). Our data are in line with studies in patients showing three-to-four-fold higher methylphenidate concentrations in oral fluid than in blood, while the opposite was true for ritalinic acid [33,34]. The present study indicates that oral fluid may serve as an alternative non-invasive matrix to assess medication adherence, as the oral fluid concentrations of dl-threo-methylphenidate in our study roughly reflected d-threo-methylphenidate concentrations in plasma.…”

Section: Discussionsupporting

confidence: 91%

Pharmacokinetics of methylphenidate and ritalinic acid in plasma correlations with exhaled breath and oral fluid in healthy volunteers

Arvidsson

Beck

Ackehed

et al. 2019

Eur J Clin Pharmacol

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Purpose The primary aim of this study was to explore the potential of alternative sampling matrices for methylphenidate by assessing the correlations between dl-threo-methylphenidate and dl-threo-ritalinic acid concentrations in exhaled breath and oral fluid with those in plasma, in repeated samples collected after a single oral dose of methylphenidate. The secondary aim was to study the enantioselective pharmacokinetics of methylphenidate in plasma, with a focus on interindividual variability in the metabolism of methylphenidate to ritalinic acid. Methods Twelve healthy volunteers received a single oral dose of dl-threo-methylphenidate (Ritalin® capsules, 20 mg). Venous blood samples were collected for 24 h, and plasma analyzed for threo-enantiomers of methylphenidate and ritalinic acid with LC-MS/MS. Repeated sampling of exhaled breath, using a particle filter device, and of non-stimulated oral fluid, using a felt pad device, was also performed. Exhaled breath and oral fluid were analyzed with a non-enantioselective LC-MS/MS method for dlthreo-methylphenidate and dl-threo-ritalinic acid. Results In all subjects, d-threo-methylphenidate was detectable in plasma for at least 15 h after the dose with a biphasic profile. lthreo-Methylphenidate was measurable in only five subjects and in most cases in low concentrations. However, one female subject displayed a biphasic concentration-time profile for l-threo-methylphenidate. This subject also had the highest d-threo-methylphenidate AUC (191 ng*h/mL versus 32-119 ng*h/mL in the other subjects). d-threo-Ritalinic acid concentrations were on average 25-fold higher (range 6-126) than the corresponding d-threo-methylphenidate concentrations. Single-time point plasma concentration ratios between d-threo-ritalinic acid and d-threo-methylphenidate 1.5-12 h after dose correlated highly (r = 0.88-0.98) with the d-threo-ritalinic acid AUC/d-threo-methylphenidate AUC ratio. In eleven subjects, dl-threo-methylphenidate in oral fluid mirrored the biphasic profile of methylphenidate (sum of dand l-threo-enantiomers) in plasma, but the concentrations in oral fluid were on average 1.8 times higher than in plasma. dl-threo-Methylphenidate was detected in exhaled breath in all subjects, but there was no consistent concentration-time pattern. Conclusions In some subjects, the pharmacologically less active l-threo-enantiomer may contribute to the total plasma methylphenidate concentrations. Monitoring methylphenidate concentrations without enantiomeric determination carries the risk of missing such subjects, which might affect how the plasma concentrations of methylphenidate are interpreted and used for clinical decision making. The use of exhaled breath and oral fluid to assess medication adherence to MPH in patients with ADHD warrants further studies.

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Section: Discussionsupporting

confidence: 91%

Pharmacokinetics of methylphenidate and ritalinic acid in plasma correlations with exhaled breath and oral fluid in healthy volunteers

Arvidsson

Beck

Ackehed

et al. 2019

Eur J Clin Pharmacol

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“…Reportedly, a dose–response relationship was observed with osmotic-controlled release oral delivery system methylphenidate (OROS-MPH) in children with combined-type ADHD, whereas such a relationship was not noted in children with ADHD of a predominantly inattentive subtype 37. Furthermore, the association between dose optimization and weight remains inconclusive; some studies have reported no relationship between the final optimal dose and body weight, while others have indicated weight as a reliable clinical parameter for dose optimization 38–40. Douglas et al reported a linear dose–response relationship between dose (0.15, 0.30, and 0.60 mg/kg) and improvements in performance 41.…”

Section: Dose Optimization In Clinical Practicementioning

confidence: 99%

“…The need for multiple doses of MPH to achieve effective symptom control further highlights the importance of an individualized or tailored treatment approach for ADHD. Recently, Chermá et al40 reported a large variation in the optimal treatment dose of 59 patients with ADHD; however, blood sample analysis revealed that the median daily dose per body weight was similar (~1.0 mg/kg). As per the available literature, genetic differences may lead to significant variability in pharmacokinetic profiles across the day at an individual level, which may result in the large variation observed 58…”

Section: Dose Optimization In Clinical Trials and Naturalistic Studiesmentioning

confidence: 99%

Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity

Huß¹,

Duhan²,

Gandhi³

et al. 2017

NDT

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Attention-deficit/hyperactivity disorder (ADHD) is a chronic psychiatric disorder characterized by hyperactivity and/or inattention and is often associated with a substantial impact on psychosocial functioning. Methylphenidate (MPH), a central nervous system stimulant, is commonly used for pharmacological treatment of adults and children with ADHD. Current practice guidelines recommend optimizing MPH dosage to individual patient needs; however, the clinical benefits of individual dose optimization compared with fixed-dose regimens remain unclear. Here we review the available literature on MPH dose optimization from clinical trials and real-world experience on ADHD management. In addition, we report safety and efficacy data from the largest MPH modified-release long-acting Phase III clinical trial conducted to examine benefits of dose optimization in adults with ADHD. Overall, MPH is an effective ADHD treatment with a good safety profile; data suggest that dose optimization may enhance the safety and efficacy of treatment. Further research is required to establish the extent to which short-term clinical benefits of MPH dose optimization translate into improved long-term outcomes for patients with ADHD.

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“…On the other hand, this limitation would not differ between the studied groups. More importantly, we did not have information on further phenotypic characteristics, and here bodyweight is the most important factor as it affect doses of methylphenidate prescribed [ 35 ]. Further, we did not study other simultaneous pharmacological treatments, which may affect doses and type of ADHD medications prescribed.…”

Section: Discussionmentioning

confidence: 99%

Medications for attention-deficit/hyperactivity disorder in individuals with or without coexisting autism spectrum disorder: analysis of data from the Swedish prescribed drug register

Johansson

Sandin

Chang

et al. 2020

J Neurodevelop Disord

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Background Clinical studies found that medication for attention-deficit/hyperactivity disorder (ADHD) is effective in coexisting autism spectrum disorder (ASD), but current research is based on small clinical studies mainly performed on children or adolescents. We here use register data to examine if individuals with ADHD and coexisting ASD present differences in the prescribing patterns of ADHD medication when compared to individuals with pure ADHD. Methods Data with information on filled prescriptions and diagnoses was retrieved from the Swedish Prescribed Drug Register and the National Patient Register. We identified 34,374 individuals with pure ADHD and 5012 individuals with ADHD and coexisting ASD, aged between 3 and 80 years. The first treatment episode with ADHD medications (≥ 2 filled prescriptions within 90 days) and daily doses of methylphenidate during a 3-year period was measured. Odds ratios (ORs) were calculated for the likelihood of being prescribed ADHD medication in individuals with and without ASD and Wilcoxon rank-sum test was used to compare group differences in dose per day. Results Individuals with ADHD and coexisting ASD were less likely to start continuous treatment with ADHD medication (ADHD 80.5%; ADHD with ASD 76.2%; OR, 0.80; 95% confidence interval, 0.75-0.86), were less likely to be prescribed methylphenidate, and were more commonly prescribed second line treatments such as dexamphetamine, amphetamine, or modafinil. No group difference was observed for atomoxetine. In adults with ADHD and coexisting ASD, methylphenidate was prescribed in lower daily doses over three years as compared to individuals with pure ADHD. Conclusions The findings indicate that there are differences in the medical treatment of individuals with or without ASD. If these differences are due to different medication responses in ASD or due to other factors such as clinicians’ perceptions of medication effects in patients with ASD, needs to be further studied.

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Methylphenidate for Treating ADHD: A Naturalistic Clinical Study of Methylphenidate Blood Concentrations in Children and Adults With Optimized Dosage

Cited by 11 publications

References 36 publications

Pharmacokinetics of methylphenidate and ritalinic acid in plasma correlations with exhaled breath and oral fluid in healthy volunteers

Pharmacokinetics of methylphenidate and ritalinic acid in plasma correlations with exhaled breath and oral fluid in healthy volunteers

Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity

Medications for attention-deficit/hyperactivity disorder in individuals with or without coexisting autism spectrum disorder: analysis of data from the Swedish prescribed drug register

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