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Final pediatric population pharmacokinetic model observations and individual predictions versus time after dose. Notes: Model observations are actual concentration-time data and are displayed with open circles. Individual predicted concentration-time profiles are displayed with lines (colored by subject). Abbreviations: DV, observations; iPreD, independent predicted concentrations; iVar, indepen dent variable.
Source publication
A new multilayer-bead formulation of extended-release methylphenidate hydrochloride (MPH-MLR) has been evaluated in pharmacokinetic studies in healthy adults and in Phase III efficacy/safety studies in children and adolescents with attention deficit hyperactivity disorder (ADHD). Using available data in healthy adults, a two-input, one-compartment,...
Context in source publication
Context 1
... parameter estimates for the pediatric PK model are shown in Table 1. Figure 2 shows the goodness-of-fit relationship between the individual population PK model observations versus time after dose. Residuals were uniformly distributed with time and MPH concentrations with no obvious bias. A posterior predictive check of the final pediatric PK model found that the fifth and 95th quartiles of the observed data were contained within the 90% confidence intervals for the fifth and 95th prediction intervals, suggesting that the model is adequate for simulating MPH concentrations in pediatric ...
Citations
... There is quite a bit of variability in reported apparent V of methylphenidate hydrochloride. After a systematic review of the reported V, it is found that the volume estimate reported in this paper seems to be reasonably close to the volume estimate reported by Gomeni et al. and the FDA summary basis of approval for Ritalin LA. [15][16][17][18] The IVIVC model was developed using the in vitro dissolution and the in vivo PK data of three ER formulations (fast, medium, and slow). The in vitro dissolution data were able to describe the in vivo PK time course adequately for each formulation evaluated. ...
Delayed‐release and extended‐release methylphenidate hydrochloride (JORNAY PM®) is a novel capsule formulation of methylphenidate hydrochloride, used to treat attention deficit hyperactivity disorder in patients 6 years and older. In this paper, we develop a Level A in vitro‐in vivo correlation (IVIVC) model for extended‐release methylphenidate hydrochloride to support post‐approval manufacturing changes by evaluating a point‐to‐point correlation between the fraction of drug dissolved in vitro and the fraction of drug absorbed in vivo. Dissolution data from an in vitro study of three different release formulations: fast, medium, and slow, and pharmacokinetic data from two in vivo studies were used to develop an IVIVC model using a convolution‐based approach. The time‐course of the drug concentration resulting from an arbitrary dose was considered as a function of the in vivo drug absorption and the disposition and elimination processes defined by the unit impulse response function using the convolution integral. An IVIVC was incorporated in the model due to the temporal difference seen in the scatterplots of the estimated fraction of drug absorbed in vivo and the fraction of drug dissolved in vitro and Levy plots. Finally, the IVIVC model was subjected to evaluation of internal predictability. This IVIVC model can be used to predict in vivo profiles for different in vitro profiles of extended‐release methylphenidate hydrochloride.
... This study in children aged 4 to < 6 years with ADHD was undertaken to assess MPH PK following a single oral dose of MPH-MLR and (1) to investigate comparability with PK parameters previously obtained in children aged 6-11 years with ADHD and (2) to determine if results in the preschoolaged children fit a general pharmacostatistical population PK model developed for MPH-MLR in an earlier modeling study [21]. ...
... A previous population PK model for MPH-MLR [21], developed in adults and children aged 6-11 years, was updated using data on the children enrolled in this study. This process included updating the analysis data set, refitting the existing population PK model to the new data set, evaluating potential new covariates, and confirming the final model fit with model-qualification activities. ...
... This process included updating the analysis data set, refitting the existing population PK model to the new data set, evaluating potential new covariates, and confirming the final model fit with model-qualification activities. The overall structure of the final PK model and the model parameters has been previously published [21]. ...
Objective
This was a single-dose, one-period, multicenter, pharmacokinetic (PK) study to evaluate the PK of methylphenidate (MPH) hydrochloride multilayer extended-release capsules (MPH-MLR) in preschool children aged 4 to < 6 years, previously diagnosed with attention-deficit/hyperactivity disorder (ADHD), and on a stable dose of MPH.Methods
Preschool-aged children (N = 10) received a single oral dose of MPH-MLR (10, 15, or 20 mg) sprinkled over applesauce; a dose equivalent to their pre-enrollment daily dose of MPH. Blood samples for the measurement of MPH concentrations were obtained pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h post-dose. No structural model was assumed in the derivation of PK values for analysis. Maximum plasma concentration (Cmax), area under the concentration–time curve (AUC), elimination half-life, clearance (CL), and volume of distribution (Vd) data were compared with a historical group of older children aged 6–11 years (N = 11) and analyzed by bodyweight. Safety (adverse event monitoring, vital signs, electrocardiogram, clinical laboratory testing, physical examination) was assessed.ResultsMean dose-normalized Cmax and area under the curve to the last measurable observation (AUC0–t) values were similar across dose groups, ranging from 0.67 ng/mL/mg (MPH 15 mg) to 0.81 ng/mL/mg (MPH 10 mg) for Cmax/dose, and from 7.80 h × ng/mL/mg (MPH 20 mg) to 8.92 h × ng/mL/mg (MPH 10 mg) for AUC0–t/dose. PK results were integrated into a previously described pharmacostatistical population PK model. Visual predictive check plots showed greater variability in the 6- to 11-year-old group than the 4- to < 6-year-old group, and CL increased with increasing body weight in a greater than dose-proportional manner. Mean CL, normalized for body weight, was constant for all dose groups, ranging from 4.88 L/h/kg to 5.80 L/h/kg. Median time to Cmax ranged from 2.00 to 3.00 h post-dose, and overall, dose-normalized Cmax concentrations indicated greater systemic exposures of MPH-MLR in preschool children aged 4 to < 6 years compared with children aged 6–11 years. Children aged 4 to < 6 years had a lower Vd than children aged 6–11 years. There were no unexpected safety signals.Conclusion
The PK of MPH-MLR in preschool children demonstrated the biphasic absorption profile described earlier in older children, and the PK profile in children with ADHD aged 4 to < 6 years was similar to the profile in those aged 6–11 years, apart from a lower Vd and relatively higher systemic MPH levels for children in the preschool group.Trial registrationClinicaltrials.gov Identifier: NCT02470234.
... 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]. The model revealed that DR/ER-MPH produces a clinical response that occurs earlier in the morning, remains constant with less fluctuation throughout the day, and has a dose-dependent duration of effect lasting into the evening versus OROS-MPH, MPH-CD, MEROS, and d-MPH-ER. ...
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 long-acting 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, high-throughput techniques and novel time-based scales are being developed to advance research on the pharmacokinetic-pharmacodynamic relationships of stimulants. Model-based pharmacokinetic-pharmacodynamic approaches can be applied to aid the development of novel formulations and individualize therapy with existing drugs.
... Aptensio XR Ò (MPH). Aptensio Ò XR was approved for use in 2015 (FDA 2015a(FDA , 2015bTeuscher et al. 2015;Wigal et al. 2015;Owens et al. 2016). It is an ER dl-MPH compound in capsule form that utilizes coated and uncoated MPH microparticles, similar to other MPH ER capsules. ...
In the last 15 years, there has been a marked increase in the number of available stimulant formulations with the emphasis on long-acting formulations, and the introduction of several novel delivery systems such as orally dissolving tablets, chewable tablets, extended-release liquid formulations, transdermal patches, and novel “beaded” technology. All of these formulations involve changes to the pharmaceutical delivery systems of the two existing compounds most commonly employed to treat attention-deficit/hyperactivity disorder (ADHD), amphetamine (AMP) and methylphenidate (MPH). In addition to these new formulations, our knowledge about the individual differences in response has advanced and contributes to a more nuanced approach to treatment. The clinician can now make increasingly informed choices about these formulations and more effectively individualize treatment in a way that had not been possible before. In the absence of reliable biomarkers that can predict individualized response to ADHD treatment, clinical knowledge about differences in MPH and AMP pharmacodynamics, pharmacokinetics, and metabolism can be utilized to personalize treatment and optimize response. Different properties of these new formulations (delivery modality, onset of action, duration of response, safety, and tolerability) will most likely weigh heavily into the clinician's choice of formulation. To manage the broad range of options that are now available, clinicians should familiarize themselves in each of these categories for both stimulant compounds. This review is meant to serve as an update and a guide to newer stimulant formulations and includes a brief review of ADHD and stimulant properties.
... Dosing and duration become particularly important medication features for adolescents, who may drive during evening hours or at night (26). An additional benefit of ER medications is that they are less likely to be diverted for recreational use (47,48) than IR-stimulants because ER capsules are difficult to crush, effectively prohibiting intranasal or intravenous administration. Also, the controlled rate of release minimizes rapid absorption and delivery to the brain (49)(50)(51). ...
Attention-deficit hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder. Three position statements have been developed by the Canadian Paediatric Society, following systematic literature reviews. Statement objectives are to:
• 1) Summarize the current clinical evidence regarding ADHD,
• 2) Establish a standard for ADHD care, and
• 3) Assist Canadian clinicians in making well-informed, evidence-based decisions to enhance care of children and youth with this condition.
Specific topics reviewed in Part 2, which focuses on treatment, include: evidence and context for a range of clinical approaches, combining behavioural and pharmacological interventions to address impairment more effectively, the role of parent and teacher (or other caregiver) training, the use of stimulant and nonstimulant medications, with effects and risks, and dosing and monitoring protocols. Treatment recommendations are based on current guidelines, evidence from the literature, and expert consensus.
... La dose et la durée d'action prennent toute leur importance chez les adolescents, qui peuvent conduire en soirée ou pendant la nuit (26). Les médicaments à LP ont l'avantage supplémentaire de moins risquer d'être détournés pour un usage récréatif (47,48) que les stimulants à libération immédiate parce que les capsules à LP sont difficiles à écraser, ce qui est efficace pour en empêcher l'admi nistration intranasale ou intraveineuse. De plus, le taux contrôlé de libération en réduit l'absorption rapide et la transmission au cerveau (49)(50)(51). ...
Le trouble de déficit de l’attention/hyperactivité (TDAH) est un trouble neurodéveloppemental chronique. La Société canadienne de pédiatrie a préparé trois documents de principes après avoir effectué des analyses bibliographiques systématiques. Leurs objectifs s’établissent comme suit :
• 1) Résumer les données probantes cliniques à jour sur le TDAH.
• 2) Établir une norme pour les soins du TDAH.
• 3) Aider les cliniciens canadiens à prendre des décisions éclairées et fondées sur des données probantes pour rehausser la qualité des soins aux enfants et aux adolescents qui présentent cette affection.
La partie 2, axée sur le traitement, porte sur les données probantes et le contexte entourant diverses approches cliniques, la combinaison des interventions comportementales et pharmacologiques pour assurer un traitement plus efficace, le rôle de la formation des parents et des enseignants (ou des autres personnes qui s’occupent de l’enfant), le recours aux stimulants et aux non-stimulants, leurs effets et leurs risques, leur posologie et les protocoles de surveillance. Les recommandations thérapeutiques reposent sur les lignes directrices à jour, les données probantes tirées de publications scientifiques et le consensus d’experts.
... The simulation results investigating the effect of the physiologically plausible simultaneous presence of two or more CES1 variants on d-MPH plasma exposure are shown in of MPH are limited, 9,34 and none have included information concerning CES1. Rs71647871 GA (p.Gly143Glu) was found to significantly reduce d-MPH apparent oral CL/F and this is in accordance with previously reported findings. ...
The aim of this study was to identify demographic and genetic factors that significantly affect methylphenidate (MPH) pharmacokinetics (PK), and may help explain interindividual variability and further increase the safety of MPH. d-MPH plasma concentrations, demographic covariates, and carboxylesterase 1 (CES1) genotypes were gathered from 122 healthy adults and analyzed using nonlinear mixed effects modeling. The structural model that best described the data was a two-compartment disposition model with absorption transit compartments. Novel effects of rs115629050 and CES1 diplotypes, as well as previously reported effects of rs71647871 and body weight, were included in the final model. Assessment of the independent and combined effect of CES1 covariates identified several specific risk factors that may result in severely increased d-MPH plasma exposure.
... deemed it necessary to begin at a higher dose, and were titrated to an optimized dose (10,15,20,30,40,50, 60 mg; all given once daily) based on response and adverse events (AEs). The primary endpoint was the change from baseline to end of DBP in ADHD Rating Scale, 4th Edition (ADHD-RS-IV) total score. ...
... Many formulations of MPH are available to address the unique needs of this population. Available extended-release (ER) formulations of MPH provide different portions of the total dose as the immediate-release (IR) component (20,22,30, and 50 %), as well as different durations of action, allowing the prescriber to tailor therapy to individual needs and responses [3][4][5]. Inter-and intra-patient variabilities have been described with these agents and contribute to the need for MPH dose titration [6]. ...
... Further statistical analysis did not identify a relationship between the optimal dose at the end of the open-label period and body weight. However, a separate analysis using a population pharmacokinetic model including data from this study showed a correlation between body weight [ranging from 20 to 80 pounds (9-36 kg)] and change from baseline in ADHD-RS-IV score [20]. Although additional studies are needed to investigate this relationship, this information may be useful to clinicians who are initiating therapy with MPH-MLR. ...
Psychostimulants remain first-line treatment options for the management of attention-deficit/hyperactivity disorder (ADHD). A multilayer extended-release bead methylphenidate capsule (provisional name Aptensio XR™, MPH-MLR) with unique release properties is being investigated for the treatment of ADHD.
The aim of this study was to assess the efficacy (primary) and safety and tolerability (secondary) of MPH-MLR compared with placebo in children and adolescents aged 6-18 years with ADHD.
This study was a parallel, double-blind, multicenter, placebo-controlled, forced-dose, phase III study in which patients were randomized to placebo or MPH-MLR 10, 15, 20, or 40 mg given once daily. There were four study phases: (1) 4-week screening/baseline; (2) 1-week, double-blind treatment (DBP); (3) 11-week, open-label, dose-optimization period; and (4) 30-day follow-up call. During the open-label dose-optimization period all patients started with MPH-MLR 10 mg, unless the investigator deemed it necessary to begin at a higher dose, and were titrated to an optimized dose (10, 15, 20, 30, 40, 50, 60 mg; all given once daily) based on response and adverse events (AEs). The primary endpoint was the change from baseline to end of DBP in ADHD Rating Scale, 4th Edition (ADHD-RS-IV) total score. Secondary endpoints included changes in ADHD-RS-IV subscales and Clinical Global Impression-Improvement Scale (CGI-I) at the end of the DBP. The primary analysis was an analysis of covariance including terms for treatment, site, and baseline ADHD-RS-IV total score.
A total of 221 patients completed the DBP. The primary endpoint had a statistically significant difference among treatments (p = 0.0046) and sites (p = 0.0018), and baseline covariate made a significant contribution (p < 0.0001). As the MPH-MLR dose increased, the ADHD-RS-IV total score improved; the 20 and 40 mg doses were statistically different (p = 0.0145 and p = 0.0011, respectively) from placebo. Females responded differently than did males (p = 0.0238); there was a significant difference among treatments for males but not for females, partly because only one-third of subjects were female and partly because some females who received placebo had considerable improvement during the DBP. Similarly, the ADHD-RS-IV subscales and CGI-I scores at the end of the DBP also showed more improvement as the dose of MPH-MLR increased. During the open-label phase, ADHD-RS-IV total scores improved (mean change from baseline -22.5) and correlated as the dose of MPH-MLR increased; CGI-I scores also improved. No unexpected AEs were noted.
Dose-related improvements in ADHD-RS-IV scores that exceeded those of placebo were observed in patients treated with MPH-MLR. No new safety signals were noted.
Methylphenidate (MPH) is currently used to treat children with attention deficit hyperactivity disorder (ADHD). Several extended-release (ER) formulations characterized by a dual release process were developed to improve efficacy over an extended duration. In this study, a model-based approach using literature data was developed to: a) evaluate the most efficient pharmacokinetic (PK) model to characterize the complex PK profile of MPH ER formulations; b) provide PK endpoint metrics for comparing ER formulations; c) define criteria for optimizing development of ER formulations using a convolution-based model linking in-vitro release, in-vivo release and hour-by-hour behavioral ratings of ADHD symptoms; and d) define an optimized trial design for assessing the activity of MPH in pediatric populations. The convolution-based model accurately described the complex PK profiles of a variety of ER MPH products, providing a natural framework for establishing an in-vitro/in-vivo correlation and for defining criteria for assessing comparative bioequivalence of MPH ER products. This article is protected by copyright. All rights reserved.
Introduction:
Since Ritalin® (Methylphenidate-Immediate release or MPH-IR) was introduced for the treatment of attention-deficit/hyperactivity disorder, multiple formulations of MPH have been developed. The specific formulation determines the pharmacokinetic (PK) profile and the onset and duration of action for the compound.
Areas covered:
Aptensio XR® is a multilayer-release MPH (MPH-MLR) consisting of an MPH-IR layer (40%) and an extended-release (ER) portion of 60% of MPH. It has an initial maximum MPH concentration at about two hours (h) and a second concentration peak at approximately 8h. This formulation allows for a rapid onset of effect by 1h and a duration of action through 12h after dosing. The chemistry, PK, efficacy and adverse event profile of MPH-MLR will be reviewed.
Expert commentary:
Although the PK profile may prove beneficial to patients in the late afternoon and early evening, it is not clear if this is an advantage compared with other MPH-ER formulations.
