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SPECIAL POPULATIONS/PEDIATRICS |
From the Royal University Hospital, Saskatoon, Saskatchewan, Canada (Dr Quinn, Ms Bode) and Purdue Pharma, Pickering, Ontario, Canada (Mr Reiz, Mr Donnelly, Dr Darke).
Address for reprints: Graeme A. E. Donnelly, Purdue Pharma, 575 Granite Court, Pickering, Ontario, Canada, L1W 3W8; e-mail: graeme.donnelly{at}purdue.ca.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: ADHD • methylphenidate • pharmacokinetics
Each of the new controlled-release products was designed to deliver methylphenidate at varying rates throughout the once-daily dosing interval. The multilayer-release (MLR) bead formulation of controlled-release methylphenidate that was evaluated in this study was designed to provide a rapid initial release of methylphenidate (40% of the total methylphenidate), to achieve an onset of action equivalent to immediate-release (IR) methylphenidate. By comparison, the most frequently prescribed controlled-release formulation (osmotic-release oral system methylphenidate) releases only 22% of the total dose during the initial release phase.3 In addition, after the initial release phase, the MLR methylphenidate formulation provides a delayed phase of controlled drug release, resulting in a biphasic concentration-time profile and a prolonged duration of action. In a single-dose, pharmacokinetic study in healthy adult volunteers, this MLR formulation was fully bioavailable, relative to the IR formulation, under fasted and fed conditions.4 The rate of increase in plasma methylphenidate concentrations during the first 2 hours postdose with the MLR methylphenidate was similar to that with the IR formulation. The more prolonged release of methylphenidate from the MLR formulation was evidenced by the higher plasma concentrations at approximately 10 to 12 hours.
The purpose of this study was to confirm the findings of a previous study in adults by comparing the pharmacokinetics of once-daily MLR methylphenidate and IR methylphenidate in a randomized, 2-way crossover study in young children with ADHD.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Patients included males or females between the ages of 6 and 12 years old who had a history consistent with ADHD; met the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for ADHD, inattentive, or combined; and were taking a stable dose of either IR or CR methylphenidate. Parents of patients must have had the ability to read, speak, and understand English and must have been mentally and physically competent to provide written informed consent for their child. Patients must have had an ability to speak and understand English to provide assent and must have been otherwise able to comply with the study protocol.
Patients were excluded if they had a true allergy to methylphenidate or amphetamines, a history of serious adverse reactions to methylphenidate, or serious hypertension, defined as any values above 100 mm Hg diastolic and 170 mm Hg systolic. Exclusion criteria included serious or unstable medical illness, comorbid psychiatric illness of sufficient severity to require treatment, or currently receiving psychotropic medications or herbal treatments. Patients must not have had a history of drug abuse, alcohol abuse, disorders of the sensory organs (particularly deafness), autism, psychosis, or any unstable psychiatric conditions.
A total of 19 children aged 6 to 12 years with ADHD were screened, and 18 were randomized. The daily dose of methylphenidate in this study was set at an equal value to the patient's prestudy dose to limit treatment disruption. Therefore, because each patient received the same daily dose in both phases, the patient acted as his or her own control, and calculation of relative pharmacokinetic parameters for the 2 treatment groups was not affected. Each patient received either a single capsule of MLR methylphenidate (Biphentin) after breakfast or 2 equal doses of IR methylphenidate (Ritalin), given after breakfast and 4 hours later. A blocked randomization procedure was used to generate the treatment allocation listing. For every 4 successive patients, 2 were allocated to receive the sequence of MLR methylphenidate followed by IR methylphenidate, and 2 were allocated to the reverse treatment order.
The children were confined to the Royal University Hospital, in the Children's Psychiatry Facility, from at least 1 hour prior to drug administration until after the 12-hour postdose blood draw in each period. Due to the short half-life of methylphenidate, discontinuation of each patient's current methylphenidate treatment for ADHD 48 hours prior to each period avoided an influence on concentration measurements related to the test drugs. There was a 14-day interval between phase I and phase II clinic visits for convenience in scheduling patients' participation while also allowing sufficient time for elimination of the drug received in phase I.
Thirty minutes before the MLR methylphenidate dose and before the first IR methylphenidate dose of the day, children were provided with a low-fat, age-appropriate breakfast of cereal with 2% milk, toast, and orange juice, so that the pharmacokinetics of methylphenidate from the 2 formulations could be compared under conditions as close as possible to routine clinical practice. Food and fluid intake were not restricted during the course of the study, but no more than 180 mL of fluid was consumed with each dose. Patients avoided both strenuous activity and complete rest, unless medically necessary or procedurally required, for the first 4 hours after dosing in each period.
Plasma samples were collected from the patients at each time point at predose and 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours postdose. Plasma samples (7 mL) were collected by an indwelling catheter into blood collection tubes containing K3 EDTA for a maximum total blood draw of 77 mL per patient per phase. The indwelling catheter was removed after the 12-hour sample, and the 24-hour sample was collected by a single needle. Sample aliquots for methylphenidate analysis, from centrifuged samples, were packed in dry ice for shipment to SFBC Analytical Laboratories, Inc (North Wales, Pa) for analysis. The plasma methylphenidate concentration data were electronically transferred from the bioanalytical division to the statistical unit of SFBC Anapharm, Inc.
Analytical Methods
Analysis of methylphenidate was done using a high-performance liquid chromatographic method with methylphenidate detection by tandem mass spectrometry using methylphenidate-d3 hydrochloride as the internal standard. The ion transitions monitored were m/z 234 
m/z 84 for methylphenidate and m/z 237 m/z 84 for the internal standard. Calibration curves were obtained by performing a quadratic regression (weighted 1/x) on the calibrations standards. The calibration range was 0.1 to 100 ng/mL. No interference was found for analyte or internal standard from endogenous plasma constituents from 6 different lots of human plasma. No interference with quantitation at the limits of quantitation was observed. Intrabatch accuracy and precision in validation had a coefficient of variance (%CV) of 1.10% to 4.35% and a relative error (%RE) of –1.05% to 1.67%. Interbatch accuracy and precision in validation had a %CV of 1.67% to 4.26% and an %RE of –0.73% to 3.75%. Analyte recovery averaged 94.08% across 3 concentrations, and mean recovery of internal standard was 95.94%. The intrabatch accuracy and precision at the lowest limit of quantitation (LLOQ) averaged 0.0927 with a %CV of 3.58% and a %RE of –7.35%. The interbatch accuracy and precision at the LLOQ averaged 0.0979 ng/mL with a %CV of 1.83% and a %RE of –2.10% across 5 batches.
Pharmacokinetic and Statistical Analysis
The mean, standard deviation (SD), %CV, and range were calculated for plasma concentrations of methylphenidate for each sampling time and treatment. AUC was calculated using the linear trapezoidal rule. The mean, SD, %CV, and range were calculated for AUC0-t (ng·h/mL), AUC0-24 h (ng·h/mL), AUC0-
(ng·h/mL), Cmax (ng/mL), Cmax 0-4 h (ng/mL), tmax (h), tmax 0-4 h (h), t1/2 (h), and K (h–1). Cmax 0-4 h was defined as the maximum observed concentration for the interval of 0 to 4 hours, and tmax 0-4 h was defined as the time to reach peak concentration for the interval of 0 to 4 hours, for each subject and for each treatment. The mean, SD, %CV, and range were also calculated for all the above, normalized to a dose of 20 mg. Analysis of variance (ANOVA) was performed on ln-transformed AUC and concentration data and untransformed time to maximum concentration, half-life, and terminal rate data. Ratios of least squares means, 90% geometric confidence intervals, and intrasubject CV were calculated for AUC and Cmax data. AUC0- for each patient was calculated as AUC0-t + (Ct/K), where Ct equals the fitted last nonzero concentration, AUC0-t equals the AUC from time 0 to the time of the last nonzero concentration, and K equals the terminal rate constant. To calculate the terminal rate constant (K), regression analyses were performed on the natural log of plasma concentration values versus time. Calculations were made between the time point where the log-linear elimination phase began and the time at which the last concentration above the limit of quantitation occurred. Linear regressions were used to compare the extent of absorption (AUC0-) with total daily dose, body mass index, and dose/body weight. Statistical significance was defined as P < .05 for a 2-tailed hypothesis.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The mean pharmacokinetic parameters are summarized in Table II, and the mean methylphenidate concentration-time curves for MLR and IR methylphenidate, normalized to a 20-mg dose, are shown in Figure 1.
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Following the morning administration at time 0, the methylphenidate concentrations of both MLR and IR methylphenidate rose rapidly, to a maximum at 2 to 2.5 hours. There was no statistically significant difference between treatments in time to maximum concentration (tmax 0-4 h) during the first 4 hours postdose (P = .307), and the maximum methylphenidate plasma concentration during the same 4-hour period (Cmax 0-4 h) for MLR methylphenidate was 78.8% (90% confidence interval [CI]: 65.6%-94.7%) of that of IR methylphenidate. Following the initial peak, achieved in approximately 2 to 2.5 hours postdose, methylphenidate plasma concentrations decreased until approximately 4 hours postdose, with both MLR and IR methylphenidate. The second rise in plasma concentration occurred earlier with a second dose of IR methylphenidate than with the single dose of MLR methylphenidate. Consequently, mean plasma concentrations were approximately 68% higher with MLR methylphenidate at 12 hours postdose. No dose dumping was observed in any patient on MLR methylphenidate, and the relative Cmax and Cmax 0-4 h were below 125%.
Although there were differences in plasma concentration-time profiles, there were no significant differences in the extent of absorption between MLR and IR methylphenidate (P = .909 and .465, for mean AUC0-t and AUC0-, respectively). The 90% confidence intervals of the relative AUC0-t and AUC0- of MLR and IR methylphenidate were within 80% to 125%, indicating bioequivalence when the products were administered under similar conditions, following a child's typical breakfast. No statistically significant sequence or period effects were observed.
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) and total daily dose (R2 = 0.1451). Similarly, there was no correlation between AUC0- and body mass index (R2 = 0.0863), but a significant correlation was observed between AUC0- and dose/body weight (R2 = 0.5595; Figure 2).
Safety
All 18 patients who received study medication were included in the safety analysis. There were very few adverse events reported for both MLR and IR methylphenidate (see Table III), and none of the events were rated moderate or severe. Two patients on 20 mg experienced 3 adverse events, 2 patients on 30 mg experienced 2 adverse events, 1 patient on 40 mg experienced 3 adverse events, 1 patient on 50 mg experienced 2 adverse events, 0 patients on 60 mg experienced an adverse event, and 1 patient on 80 mg experienced 4 adverse events. There were no discontinuations due to adverse events.
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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ratios, that equivalent doses of MLR and IR methylphenidate are similarly bioavailable, allowing for direct conversion from IR methylphenidate to MLR methylphenidate, whereas comparative Cmax values suggest that MLR methylphenidate avoids the peaks and troughs associated with twice-daily dosing. Low levels of adverse events were noted on both formulations of methylphenidate. The pharmacokinetic profile of MLR methylphenidate in children is similar to that previously demonstrated in adults.4 In adults, AUC was 70.48 ng·h/mL following a 20-mg dose, compared to a dose-normalized AUC of 84.62 ng·h/mL in children in the present study. Similarly, dose-normalized Cmax was 6.91 ng/mL in children and 6.12 ng/mL in adults.4 The terminal rate constant of the test formulation was also not greatly different in children (0.15 ± 0.04 h–1) from that previously observed with the same formulation in fed adults (0.15 ± 0.03 h–1). Patients in this study were on stable, individually titrated therapeutic doses of methylphenidate over a wide range (20-80 mg/d). Within this dose range, no relationship between AUC and dose was observed, and the dose was not greater as body mass was increased. However, AUC was significantly correlated with dose/body weight. Assuming similar levels of efficacy in all study subjects, this suggests that titration of the dose according to clinical response results in a wide therapeutic dose range primarily determined by the individual concentration/effect responses of each patient, rather than a strict correlation of dose to age or body weight.
Like all controlled-release methylphenidate products, MLR methylphenidate provides a compromise between early morning and later day effects. Multilayer-release methylphenidate delivers 40% of the total dose of methylphenidate in the morning, and the observed time to peak concentration was not significantly different from IR methylphenidate. The remaining 60% of the total methylphenidate dose is released over the remainder of the school day and into the early evening homework period. Therefore, MLR methylphenidate may provide morning efficacy that approaches that of IR methylphenidate with a longer duration of effect. In a previous study of MLR methylphenidate in a simulated classroom setting, onset of action occurred within 1 hour of administration and persisted for at least 10 hours.5
The ideal once-a-day methylphenidate product has been defined as having a rapid onset, an absorption phase corresponding to peak activities when control is most needed (at school and during homework), minimal potential for appetite suppression by providing a plasma concentration trough around lunchtime, and allowing for a normal dinner appetite and sleep schedule.6 Each of the new controlled-release methylphenidate formulations attempts to address these requirements by using proprietary systems to control the release of methylphenidate. There are currently 3 second-generation controlled-release methylphenidate formulations on the US market, but only osmotic-release (OR) oral system methylphenidate is approved in Canada.
Osmotic-release methylphenidate uses an IR overcoat that delivers 22% of the total available methylphenidate, with the remaining 78% being slowly released over a 12-hour period from the OR oral system. It has been argued that this "ascending ramp" delivery profile is needed to avoid acute tolerance.7 However, the need for ascending plasma concentrations may not be as important as the achievement of optimized plasma concentrations in individual patients because a possible effect of acute tachyphylaxis on the response to methylphenidate has not been quantified, and its clinical significance remains theoretical.3
Another controlled-release methylphenidate capsule, controlled-delivery (CD) methylphenidate, uses bead technology and is composed of 30% IR methylphenidate beads and 70% extended-release (ER) methylphenidate beads, and it was designed to begin to release methylphenidate approximately 1 hour after placement in an aqueous medium.8 The resulting pharmacokinetic profile resembles that of earlier sustained-release methylphenidate products, with a more rapid onset and a secondary peak.9,10 In a comparison of OR and CD methylphenidate pharmacokinetic profiles, OR methylphenidate was shown to have lower plasma methylphenidate levels between hours 1 and 4 and higher levels between hours 8 and 12, with a significantly higher AUC over the first 6 hours for the CD methylphenidate.10
Controlled-release methylphenidate using another bead technology, spheroidal oral drug absorption system (SO) methylphenidate, contains 50% IR methylphenidate beads and 50% ER methylphenidate beads.3 The latter are polymer coated, providing a 4-hour delay in release of methylphenidate,3 resulting in a biphasic concentration-time profile similar to twice-daily IR methylphenidate.6,11 In a comparison of the pharmacokinetic profiles of healthy adults, there was a higher AUC over the first 4 hours for SO methylphenidate compared to OR methylphenidate.6 Based on this concentration-time profile, the onset of action of SO methylphenidate is more likely to be equivalent to twice-daily IR methylphenidate, but at the expense of late-day effects, to a greater extent than other once-a-day products.12
Comparative pharmacodynamic studies of OR and CD methylphenidate13 and OR and SO methylphenidate14 confirm that greater efficacy is observed at the time of maximum difference in plasma concentration. Improvements in behavior observed during the first 6 hours were significantly greater for patients on CD methylphenidate than those on OR methylphenidate,13 reflecting the increased plasma concentrations obtained during that time period.10 Likewise, SO methylphenidate was more effective than OR methylphenidate for the initial 4 hours postdose,14 during which time plasma concentration would be expected to be higher.6
Based solely on the pharmacokinetic profile of MLR methylphenidate and the assumption that greater efficacy will be obtained at the time points when plasma concentration is higher,3 morning efficacy is likely to be greater than that of OR methylphenidate, although pharmacokinetic or clinical studies directly comparing MLR methylphenidate with other controlled-release methylphenidate products have not been conducted.13 The duration of effect of MLR methylphenidate is also likely to be longer than IR methylphenidate, and based on the reported plasma concentration, 12 hours postdose,6 it is likely to be longer than SO methylphenidate and as long as OR methylphenidate. However, only a direct comparison between MLR methylphenidate and these formulations can confirm these observations. It is clear from the pharmacokinetic and clinical data that each of these different controlled-release methylphenidate formulations offers patients a wide range of ADHD treatment options, in consideration of the specific needs of individual patients.
Conclusion
The results of this study indicate that MLR methylphenidate is similarly bioavailable in children with ADHD compared to an equivalent dose of IR methylphenidate administered twice daily while avoiding the peaks and troughs associated with such dosing, with no evidence of dose dumping. Due to the nonnormal distribution of these parameters, nonparametric statistics would give greater accuracy in describing both products. The novel multilayer-release formulation of MLR methylphenidate provides for release of 40% of the total dose as an immediate-release component, with the remainder in a controlled-release component. This results in a biphasic pharmacokinetic profile, which differs substantially from other second-generation controlled-release methylphenidate products. It therefore provides a distinctive treatment option for the clinician prescribing once-daily methylphenidate preparations for ADHD, combining both a rapid onset of action and a prolonged duration of effect.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. American Academy of Child and Adolescent Psychiatry. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry. 2002;41: 26S-49S.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
2. CADDRA Guidelines Steering Committee. Guidelines for the Diagnosis and Management of ADHD. Toronto: Canadian ADD Resource Alliance; 2005.
3. Patrick KS, González MA, Straughn AB, Markowitz JS. New methylphenidate formulations for the treatment of attention-deficit/hyperactivity disorder. Expert Opin Drug Deliv. 2005;2: 121-143.[CrossRef][Medline] [Order article via Infotrieve]
4. Purdue Pharma Canada. Biphentin® (methylphenidate HCl) [product monograph]. Pickering, Ontario: Purdue Pharma; 2006.
5. Schachar R, Ickowicz A, Crosbie J, et al. Evaluation of controlled-release methylphenidate in the treatment of ADHD [abstract]. Proceedings of the 48th Annual Meeting of the AACAP; October 23-28, 2001; Honolulu, Hawaii.
6. Markowitz JS, Straughn AB, Patrick KS, et al. Pharmacokinetics of methylphenidate after oral administration of two modified-release formulations in healthy adults. Clin Pharmacokinet. 2003;42: 393-401.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
7. Swanson J, Gupta S, Lam A, et al. Development of a new once-a-day formulation of methylphenidate for the treatment of attention-deficit/hyperactivity disorder: proof-of-concept and proof-of-product studies. Arch Gen Psychiatry. 2003;60: 204-211.
8. Wigal SB, Sanchez DY, DeCory HH, D'Imperio JM, Swanson JM. Selection of the optimal dose ratio for a controlled-delivery formulation of methylphenidate. J Appl Res. 2003;3: 46-63.
9. Metadate® CD (methylphenidate HCl) [package insert]. Rochester, NY: Celltech Pharmaceuticals, Inc; 2001.
10. González MA, Pentikis HS, Anderl N, et al. Methylphenidate bioavailability from two extended-release formulations. Int J Clin Pharmacol Ther. 2002;40: 175-184.[Web of Science][Medline] [Order article via Infotrieve]
11. Ritalin® LATM (methylphenidate HCl) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2002.
12. Swanson JM, Lerner M, Wigal T, et al. The use of a laboratory school protocol to evaluate concepts about efficacy and side effects of new formulations of stimulant medications. J Atten Disord. 2002;6(suppl 1): S73-S88.[Medline] [Order article via Infotrieve]
13. Swanson JM, Wigal SB, Wigal T, et al. A comparison of once-daily extended-release methylphenidate formulations in children with attention-deficit/hyperactivity disorder in the laboratory school (the Comacs Study). Pediatrics. 2004;113(3 pt 1): e206-e216.
14. Lopez F, Silva R, Pestreich L, Muniz R. Comparative efficacy of two once daily methylphenidate formulations (Ritalin LA and Concerta) and placebo in children with attention deficit hyperactivity disorder across the school day. Paediatr Drugs. 2003;5: 545-555.[CrossRef][Medline]
[Order article via Infotrieve]
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