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Selection of the Optimal Dose Ratio for a Controlled-Delivery Formulation of Methylphenidate
Sharon B. Wigal, PhD*
Dorothea Y. Sanchez, PhD†
Heleen H. DeCory, PhD†
Joyce M. D’Imperio, PharmD†
James M. Swanson, PhD*
*The University of California at Irvine
Child Development Center (UCI-CDC)
19722 MacArthur (Centerpointe)
Irvine, CA 92612
†Celltech Americas, Inc.
P.O. Box 31710
755 Jefferson Road
Rochester, NY 14603
KEY WORDS: ADHD, methylphenidate, children, adults, Metadate® CD.
Objective: Metadate® CD (methylphenidate HCl, USP) Extended-Release Capsules, CII, is a once-daily methylphenidate (MPH) formulation containing a combination of immediate-release (IR) and extended-release (ER) MPH-coated beads used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). The objective of these studies was to identify the optimal ratio of IR to ER MPH beads for this formulation that would result in a once-daily MPH product that could replace Ritalin® given bid.
Methods: Two sequential studies were conducted: 1) an open-label, randomized, six-period, crossover pharmacokinetic (PK) study in 22 healthy adults comparing 20:80, 30:70, and 40:60 IR to ER prototype formulations (25 mg qd), Ritalin® (10 mg qd and 10 mg bid) and Ritalin® SR (20 mg qd); and 2) a double-blind, two-stage, crossover PK and pharmacodynamic (PD) study in 23 children with ADHD in a laboratory school setting comparing the 30:70 and 40:60 IR to ER prototype formulations (20 mg or 40 mg qd), Ritalin® (10 mg bid), and placebo. Blood samples were collected and MPH plasma concentrations were used to calculate PK parameters for each treatment. Efficacy measures included the SKAMP (Swanson, Kotkin, Atkins, M/Flynn, Pelham Scale) rating scale, the CLAM (Conners, Loney, and Milich) scale, and the PERMP (10-minute permanent products math test).
Results: PK analysis in healthy adult subjects showed that all three prototype formulations exhibited biphasic MPH plasma concentration versus time profiles with a sharp initial slope culminating in an initial peak at approximately 1.5 hours and a second peak 5 to 8 hours later. The relative magnitude of the first and second peaks differed among the prototype formulations with the 30:70 and 40:60 formulations being more comparable to Ritalin® bid. PK analysis of the 30:70 and 40:60 formulations in children with ADHD showed MPH plasma concentration versus time profiles similar to those obtained in adults. Both prototype formulations were comparable in efficacy to Ritalin® (bid) and overall statistically significantly better than placebo in the primary efficacy measures used, but the 30:70 formulation produced a more consistent treatment effect over the entire study observation period. All treatments were well tolerated in both children and adults.
Conclusions: Both the 30:70 and 40:60 prototype formulations produced biphasic plasma concentration versus time profiles similar to Ritalin® bid in healthy adult subjects and in children with ADHD. Given once in the morning, both were effective in controlling ADHD symptoms in children and were comparable in efficacy to Ritalin® given bid. However, the 30:70 formulation was the preferred formulation because of its more consistent treatment effect and was therefore chosen for commercial development.
Attention Deficit Hyperactivity Disorder (ADHD) is the most common neurobehavioral disorder of childhood, occurring in an estimated 3% to 6% of school-aged children.1 Characterized by two sets of core symptoms, namely, inattention and a combination of hyperactive and impulsive behaviors,2 ADHD also can be accompanied by internalizing disorders such as sadness and anxiety, as well as aggressive and oppositional disorders.3–5 In addition, ADHD can continue into adolescence and adult life.6,7
Methylphenidate (MPH) and amphetamine are considered the drugs of choice for ADHD1,8,9; however, MPH continues to be the most commonly prescribed central nervous system stimulant.10 The drug is primarily metabolized by de-esterification to ritalinic acid, which is not pharmacologically active,11 resulting in a low absolute bioavailability12 and a short half-life (2–3 h)13 and duration of action.14 Consequently, conventional immediate-release (IR) formulations of MPH are administered two to three times a day to maintain efficacy over the duration of a typical school- or workday.8,9 Twice-a-day dosing is generally prescribed for those patients requiring ADHD symptom control over the course of the schoolday, whereas three-times-a-day dosing can be beneficial in patients involved in after-school or early evening activities. Multiple dosing, however, can present a problem for ADHD children who can forget to take a dose during school hours, and/or for school officials who must handle these controlled medications. Sustained-release (SR) or extended-release (ER) wax-matrix formulations of MPH were developed to alleviate the need for multiple daily dosing. However, whereas efficacy of MPH after administration of ER or SR formulations is sustained for longer times compared with the conventional IR formulations,14,15 the onset of action of these formulations is perceived to be slow, and it has been reported that they are not as effective as IR formulations given twice per day.16 Consequently, the ER/SR formulations have not been widely accepted in clinical practice.
Recent efforts have been directed toward the development of once-daily MPH formulations using delivery systems that combine both IR and ER MPH components. Ideally, such formulations would release MPH at a fast enough rate (within 1 h) to obtain efficacy early on and should continue to release MPH for an extended duration thereafter to eliminate the need for additional dosing. In addition, they should release MPH in such a way as to minimize the peaks and troughs seen after multiple dosing of IR formulations without producing a flat MPH plasma concentration profile that could lead to acute tolerance.17
Metadate® CD (methylphenidate HCl, USP) Extended-Release Capsules, CII, is a controlled-delivery (CD) formulation of MPH containing both IR and ER MPH-coated particles, or “beads,” less than 1.18 mm in diameter. Designed to replace IR MPH given bid, the most commonly prescribed IR MPH dosing regimen at the time of these studies as well as today,10,18,19 Metadate® CD capsules contain a 30:70 ratio of IR to ER MPH-coated beads and have been shown to be safe and effective in controlling ADHD symptoms in children aged 6 and older.20,21 The studies described here were used to identify the optimum ratio of IR to ER MPH-coated beads in Metadate® CD which best met the criteria outlined in this article. Thus, they represent an historical perspective on the development of this product. Specifically, the first study compared the pharmacokinetic (PK) profiles of three prototype formulations, each containing different ratios of IR to ER beads, with those of Ritalin® and Ritalin® SR in adult subjects and identified two formulations for further clinical evaluation. The second study evaluated the preliminary safety and efficacy of the two prototype formulations identified in the first study in children with ADHD in a laboratory school setting while simultaneously determining the PK profile of these formulations in children.
Placebo capsules and prototype formulations containing IR to ER MPH-coated beads in a ratio of 20:80, 30:70, and 40:60 were obtained from Eurand Americas, Inc. (Vandalia, OH). Ritalin® (10 mg) and Ritalin® SR (20 mg) tablets were obtained from Novartis Pharmaceuticals (East Hanover, NJ).
For the PK/PD study in children, Ritalin® (10 mg) tablets were placed into capsule shells by Eurand Americas, Inc. The resulting capsules were tested according to the USP dissolution conditions for MPH tablets and showed a comparable dissolution profile to intact Ritalin® tablets. All medications were supplied in white, opaque, size 3 hard gelatin capsule shells and were packaged in blister cards to enhance compliance.
Study 1: Adult PK Study
Subjects and Study Design
The study protocol and subject informed consent form were approved by the Institutional Review Board (Harris Laboratories, Inc.). All subjects who enrolled in the study were determined to be healthy by means of a medical history, physical examination (including a 12-lead electrocardiogram), and clinical laboratory tests (hematology, serum chemistry, urinalysis, HIV antibody screen, serum pregnancy, and a screen for alcohol or drugs of abuse). Additional inclusion and exclusion criteria are given in Table 1.
Subjects were randomized to a six-period, open-label crossover sequence, with each treatment period lasting 1.5 days. Subjects were randomly assigned to receive Ritalin® (10 mg qd), Ritalin® (10 mg bid), Ritalin® SR (20 mg qd), the 20:80 prototype formulation (25 mg qd), the 30:70 prototype formulation (25 mg qd), or the 40:60 prototype formulation (25 mg qd). The second daily dose, for Ritalin® bid, was received 4 hours after the first dose, and there was a 1-week washout period between each treatment. Blood samples (5-mL) were collected pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours post-dose for each treatment. Plasma samples were prepared and transferred to MDS Harris (Lincoln, NE), and d,l-MPH concentrations were determined by a liquid chromatography-mass spectrometry-mass spectrometry (LC/MS/MS) method validated for the determination of d,l-MPH in human heparinized plasma using meperidine as the internal standard. Briefly, compounds were extracted from alkalinized plasma with hexane:ethyl acetate (3:1, v/v). The organic layer was dried down under N2 in a water bath at 37˚C, then reconstituted with mobile phase and injected. The method was validated over a concentration range of 0.25 to 10 ng/mL MPH with a limit of quantification of 0.25 ng/mL.
Subjects fasted for at least 10 hours before each treatment and continued to fast up to 6 hours thereafter at which time a standard clinic menu and meal schedule were followed. The same menu and meal schedule were administered uniformly to all subjects during each treatment. Water was allowed ad lib during the study until 1 hour before dosing through 1 hour after dosing. All doses were swallowed by the subjects with 240 mL of room temperature water. Subjects were confined to the clinical site on the night before each dosing and until 24 hours post-dose, but were allowed to leave the clinic during washout periods. Alcohol, caffeine, and xanthine-containing beverages were restricted during the confinement period. At each check-in, a urine sample was collected to test for alcohol and drugs of abuse and female subjects underwent serum pregnancy tests.
PK and Statistical Analysis
PK parameters were calculated by a noncompartmental analysis of the plasma concentration-time data using WinNonlin™ software (Pharsight Corporation, Cary, NC) and included: Cmax (the maximal MPH concentration measured), Tmax (the time at which Cmax occurred), AUC(0-t) (the area under the concentration vs time curve from time 0 to the last measurable concentration; calculated by trapezoidal integration), AUC(0-inf) (the area under the concentration vs time curve extrapolated to infinity; calculated using the equation AUC(0-inf) = AUC(0-t) + Ct/kel, where Ct is the last measurable plasma concentration), kel (the terminal elimination rate constant estimated by linear regression of the terminal linear portion of the log-transformed concentration vs time data), and t1/2 (apparent elimination half-life calculated as 0.963/kel). For those treatments resulting in a biphasic plasma concentration versus time profile, mean maximal plasma concentrations for the first and second peaks (Cmax-1 and Cmax-2, respectively) were obtained directly from the mean MPH plasma concentration versus time profiles.
The statistical analysis used was based on the Food and Drug Administration guidance, issued July 1, 1992, and entitled “Statistical Procedures for Bioequivalence Studies Using a Standard Two-Treatment Crossover-Design.” A parametric (normal theory) general linear model was applied to each of the above variables using SAS® (version 6.08). In addition, the logarithmic transformation of the Cmax, AUC(0-inf), and AUC(0-t) were analyzed using the same model. The analysis of variance (ANOVA) model included the following factors: sequence, subject within sequence, period, and treatment. The two one-sided hypotheses were tested at the 5% level for the parameters by constructing 90% confidence intervals for the ratio of the test and reference means. The 90% confidence intervals were obtained from the anti-logs of the lower and upper bounds of the 90% confidence intervals for the difference in the means of the log-transformed data.
Vital signs (blood pressure and pulse) were measured pre-dose, immediately after dosing, and at 4 to 8 points after dosage (at 1-h intervals). In addition, the subjects were questioned concerning their well-being before dosing, and at 3, 6, and 24 hours after drug administration. All adverse events occurring during the study were reviewed by the investigator to assess relationship to drug treatment (unrelated, unlikely, possibly, probably, almost certainly). In addition, each sign or symptom reported was graded on a three-point scale (mild, moderate, or severe) and the date and time of onset, time relationship to drug dosing, duration, and outcome were noted.
Subjects and Study Design
The study protocol and the subject informed consent form were approved by the Institutional Review Board (Office of the Vice Chancellor for Research, University of California at Irvine). Males and females aged 7 to 12 years were eligible to participate in the study if they met one of the three DSM-IV criteria for the diagnosis of ADHD, and demonstrated that they needed and tolerated MPH treatment. Additional inclusion and exclusion criteria are summarized in Table 2.
After an initial screening week, qualified subjects were randomly assigned to a two-stage double-blind study sequence consisting of four study treatments, each lasting for a period of 1 week. Subjects attended the University of California at Irvine, Child Development Center (UCI-CDC) laboratory school classroom on 4 consecutive Saturdays for evaluation of the four treatment conditions and for collection of PK blood samples. Subjects were also evaluated by their regular community classroom teacher and by a parent during each week. Stage I was a two-way crossover comparison of treatment A (Ritalin®, 10 mg bid) with treatment B (placebo bid). In treatment A, subjects were given one encapsulated tablet of Ritalin® (10 mg) and one capsule of placebo after breakfast, and one encapsulated tablet of Ritalin® (10 mg) after lunch for 7 days; whereas in treatment B, subjects were given two placebo capsules after breakfast and one placebo capsule after lunch for 7 days. Stage II was a two-way crossover comparison of treatment C (the 40:60 MPH IR:ER prototype formulation) and treatment D (the 30:70 prototype formulation), with half the subjects in each treatment group randomized to a 20-mg/day dosage and the other half to a 40-mg/day dosage. Thus, in treatment C, subjects were given a daily morning dose (after breakfast) of either 1) two 20-mg capsules of the 40:60 prototype formulation or 2) one 20-mg capsule of 40:60 the prototype formulation and one capsule of the placebo; and a midday dose (after lunch) of one capsule of the placebo for 7 days. Likewise, in treatment D, subjects were given a daily morning dose (after breakfast) of either 1) two 20-mg capsules of the 30:70 prototype formulation or 2) one 20-mg capsule of the 30:70 prototype formulation and one capsule of the placebo; and a midday dose (after lunch) of one capsule of the placebo for 7 days. Blood samples (3-mL) were collected pre-dose and at 0.5, 1.5, 2, 3, 4.5, 6, 7.5, and 9 hours after the morning dose on the last day (Saturday) of each treatment week while children attended the UCI-CDC school. Plasma samples were prepared, transferred to MDS Harris (Lincoln, NE), and analyzed as described for the adult PK study.
Treatment response was assessed by: 1) the Swanson, Kotkin, Atkins, M/Flynn, Pelham (SKAMP) Deportment and Attention ratings performed every 1.5 hours (0–9 h) by the classroom teachers while subjects attended the UCI-CDC school at the end of each treatment week, 2) the PERMP (permanent products math test) completed by subjects in the UCI-CDC laboratory every 1.5 hours (0–9 h); 3) the SKAMP ratings performed by the regular community classroom teacher, and 4) the Conners, Loney, and Milich (CLAM) ratings performed once every Monday, Wednesday, and Friday of each treatment week by the regular community classroom teacher and the parent. The UCI-CDC laboratory school setting has been described previously and used in multiple evaluations in the development of stimulant treatments for ADHD.22–24 The SKAMP and CLAM tools are widely recognized as valid, reliable rating instruments for assessing the intensity of symptoms of ADHD.25,26 The version of the SKAMP used in the present study is a 10-item scale that measures impairment of functioning at school, providing two index scores based on average ratings from subsets of items (six items for the Attention index and four items for the Deportment index); whereas the CLAM is a 16-item scale that provides three established index scores based on averaging from subsets of items (10 items for the Conners Global Index [CGI], five items for the inattention/overactivity index [I/O], and five items for the aggression/defiance [A/D] index). The PERMP is an objective, performance-based measure of academic productivity consisting of a 10-minute math test.24 The version used had 100 problems arranged on four pages (one page each of addition, subtraction, multiplication, and division) in ascending order of difficulty. The UCI-CDC classroom teacher SKAMP measure was used as the primary outcome measure to compare the 40:60 and 30:70 formulations, whereas the regular community classroom teacher Conners Global Index (CGI) scores from the CLAM was used as the primary outcome measure to assess the efficacy of the prototype formulations compared with the placebo.
PK and Statistical Analysis
For analysis of efficacy measures, an analysis of variance (ANOVA) for a crossover design was performed when comparing treatments with subject, dose, period, order, treatment, and session included as factors when appropriate. Because the primary objective was to assess differences between the 30:70 and 40:60 formulations and to assess differences between the two dosages, between-subject and within-subject analyses of efficacy parameters were performed using split-plot ANOVAs.
PK parameters were calculated by a noncompartmental analysis of the plasma concentration-time data for each subject on each UCI-CDC schoolday. The following parameters were calculated to summarize the profiles (0–9 h post-dose) after administration of the Ritalin® (bid) treatment and the prototype formulations: Cmax (observed maximum concentration, calculated after the morning dose [0–3 h] and the afternoon dose [4.5–9 hours]); Tmax (observed time to maximum concentration calculated after the morning dose [0–3 h] and afternoon dose [4.5-9 h]); and AUC(0–9) (trapezoidal area under the concentration vs time curve from time 0–9 h). Statistical analyses were performed on log transformation of Cmax and AUC values and the rank transformations of Tmax. Like with analyses of efficacy parameters specified previously, split-plot ANOVAs were performed. All statistical tests were performed using two-tailed tests at the .05 level of significance.
The subjects and parents were questioned concerning the subjects’ well-being at each visit to the UCI-CDC classroom. Additional safety assessments included the Side Effects Rating form, completed during all treatments by the children’s regular community classroom teacher on Mondays, Wednesdays, and Fridays of each treatment week, daily by parents, and on each Saturday by the UCI-CDC classroom teacher. All adverse events occurring during the study were reviewed by the investigator to assess relationship to drug treatment (unrelated, unlikely, possibly, probably, almost certainly). In addition, each sign or symptom reported was graded on a three-point scale (mild, moderate, or severe) and the date and time of onset, time relationship to drug dosing, duration, and outcome were noted.
Clinical laboratory tests were performed at the UCI local laboratory at baseline and at the end of the trial, and included blood count with differential, biochemistry (Na, K, Ca, PO4, total protein, glucose, alkaline phosphatase, AST, ALT, total bilirubin, creatinine, albumin) and urinalysis (osmolality, pH, glucose, protein white blood cells and casts). Vital signs, including blood pressure, heart rate, and tympanic temperature, were measured at each visit to the UCI-CDC laboratory classroom.
PK Study in Healthy Adult Subjects
Twenty-two subjects (14 males and 8 females) enrolled in the study, but 4 withdrew after completing some but not all of the treatments. Reasons for withdrawal included violation of the caffeine and nonprescription medication restriction (n = 1), personal reasons (n = 1), failure to check-in (n = 1), and positive urine screen for amphetamines (n = 1). The weight, height, and age (mean ± standard deviation [SD]) of subjects completing all treatments (n = 18) were 69.8 ± 11.9 kg, 172.8 ± 8.9 cm, and 30.7 ± 9.7 years, respectively.
Each of the six MPH treatments resulted in a unique mean MPH plasma concentration versus time profile, with the single dose of Ritalin® and Ritalin® SR (20 mg qd) showing single input kinetics, and the bid dosing of Ritalin® and the three prototype formulations exhibiting dual input kinetics. In agreement with previous studies,27 both the qd and bid Ritalin® treatments produced a sharp initial rise in plasma concentrations culminating in a peak at approximately 1.5 to 2.0 hours, whereas the bid treatment produced a second peak at approximately 6.0 hours (or 2 h after administration of the second dose). The Ritalin® SR (20 mg qd) treatment produced a slower rise in plasma concentrations culminating in a single peak at approximately 3.0 hours, also consistent with previous reports.27,28 The comparative mean plasma concentration versus time profiles for MPH after a single oral dose of the 20:80, 30:70, and 40:60 prototype formulations (25 mg) or two oral doses of Ritalin® (10 mg at 0 and 4 h) are presented in Figure 1. The mean MPH plasma concentration versus time profiles for the prototype formulations consisted of sharp initial rises in plasma concentrations (as a result of the IR components in these formulations) similar to that of Ritalin®, culminating in an initial peak at approximately 1.5 hours (Cmax-1) followed by a second peak between 5 and 8 hours post-dose (Cmax-2). The relative magnitude of the first and second peaks differed among the prototype formulations: the formulation with the 30:70 ratio of IR to ER beads presented a mean profile with both peaks having similar maximal concentrations, whereas for the 40:60 formulation, the first peak, and for the 20:80 formulation, the second peak, reached higher plasma levels.
A summary of the mean MPH PK parameters of the six treatments is shown in Table 3. As observed from the MPH plasma concentration versus time profile, the Cmax corresponded with the first peak (Cmax-1) for the 40:60 formulation, but with the second peak (Cmax-2) for Ritalin® bid and for the 20:80 formulation. Because the maximal plasma values for the two peaks in the mean MPH plasma profile for the 30:70 formulation were so similar, the Cmax and Tmax calculated for this formulation by noncompartmental PK analysis fell in between the two individual peak values. As expected, Cmax-1 values, obtained directly from the mean MPH plasma concentration versus time profiles, were directly proportional to the amount of IR MPH in each formulation (r2 = 0.96).
Results of the ANOVAs of the least-squares means showed that the AUC(0-t) for the prototype formulations were comparable to that of Ritalin® (10 mg bid) despite different nominal concentrations of these products, with the exception of the 40:60 formulation which was significantly greater than that of Ritalin® bid (P ≤ .05). However, the AUCs(0-inf) for all three prototype formulations were greater than that of Ritalin® bid (P ≤ .05). Finally, the mean elimination rates for the prototype formulations were similar to one another, but longer than those for Ritalin® and Ritalin® SR (P ≤ .05).
All treatments were well tolerated. A total of 84 adverse events were reported; of these, 28 were considered “probably” or “almost certainly” related to the treatment and included feeling tired (n = 12), lightheadedness (n = 6), feeling relaxed (n = 2), difficulty concentrating (n = 2), sleepiness (n = 2), dizziness (n = 1), drowsiness (n = 1), and headache (n = 2). None of these adverse events were considered serious, and all were graded as mild. There was no evidence of any differences in the reported incidences or types of adverse events among the prototype formulations and Ritalin®. In general, the types of adverse events reported have been previously reported with MPH.29 There were no changes in physical examination findings in any subject between screening and the end of the study, and none of the treatments produced any detectable effect on vital signs.
PK/PD Study in Children
Twenty-seven subjects enrolled in the study; however, four withdrew before completing the trial. Reasons for study withdrawal included difficulty swallowing medication (n = 1), inability to tolerate placebo (n = 2), and withdrawal of consent (n = 1). The weight, height, and age (mean ± SD) of subjects who were assessed on the SKAMP in at least one UCI-CDC laboratory classroom session (n = 25) were 36.9 ± 7.6 kg, 142 ± 8.4 cm, and 10 ± 1.4 years, respectively. Of these subjects, 22 were Caucasian, 2 were black, and one was Asian; 21 were male and 4 were female.
The mean MPH plasma concentration versus time curves after administration of the prototype (30:70 and 40:60 ratio of IR:ER beads) formulations and Ritalin® (10 mg bid) to children with ADHD are shown in Figure 2, whereas a comparison of the PK parameters for each treatment is shown in Table 4. Both prototype formulations and Ritalin® produced a rapid increase in plasma concentration resulting in an early peak at approximately 1.5 hours post-dose. Thereafter, Ritalin® produced a trough at approximately 4 to 5 hours, a time when both the 30:70 and 40:60 formulations were producing a second peak. Results of the ANOVAs indicated that the two prototype formulations did not differ from one another with the exception of the 40-mg/day dose of the 40:60 prototype formulation which resulted in a morning maximal peak plasma (morning log Cmax) and exposure rate (Log AUC(0–9)) significantly greater than that of the corresponding dose of the 30:70 formulation. The greater morning log Cmax with the 40:60 formulation was not unexpected because this formulation delivers more drug in the morning than the 30:70 formulation. In addition, the time to peak concentration was slightly longer for the 30:70 formulation than for the 40:60 formulation in the 20-mg/day group, but not in the 40-mg/day group. As expected, at 40 mg/day, the morning and afternoon maximal peak plasma values as well as rate of exposure were statistically significantly greater than those of the 20-mg/day group of the corresponding formulation and also were significantly greater than those of Ritalin® (10 mg-, bid) (P <.05). Further PK comparisons between Ritalin® bid and the prototype formulations indicated that, at 20 mg/day, the morning and afternoon maximal peak plasma values and exposure rates (Log AUC(0–9)) of both prototype formulations were comparable to those of Ritalin® (10 mg bid). However, whereas there was no difference in the timing of the morning Tmax between Ritalin® and the prototype formulations, the afternoon Tmax occurred earlier for the prototype formulations than for Ritalin® (data not shown).
The UCI-CDC classroom teacher SKAMP overall mean (across all post-dose observation periods) Deportment and Attention ratings are shown in Figure 3. The mean decrease relative to placebo in Deportment ratings after the 30:70 or 40:60 prototype treatment ranged from 0.6 to 0.9, whereas that in Attention ratings ranged from 0.4 to 0.6. Results of the ANOVAs show that the overall Deportment score means of either prototype formulation, irrespective of dose, were statistically significantly different from placebo (P ≤ .05), but did not differ from Ritalin® (bid) treatment. Further analysis of the data by time post-dose showed that in the placebo group, mean ratings of Deportment and Attention increased (worsened) during the course of the day. Mean Deportment and Attention ratings for Ritalin® (bid) treatment decreased (improved) at the 1.5-hour observation and then increased (worsened) at the 3- and 4.5-hour observations, as the effects of the morning dose wore off; ratings again decreased (improved) at 6 hours, coinciding with increasing plasma MPH concentrations after the afternoon dose. For both prototype treatments at both doses, mean Deportment ratings decreased (improved) at the 1.5-hour post-dose observation and remained lower than placebo through the 7.5-hour observation period with an exception at 6 hours for the 20-mg/day dose of the 30:70 and 40:60 formulations and the 40-mg/day dose of the 40:60 formulation. Because the mean ratings for these three treatments were again decreased (improved) at the 7.5-hour observation period relative to placebo, it is likely that the results obtained at 6 hours are an artifact. More importantly, mean Deportment ratings for the 30:70 formulation (both dosages) were lower than placebo at 9 hours, whereas mean ratings of the 40:60 formulation (both dosages) were comparable to placebo at this time point. As was the case for Deportment ratings, the mean Attention ratings after the prototype treatments decreased (improved) at the 1.5-hour post-dose observation relative to baseline values and were lower than placebo from the 3-hour post-observation period through the 9-hour post-observation period with the exception of the 40-mg/day treatment with the 40:60 formulation which was similar to placebo at 9 hours.
Comparisons of overall mean scores on PERMP completed by the subjects while attending the UCI-CDC classroom (data not shown) indicated that both prototype formulations produced statistically significantly more Number Attempted and Number Correct scores than placebo (P ≤ .05) and, at the 40-mg/day dosage, statistically significantly more Number Attempted and Number Correct scores than the Ritalin® (bid) treatment (P ≤ .05). Further comparison of the prototype formulations to one another showed that there were no statistically significant differences between the two formulations in either the Number Attempted or Number Correct scores. In agreement with the UCI-CDC classroom teacher SKAMP Deportment and Attention ratings, analysis of the PERMP scores by time post-dose showed that mean performance for the placebo group decreased (worsened) during the course of the day. Likewise, mean performance for the Ritalin® (bid) treatment decreased (worsened) at midday as the effects of the morning dose wore off and again increased (improved) at 6 hours after administration of the afternoon dose. Mean performance for the prototype treatments, regardless of dosage, increased (improved) at the 1.5-hour observation relative to baseline and was higher (better) than placebo through the 9-hour observation period with the exception of the 20-mg/day treatment with the 40:60 formulation which was comparable to placebo at 6 and 9 hours.
Mean ratings by the regular community classroom teacher on the SKAMP and the CLAM were consistent with those of the UCI-CDC teacher ratings and PERMP. The mean scores for Ritalin® and the prototype treatments were generally comparable to one another and lower (better) than those of placebo. Results of the regular community classroom teacher Conners Global Index subscale are presented in Figure 4. Both prototype formulations were statistically significantly better than placebo (P <.05) but comparable to Ritalin®. Further comparison of the prototype formulations to one another showed that at the 20-mg/day dosage, the prototype formulations produced comparable Conners Global Index ratings to one another; however, at the 40-mg/day dosage, the 40:60 formulation produced lower (better) ratings than the 30:70 formulation (P = .03). Analysis of the regular community classroom teacher CLAM I/O, A/D, Mixed (I/O + A/D) subscale ratings and the SKAMP Deportment and Attention ratings revealed that, at 20 mg/day, both formulations had statistically significantly lower (better) scores than placebo on all measures (P <.05) except SKAMP Attention. In the 40-mg/day group, both prototype formulations had significantly lower (better) scores than placebo on the CLAM Mixed and SKAMP Attention and Deportment ratings; however, whereas the 30:70 formulation had lower mean scores than placebo on the CLAM I/O and A/D ratings, only the 40:60 formulation had statistically significantly lower (better) scores on these ratings (data not shown).
Finally, mean rating by the parents on the CLAM I/O, A/D, Mixed, and Conners Global Index subscales revealed treatment effects similar to those noted with the regular community classroom teachers and UCI-CDC teachers. Again, the mean scores for Ritalin® and the prototype formulations were generally comparable to one another and statistically significantly lower (better) than those of placebo (P <.05) with the exception of the 20-mg/day dosage of the 30:70 formulation which was comparable to placebo on all four subscales. The reason for this discrepancy is unclear but may be the result of the decreased standardization for measurement in the home setting.
Both the prototype formulations and Ritalin® were well tolerated. A total of 52 adverse events were reported in response to a general query about adverse events. Of these, 35 were considered “related,” “probably related,” or “possibly related” to the study treatment and included abdominal pain (n = 4; one event with the 40-mg dosage of the 40:60 formulation and three with placebo), fever (n = 1 with placebo), headache (n = 1 with placebo), ill feeling (n = 1 with placebo), stomach pain (n = 1 with placebo), trauma (n = 2; one each with placebo and Ritalin®), flushed skin (n = 1 with Ritalin®), anorexia (n = 6; two events each with Ritalin® and the 20-mg dosage of the 40:60 formulation, and one event each with the 20- and 40-mg dosage of the 30:70 formulation), diarrhea (n = 2; one each with placebo and Ritalin®), nausea (n = 2; one each with Ritalin® and the 20-mg dosage of the 30:70 formulation), nausea and vomiting (n = 1 with placebo), agitation (n = 2; one each with Ritalin® and the 40-mg dosage of the 40:60 formulation), depression (n = 1 with the 20-mg dosage of the 40:60 formulation), dizziness (n = 1 with placebo), emotional lability (n = 1 with Ritalin®), hyperactivity (n = 2; one each with placebo and the 20-mg dosage of the 30:70 formulation), insomnia (n = 2; one each with Ritalin® and the 40-mg dosage of the 30:70 formulation), mental concentration difficulty (n = 1 with placebo), muscle twitch (n = 1 with Ritalin®), sleeplessness (n = 1 with Ritalin®), and bladder incontinence (n = 1 with the 20-mg dosage of the 30:70 formulation). Of these adverse events, most were mild in intensity whereas six were judged moderate in intensity and included: fever, ill feeling, stomach pain, anorexia (treatment with the 20-mg dosage of the 40:60 formulation only), nausea (treatment with Ritalin® only), and depression.
Because the administration of the Side Effects Rating Form involved queries about specific adverse events, the frequency of adverse events reported in the parents’ and teachers’ Side Effect Rating Form was higher than that obtained from the reports elicited by general inquiry (data not shown). However, there were no consistent differences noted by dosage or formulation, and all adverse events reported are those previously reported with MPH.29 In contrast, the prevalence of adverse events recorded in the UCI-CDC teacher Side Effect Rating Form was lower than that of the parents and regular teachers with only 13 adverse events noted in the 20-mg/day group and 8 in the 40-mg/day group. With the exception of buccal-lingual movements, which occurred in two patients each treated with 20 mg of the 30:70 formulation and 40 mg of the 40:60 formulation, adverse events were recorded for only one subject per treatment, and no clear differences by either dosage or prototype formulation were noted.
Finally, there were no significant changes in clinical laboratory parameters noted. Any deviations from reference range were small and randomly distributed, and none of the formulations of MPH produced any detectable effects on vital signs.
The objective of the studies described here was to identify the optimal ratio of IR to ER MPH-coated beads in prototype formulations of Metadate® CD resulting in a once-daily MPH formulation which could be used in place of Ritalin® given bid. Comparison of three different prototype formulations, one containing a 20:80 ratio, one containing a 30:70 ratio, and one containing a 40:60 ratio of IR to ER beads, in healthy adult volunteers showed that all three exhibited biphasic plasma concentration characteristics similar to that following Ritalin® bid treatment, with a sharp initial slope culminating in a plasma peak at approximately 1.5 hours, followed by a second increase in MPH concentrations culminating in a delayed, second plasma peak at approximately 5 to 8 hours. The first peak reflected the amount of MPH contained in the IR portion of each formulation; however, despite there being the equivalent of 15 to 20 mg MPH in the form of ER MPH beads in the various formulations, the second peak for the prototype formulations did not reach as high a plasma concentration or as sharp a peak as the afternoon dose of Ritalin® (10 mg). This can be attributed to the delivery characteristics of the ER beads; in vitro dissolution experiments have shown that the ER beads begin to release MPH approximately 1 hour after placement in aqueous medium and continue to release MPH for 12 hours (unpublished data). Thus, the ER beads of the prototype formulations did not release MPH in a bolus-like fashion, but slowly released MPH over an extended time-period resulting in a wider, less prominent afternoon plasma peak.
Comparison of the PK parameters of the different treatments led to two interesting observations. First, the elimination half-lives obtained with the prototype formulations (6.3–7.2 h) were longer than those observed for Ritalin® or Ritalin® SR (2.8–3.3 h). This can be attributed to the continued absorption of MPH from the ER beads of the formulation over time, obfuscating the calculation of an accurate terminal elimination constant. Secondly, total exposure, as measured by AUC(0–t), was comparable between the 20:80 and 30:70 formulations and Ritalin® (bid) despite the prototype formulations having higher nominal doses than Ritalin® (bid), whereas exposure of the 40:60 formulation was greater than that of Ritalin® (bid). This is likely the result of presystemic de-esterification of MPH in the gastrointestinal (GI) tract, which limits its oral bioavailability.30 The net effect of presystemic de-esterification is expected to be greater with ER formulations, because these formulations release MPH over a longer timeframe than IR formulations thereby exposing a greater proportion of the MPH dose to the de-esterification enzymes. Because the 40:60 formulation released a relatively smaller proportion of its nominal dose in the form of ER MPH than the other two prototype formulations, its exposure was not affected as much, resulting in an AUC(0-t) consistent with its nominal dose and greater than that of Ritalin® (10 mg bid). The exposure rate for Ritalin® SR (20 mg), while also considered an ER formulation, was similar to that of Ritalin® (bid) in agreement with previous studies,27 and consistent with in vitro dissolution studies which showed that it releases MPH over a shorter timeframe than the ER MPH-coated beads of the prototype formulations (data not shown). However, it is important to note that the de-esterification enzymes have a preference for the levo isomer of MPH30 which is pharmacologically inactive.31,32 It follows that whereas MPH formulations with relatively larger proportions of slow-release MPH components can have decreased bioavailability relative to IR formulations of the same nominal dosage, the amount of the pharmacologically active enantiomer absorbed is probably similar. In this regard, Modi et al. showed that the ratio of d- to l-MPH after administration of Concerta® (an osmotic controlled ER formulation of MPH) to healthy volunteers was approximately 40:1,33 whereas previous studies using IR forms of MPH showed the ratio to be approximately 10:1.34
All three prototype formulations met the criteria outlined for a new controlled-delivery formulation of MPH, ie, all three formulations exhibited biphasic characteristics without the need for a midday dose and without producing an extended, flat plasma concentration profile. In addition, the initial slopes in the plasma concentration versus time profile for the prototype formulations were sharper than that of Ritalin® SR, and the Tmax for the early plasma peak for the prototype formulations were earlier than that of Ritalin® SR. However, whereas the 20:80 formulation met all the criteria outlined, the relatively low plasma levels achieved early in the MPH plasma concentration versus time profile were of concern. In addition, the shape of the plasma concentration versus time profile for the 20:80 formulation was reminiscent of the experimental “pure ascending” profile without a large morning bolus studied by Swanson et al.17 Swanson et al. investigated the time course of efficacy produced by two experimental patterns of MPH delivery compared with Ritalin® (10 mg bid) and placebo in children with ADHD. Their results showed that the experimental “pure ascending” profile was no better than placebo on measures of Attention and Deportment in the morning but comparable in efficacy to Ritalin® bid in the afternoon. Thus, because of the potential for lack of efficacy in the morning hours, the 20:80 prototype formulation was not considered for further development.
Analysis of MPH plasma levels in children after administration of the 30:70 and 40:60 prototype formulations revealed plasma concentration versus time profiles similar to the corresponding formulations in adults. Both formulations produced early sharp peaks, at approximately 1.5 hours, as did the Ritalin® bid treatment, suggesting a rapid initial uptake. Both formulations also showed a second peak at approximately 5 hours in children with ADHD, with the 30:70 formulation producing a more pronounced peak than the 40:60 formulation at a time when the Ritalin® bid treatment was at its lowest point on the plasma concentration versus time profile, before absorption of the midday dose. However, as expected, the absolute plasma concentrations of MPH resulting from a given dose were higher in children than adults, a difference traditionally attributed to differences in dose-weight ratio. Thus, these data are in agreement with observations that the PK profiles of MPH in adults and school-aged children are qualitatively similar and that there are no apparent age-related differences in absorption, distribution, metabolism, or excretion of MPH.31,35,36 It is important to note that PK analysis in the children’s study was done on the last day of each treatment week and that pre-dose plasma levels were negligible for either formulation at both dosages. In other words, steady-state levels of MPH were not achieved, nor are they desirable because dosing regimens that produce steady-state levels can produce tolerance to the effects of the drug and reduce its therapeutic effect.17 For this reason, the customary prescribed dosing regimen of IR MPH formulations is twice daily, at breakfast and at midday, not every 12 hours.
Primary efficacy measures, including the UCI-CDC laboratory classroom teacher SKAMP Deportment and Attention Ratings and the regular community classroom teacher Conners Global Index scores, showed that overall, both formulations given once in the morning were comparable in efficacy to Ritalin® (bid) but statistically significantly superior to placebo. Of note, Deportment ratings after the prototype formulations and Ritalin® (bid) treatment showed more improvement, compared with placebo, than the Attention ratings, in agreement with reports that effect sizes are generally larger for behavioral than for cognitive changes in response to stimulants.37,38 However, in contrast to previous reports,39–41 there was no apparent difference in the duration of treatment effect between these ratings. Although statistical analyses were not done for each individual time point for the UCI-CDC SKAMP ratings, mean scores for the 30:70 and 40:60 prototype formulations and Ritalin® were lower (ie, better) than placebo at 7.5 hours, and the 30:70 formulation and Ritalin® were lower than placebo at 9 hours in both Deportment and Attention ratings. More importantly, the prototype formulations did not show the prominent decrease in efficacy at the 3- and 4.5-hour post-dose observations seen with Ritalin® as the effects of the morning dose of Ritalin® wore off before the administration of the midday dose.
Results of the secondary efficacy measures were generally in agreement with the SKAMP Deportment and Attention ratings obtained in the UCI-CDC classroom. There were some inconsistencies in the regular community classroom teacher ratings and parent ratings that can be attributed to greater standardization for measurement in a laboratory school setting than in a community school setting or home setting (as a result of training factors, and so on). However, overall, efficacy measures performed by the subjects, teachers, and parents in “real-life” situations showed a therapeutic response to both formulations. Interestingly, the lower dosage of the prototype formulations, while producing better mean scores than placebo, were not statistically significantly different from placebo on the regular teacher SKAMP Attention rating, whereas they were statistically significantly different from placebo on the SKAMP Deportment ratings and all of the CLAM ratings, again consistent with the observation that effect sizes may be larger for behavioral than for cognitive changes.
Finally, both prototype formulations and Ritalin® were safe and well tolerated in both the PK study in adults and the PK/PD study in children. There were no serious adverse events reported during either of the studies or any unexpected adverse events. Overall the prevalence of adverse events associated with the prototype formulations did not differ from those of Ritalin® treatment and the types of adverse events were consistent with those previously reported for MPH.29
In summary, the results of the PK study in adults showed that the 30:70 and 40:60 prototype formulations had promising biphasic PK profiles. Further study of these formulations in children with ADHD showed that both formulations, given once in the morning, were superior to placebo and comparable to Ritalin® bid treatment on all primary efficacy measures. Finally, UCI-CDC classroom SKAMP Deportment and Attention ratings obtained at 1.5-hour intervals showed that both formulations produced therapeutic responses that persisted through the afternoon without the need for an additional dose and without a decrease in efficacy at midday. However, the 30:70 prototype formulation appeared to have a more consistent effect through the 9-hour post-dose observation period, and therefore was chosen as the optimal formulation to bring forth into commercial development.
Funding for this study was provided by Celltech Americas, Inc. Dr. Wigal’s time in preparing the manuscript was made possible by NIMH K23 grant MH2042. The authors thank Elizabeth J. Davidson and Dr. Roy J. Simmons for their efforts in initiating the publication of the manuscript and Dr. Peter Feig for his participation in the design of the study.
The clinical portion of the first study was conducted at Harris Laboratories, Inc. (Phoenix, AZ), whereas that of the second study was conducted at the University of California Child Development Center (Irvine, CA); the pharmacokinetic assays for the first and second study were conducted at MDS Harris (Lincoln, NE); and the statistical analysis was conducted by MDS Harris and Virtu Stat. Ltd. (North Wales, PA), respectively.
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Table 1. Summary of Inclusion and Exclusion Criteria Used in Subject Selection for the Adult Pharmacokinetic Study
Males and females between 18 and 50 years
– Voluntary consent to participate in the study
– Body weight not more than 10% above or below the ideal body (as listed in the Metropolitan Life Insurance Bulletin, 1983)
– No clinically significant abnormal findings on the physical examination, medical history, or clinical laboratory results during screening
– Female subjects using a medically acceptable form of birth control
– Voluntary consent to participate in the study
– Positive serum pregnancy test at screening
– History of clinically significant gastrointestinal tract, renal, hepatic, endocrine, oncologic, pulmonary, or cardiovascular disease; or a history of tuberculosis, epilepsy, diabetes, psychosis, glaucoma, or any other condition, which would jeopardize the safety of the subject or impact the validity of the study results
– History of allergic or adverse response to methylphenidate or any related drug
– Participation in a previous clinical trial within 30 days before study enrollment
– Plasma donation within 7 days before study enrollment
Blood donation of one pint or more within 30 days before study enrollment
Abnormal diet or substantial changes in eating habits within 30 days
– Treatment with any known enzyme-altering agents (barbiturates, phenothiazines, cimetidine, and so on) within 30 days before study enrollment
– Use of any prescription medication within 14 days before study enrollment (excluding hormonal contraceptive or hormonal replacement therapy)
– Use of any over-the-counter (OTC) medication within 7 days before study enrollment
– History of drug or alcohol abuse or addiction within the last 2 years
Table 2. Summary of Inclusion and Exclusion Criteria Used in Subject Selection for Children Pharmacokinetic/Pharmacodynamic Study
– Males or premenarchal females between the ages of 7 and 12 years
– Willing to provide consent either orally or by signing the consent form
– Parent willing to sign and date the consent form
– Diagnosed with ADHD by meeting one of the three DSM-IV criteria as specified in the Diagnostic Interview Schedule for Children (DISC) and/or the Swanson, Nolan, and Pelham (SNAP) tool
– Normal blood pressure, pulse rate, and temperature (tympanic)
– A positive response to MPH as judged by the Investigator through the screening assessment tools administered during the screening week
– Prior successful treatment of ADHD symptoms with a MPH product without any adverse events. MPH products restricted to 1) immediate-release MPH twice daily, the first daily dose required to be between 7.5 and 15 mg and the second daily dose required to be between 5 and 15 mg, yielding a total daily dose of between 12.5 and 30 mg, or 2) a sustained-release (SR) MPH product taken once daily, the single daily dose required to be 20 mg
– Participation in another drug study during the preceding 30 days
– A concurrent illness or condition with symptoms that could affect performance of any of the tests performed
– Individuals with a primary diagnosis of oppositional-defiant disorder or conduct disorder
– A family history of drug abuse
– Unable to follow instructions given in the study
– Individuals who were severely depressed, psychotic, anxious, tense, or agitated; or had seizures or a family history of Tourette’s syndrome
– Subjects taking a medication in addition to MPH for ADHD
– A documented allergy or intolerance to MPH
– Individuals who were diagnosed with hyperthyroidism, were lactose-intolerant, or had glaucoma
– Subjects unable to comply with blood drawing procedures during initial screening
– Use of any of the following medications: amphetamines, pemoline, tricyclic antidepressants, MAO inhibitors, serotonin reuptake inhibitors, neuroleptics, benzodiazepines, or benzodiazepine derivatives, clonidine, anticonvulsant medications, cough/cold preparations containing stimulants or sedatives
Table 3. Mean (± SD)* Plasma Methylphenidate Pharmacokinetic Parameters in Adults
20:80 30:70 40:60
Ritalin® Ritalin® Ritalin® SR Formulation Formulation Formulation
(10 mg, qd) (10 mg, bid)† (20 mg, qd) (25 mg, qd) (25 mg, qd) (25 mg, qd)
PK Parameter (N = 21) (N = 20) (N = 19) (N = 20) (N = 19) (N = 20)
Cmax (ng/mL) 4.82 (1.83) 6.38 (2.38) 5.53 (2.38) 3.66 (1.33) 3.94 (1.61) 5.19 (2.12)
Tmax (h) 1.9 (1.0) 5.2 (1.4) 3.2 (1.1) 6.9 (2.2) 4.1 (2.8) 2.0 (1.5)
AUC(0-t) (ng*h/mL) 22.5 (9.45) 43.8 (18.0) 44.7 (21.3) 43.5 (17.3) 44.1 (19.7) 49.0 (21.1)
AUC(0-inf) (ng*h/mL) 24.3 (9.62) 45.8 (18.2) 47.2 (22.0) 50.8 (22.0) 49.9 (22.7) 54.9 (25.5)
t1⁄2 2.90 (0.637) 2.93 (0.789) 3.41 (0.674) 7.20 (1.80) 6.80 (1.52) 6.33 (2.45)
Cmax-1 (ng/mL)‡ —§ 4.48 (1.94) —§ 2.33 (1.05) 3.43 (1.48) 4.88 (2.21)
Cmax-2 (ng/mL)‡ —§ 5.81 (2.15) —§ 3.49 (1.42) 3.40 (1.46) 3.68 (1.51)
*Mean = arithmetic means.
†Ritalin® (10 mg bid) was administered at 0 and 4 hours (20 mg total).
‡Obtained directly from the mean MPH plasma concentration versus time curves of each treatment.
Table 4. Comparison of Mean* Methylphenidate Pharmacokinetic Parameters in Children With ADHD
Pharmacokinetic 30:70 40:60
Parameter Formulation Formulation P value†
20 mg/day group
Log Cmax (morning) 2.11 2.21 .33
Rank Tmax (morning) 24.0 16.7 .05
Log Cmax (afternoon) 2.20 2.07 .15
Rank Tmax (afternoon) 23.3 16.0 .06
Log AUC(0–9) 4.11 4.05 .37
40 mg/day group
Log Cmax (morning) 2.75 3.02 .02
Rank Tmax (morning) 22.5 25.3 .49
Log Cmax (afternoon) 2.76 2.88 .24
Rank Tmax (afternoon) 24.7 23.6 .79
Log AUC(0-9) 4.71 4.88 .05
*Least-squares mean calculated from the regression analysis.
†Statistically significant difference defined as P <.05.
Figure 1. Mean methylphenidate plasma concentration over time after the administration of a single morning dose (25 mg) of 20:80 (open diamond), 30:70 (open triangle), or 40:60 (open box) IR:ER bead formulations or two doses (10 mg each at 0 and 4 h) of Ritalin® (dashed line) in healthy adult subjects.
Figure 2. Mean methylphenidate plasma concentrations over time after administration of a single morning dose (20 mg or 40 mg, respectively) of 30:70 (open triangle, black triangle) and 40:60 (open box, black box) IR:ER bead formulations or two doses (10 mg each at 0 and 4 h) of Ritalin® (dashed line) in children with ADHD.
Figure 3. UCI-CDC Teacher SKAMP Overall Mean Deportment and Attention Scores. Data represent least-squares means calculated from the regression analysis. Asterisks indicate differences between placebo and prototype formulations are significantly different (P ≤.05).
Figure 4. Regular community schoolteacher Conners Global Index Scores. Data represent least-squares means calculated from the regression analysis. Asterisks indicate differences between placebo and prototype formulations are significantly different (P ≤.05).
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