Sustained Release Methylphenidate:
`Pharmacokinetic Studies in ADDU Males
`
`BORIS BIRMAHER, M.D., LAURENCE L. GREENHILL, M.D., THOMAS B. COOPER, M.A.,
`JANE FRIED, M.D., AND BARBARA MAMINSKI, M.S.
`
`Abstract. Methylphenidate is widely used in the treatment of school-age children with attention deficit
`disorder with hyperactivity (ADDH).
`It is available in a short-acting (MPH) and a long-acting (MPH-SR)
`preparation. Nine males with ADDH participated in a l-day pharmacokinetic study following a single morning
`dose of 20 mg. MPH-SR. Data are presented on MPH-SR's half-life (T 1/2), peak concentrations achieved (Cmax)
`and the time to the peak plasma concentrations (T max). Similar data were gathered from a second group of eight
`ADDH males treated with a higher, single morning dose of standard, short-acting MPH. After adjusting for dose
`differences, comparisons of the two sets of plasma concentration curves suggest that MPH-SR has a longer T max,
`but that it does not reach the same Cm.. as an identical dose of standard MPH. J. Am. Acad. Child Adolesc.
`Psychiatry, 1989, 28, 5:768-772. Key Words: attention deficit disorder, methylphenidate, methylphenidate-SR,
`psychopharmacology.
`
`Attention deficit disorder with hyperactivity (ADDH) has
`a very high response to stimulant medication; controlled
`studies (Gittelman-Klein, 1975, 1987; Barkley, 1982) show
`up to 70% response rate to methylphenidate (MPH). Stimu(cid:173)
`lants act by decreasing motor hyperactivity and increasing on(cid:173)
`task attention (Werry et al., 1987; Douglas et al., 1988). Yet
`MPH administration has been troubled because its brief half(cid:173)
`life 00.3 hours (Gualtieri et al., 1981, 1982, 1984) necessitates
`twice per day dosing, once after breakfast and once during
`the school day. Children are often reluctant
`to take the
`medication in school, which results in poor compliance
`(Brown et al., 1985; Firestone, 1982). A slow release formu(cid:173)
`lation (sustained-release Ritalin") (MPH-SR) has been made
`available for a once per day morning dose (The Medical
`Letter, 1984, 1988).
`Controlled studies of MPH-SR (Whitehouse et al., 1980;
`Pelham et al., 1987; Greenhill et al., 1987) have shown short(cid:173)
`term efficacy for the drug. Whitehouse et al. (1980) reported
`that MPH and MPH-SR were equally effective. Thirty chil(cid:173)
`dren diagnosed as having "minimal brain dysfunction" were
`treated in a double-blind study that compared a single morn(cid:173)
`ing dose of MPH-SR with two doses of MPH-SA 10 mg. This
`study lacked dose-ranging and had no placebo group. Pelham
`
`Accepted March 9. 1989.
`Dr. Birmaher is Assistant Professor ofPsychiatry. Western Psychi(cid:173)
`atric Institute and Clinic. Pittsburgh. Dr. Greenhill is Associate Pro(cid:173)
`fessor of Clinical Psychiatry. Mr. Cooper is Director of the Psycho(cid:173)
`pharmacological Laboratories. Dr. Fried is Research Pediatrician.
`and Ms. Maminski
`is Research Scientist at
`the New York State
`Psychiatric Institute. New York.
`This work was supported in part by BRSG Grant No. 903-E7563
`and by NIMH Center Grant MH-3096. Special thanks must be given
`to two friends and colleagues. who helped greatly with the preparation
`of this manuscript: James Perel, Ph.D.. Professor of Psychiatry and
`Pharmacology. University ofPittsburgh; and Edward Jackson, M.D ..
`Professor ofPharmacology and Medicine. University ofCalifornia at
`San Diego.
`Request reprints from Dr. Greenhill. 722 West 168th Street. New
`York. NY /0032.
`0890-8567/89/250 1-0768$02.00/0© 1989 by the American Acad(cid:173)
`emy of Child and Adolescent Psychiatry.
`
`768
`
`et al. (1987), using a double-blind, placebo controlled design
`to study 13 boys in a summer program, reported that both
`drugs showed equal efficacy on the Abbreviated Conners
`Rating Scale but that MPH-SR had onset of action I hour
`later than MPH. They also found that the effects of MPH-SR
`were still evident 8 hours after ingestion, and its peak of action
`measured by a continuous performance task was I hour later
`than that seen with MPH. A panel of 11 experts reviewed
`"blinded" clinical records and found that MPH was a more
`effective treatment agent than was MPH-SR.
`One longer-term study has questioned the efficacy of single
`morning administration of MPH-SR over time. Fried et al.
`(1987) administered MPH-SR to 40 ADDH boys, aged 7 to
`12 years and followed them for 6 months. Forty-five percent
`of the boys dropped out of the study, and those who remained
`in required an increase in MPH-SR dose or required addi(cid:173)
`tional doses of standard MPH. The reason for this lack of
`efficacy is not clear, because MPH-SR employs the same
`active methyphenidate that has been found to be clinically
`effective at the 20 mg. per day dose in over 22 controlled
`studies (Barkley, (982). Possible explanations of MPH-SR's
`relative inefficacy include problems in absorption in the gas(cid:173)
`trointestinal track from its wax-matrix resin vehicle, delayed
`absorption, pharmacokinetic differences or differences at the
`brain receptor level (pharmacodynamic differences) or tach(cid:173)
`yphylaxis (Jackson, pers. commun.). Only one report dis(cid:173)
`cussed the excretion of urinary ritalinic acid, MPH's major
`metabolite, after administration of MPH-SR to children
`(FDA, (982). MPH-SR was found to be absorbed more slowly
`but as completely as standard MPH. Ritalinic acid's time to
`peak concentration (Tmax) was slower than the standard prep(cid:173)
`aration, and is listed at 4.7 hrs (1.3 to 8.2 hours). Ritalinic
`acid does not cross the blood-brain barrier and is not psy(cid:173)
`choactive. Its concentration, either in blood or urine, does
`not correlate well with concentrations of the active parent
`compound, MPH. No studies have yet reported MPH-SR
`plasma concentrations following oral administration to hu(cid:173)
`man subjects.
`MPH-SR concentrations in plasma following administra(cid:173)
`tion to ADDH children could clarify the bioavailability issue.
`The authors measured plasma levels of MPH-SR in ADDH
`
`MYLAN EX 1039 Page 1
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`

`

`SUSTAINED RELEASE METHYLPHENIDATE
`
`769
`
`between pharmacokinetic parameters derived by either
`model. Parsimony dictates using the model with the least
`number of compartments. Other data were analyzed using
`BMDP (Dixon, 1985).
`Scores of the Purdue peg board, activity monitor, and
`steadiness test were correlated with plasma and saliva levels.
`The data from this study suggest that methylphenidate
`plasma levels can be collected from ADDH boys with little
`difficulty. Cooperation with the procedure may have been
`greatly enhanced for some children by the volunteer's fee.
`However, two other children declined the study because of
`fear of needles, despite any possible monetary inducement.
`An earlier report (Greenhill et al., 1983) described a meth(cid:173)
`ylphenidate pharmacokinetic study of standard MPH using
`identical plasma collection techniques and pharmacokinetic
`modeling. The six ADDH males were younger (mean age
`8.59 ± 1.3 years, range 6.58 to 10.38 years), and they had
`been given a higher single morning dose of standard MPH
`(mean loading dose, 0.89 ± 0.14 mg/kg, range 0.64 to 1.0I
`mg/kg), After adjusting for dose, these data may be cautiously
`used for contrast purposes.
`
`Results
`All subjects tolerated the MPH-SR medication without
`reported side effects. Peak plasma levels of the parent com(cid:173)
`pound, MPH, ranged between 4.08 and 17.49 ng/rnl, with a
`mean maximum plasma concentration (Crn ax ) of 8.54 ± 2.84
`ng/rnl . Correlations between the peak plasma level and the
`dose-by-weight (r = 0.8765, p < 0.01) were significant. Time
`of peak plasma level (Trna»
`ranged between 1.85 and 4.90
`hours, with a mean time to peak of 3.36 ± 1.08 hours. Plasma
`half-life (T IJ2 B) ranged between 2.20 and 6.26 hours, with
`a mean of 4.12 ± 1.52 hours. Plasma levels were easily
`detectable at 7 hours after the single dose of 20 mg and
`averaged 7.22 ± 3.82 ng/ml in plasma.
`The area-under-the-curve (AVC) for the nine boys on
`MPH-SR (73.81 ± 36.63) correlated with the dose-by-weight
`of the medication taken, r = 0.8040, p < 0.01. Measurements
`of half-life and AVC for MPH-SR are shown in Table 1.
`Beta or metabolic phase demonstrated by the curves in
`these eight subjects closely matches the monoexponential
`decay curve that might be predicted from a standard single(cid:173)
`release tablet. This can be shown most clearly for a single
`
`males. The study focused on whether MPH-SR (given once
`daily) produces very low methylphenidate plasma concentra(cid:173)
`tions or shows delayed absorption and a delayed peak when
`compared to data previously collected on plasma levels of
`standard MPH (Greenhill et al., 1983).
`
`Method
`Thirteen males, aged 8 to 14, were selected for the phar(cid:173)
`macokinetic study. They met DSM-llI (APA, 1980) criteria
`for the diagnosis of ADDH and scored at least 1.8 out of a
`possible 3 points on Factor IV (hyperactivity factor) of the
`Conners teacher questionnaire (Goyette et al., 1978; Connors,
`1985). All boys had been responders to standard MPH, which
`was defined as a 25% drop in the Factor IV CTQ score; eight
`had been treated previously with MPH-SR. Consents were
`obtained from both parent and child concerned, and an
`Institutional-Review-Board-approved volunteer's fee was paid
`to the family, after the day-long study was fully completed.
`All the children were drug-free and refrained from eating
`or drinking caffeinated beverages 12 hours before the study.
`A vein catheter was placed in the non-dominant arm, and a
`slow infusion of 5% Dextrose in water was maintained. In
`three children, the arm vein catheter did not work and had
`to be removed in order to prevent infiltration. Another child's
`data was not used because the saliva data indicated that he
`had chewed up the MPH-SR tablet, and it acted quickly, like
`standard methylphenidate. This left nine children, whose
`mean age was 11.398 ± 1.85 years (range 8.08 to 13.4 years),
`and who had a mean Hollingshead (1957) socioeconomic
`status of 4.11 ± 1.27.
`The children received 20 mg of MPH-SR (0.44 ± 0.20 mgJ
`kg, range 0.2 to 0.83 mg/kg) in a single morning dose at 8:30
`AM. Standard, short-acting methylphenidate was not used in
`this study. Therefore, both plasma and saliva MPH levels
`were collected at hourly intervals for 8 hours. The children
`were given hourly tests of motor steadiness (Gardner steadi(cid:173)
`ness test, see Gardner et al., 1979), hand-eye coordination
`(Purdue form board), and activity levels (measured using an
`actometer).
`Plasma and saliva MPH levels were assayed using standard
`methods described elsewhere (Danhof and Breimer, 1978;
`Mucklowet al., 1978, 1982; Hungund et al., 1979; Greenhill
`et al., 1987). The coefficient of variation for this method is
`8% for interassay and 5% for intra-assay. The mean plasma
`concentration of MPH at each collection time, the l-hour
`measure most often associated with the peak, the slope of the
`absorption phase, and area under-the-curve were included in
`the pharmacokinetic analysis. The raw data were subjected to
`iterative exponential stripping procedure (Bergner et al.,
`1973). The parameters derived from above were used as
`starting values for estimation of pharmacokinetic parameters
`using nonlin analysis (NONLlN, 1984) with assumption of a
`one-compartment open model. Although the pharmacoki(cid:173)
`netics of MPH have been adequately described in the rat in a
`two-compartment open model (Gal et al., 1977), the use of a
`one-compartment equation for human data has been shown
`to introduce negligible (l % to 3%) errors in drug clearance
`calculations (Hungund et al., 1979). Test with an F·test
`(Boxenbaum et aI, 1974) showed essentially no difference
`
`TABLE I. Pharmacokinetic Data on MPH-SR Plasma Levels
`C....
`T 'h.
`AVe•.f
`ng/rnl/hr
`(hr)
`(ng/rnl)
`4.90
`74.50
`4.10
`46.27
`3.09
`163.40
`4.72
`56.53
`2.69
`72.80
`6.26
`84.70
`2.20
`68.10
`2.87
`37.47
`6.26
`60.54
`4.12
`73.81
`1.52
`36.63
`
`T ....
`(hr)
`
`2.19
`3.54
`4.23
`4.06
`3.54
`1.85
`4.90
`3.87
`2.04
`3.36
`1.08
`
`8.03
`5.87
`17.49
`6.85
`8.55
`8.53
`10.70
`4.08
`6.77
`8.54
`3.48
`
`Patient
`No .
`7
`21
`27
`33
`42
`43
`63
`73
`74
`Mean
`SO
`
`Dose
`(mg/kg)
`0.32
`0.38
`0.83
`0.35
`0.36
`0.55
`0.62
`0.31
`0.20
`0.44
`0.20
`
`MYLAN EX 1039 Page 2
`
`

`

`770
`
`BIRMAHER ET AL.
`
`I
`1
`+-+
`
`. /
`+
`
`/
`
`./'6
`
`6
`
`~ -6. " PH-SR
`
`. - •
`
`.,P H-SA
`
`1
`+..........+
`1
`"""
`I
`""" ,
`+-+
`6 -6
`"<,
`1
`' --6-
`6 ..........
`I ' Li'-~
`
`20
`
`15
`
`10
`
`5
`
`E<,
`'".5-
`0q
`~
`
`~c0u
`
`Ia.
`:>
`
`o +----+--+--+----+--+---+------;c--_+_~
`o
`60
`120
`180
`240 30 0 360 420
`48 0 54 0
`
`TIME ( Minutes) After Sing le Oro I Dose
`
`FIG. 2. Plasma MPH concentrations after either 20 mg MPH·SR
`(N = 9) or 25 mg MPH-SA (N = 6).
`
`for MPH-SR (24.1 ng versus 8.8 ng, pooled t test = 4.04, P <
`0.0014). The Cm • • correlates with dose across these two sam(cid:173)
`ples (r = 0.8280, p < 0.005), indicating that differences in
`peak concentration are related more to the large differences
`in dose than to type of preparation. The time to peak, T maa ,
`was significantly longer for MPH-SR (3.36 ± 1.08 hours) than
`that for the standard, short-acting preparation (1.625 ± 0.77
`hours, t = 3.43, p < 0.0045). Half-life, on the other hand,
`showed little difference between the two MPH preparations
`(standard MPH, 3.33 ± 0.65 hours; MPH-SR, 4.12 ± 1.52
`hours; pooled t = 1.2, P < 0.2514).
`As with the current MPH·SR sample, the standard MPH
`group also demonstrated a significant negative correlation
`between plasma levels and drop in Gardner Steadiness Test
`error rate (r = 0.91, P < 0.000 I) during the absorption phase.
`MPH peaked significantly sooner in the standard MPH(cid:173)
`treated group (1.7 hours versus 2.6 hours, pooled t test = 3.6,
`P < 0.0026).
`Dosage effects on comparisons between these two groups
`were adjusted for by calculating the area under the curve per
`milligram (AVC/mg/kg). Using this approach, the group on
`standard MPH (mean AVC/dose = 128.51 ± 43.19) showed
`a lower dose-adjusted AVC from the mean of the group on
`MPH-SR (AVC/dose = 177.87 ± 62.91). These differences
`did not reach significance, however, when tested by either t
`test (Pooled t = 1.67, P < 0.1197) or non parametric statistics
`(Kruskal-Wallis = 2.72, p < 0.0990; Mann Whitney = 13, P
`< 0.0990).
`
`Discussion
`This study is a preliminary descriptive report on a fixed(cid:173)
`dose pharmacokinetic study ofMPH-SR in boys with ADDH.
`A single, acute loading dose was given and plasma concentra(cid:173)
`tions were followed for 8 hours. Observations were limited to
`tests of motor steadiness and Purdue Peg board performance,
`and motor counts using simple summation-type mechanical
`activity counters. The results suggest that MPH-SR is indeed
`slow in release, reaching a peak in twice the period of time
`reported in several other studies (Gualtieri et al., 1982; Green(cid:173)
`hill et al., 1983; Pelham et al., 1987) of ADDH boys given a
`single, oral dose of standard MPH.
`There are many limitations inherent in this study. Ideally,
`the boys in this study should have been their own controls.
`
`subject, which is demonstrated in Figure I. The figure is a
`computer-generated graph using NON LIN to curve-fit the
`data from Subject 7. The smoothness ofthe slope of the decay
`phase seen here does not support the general notion of a
`multiple-release vehicle, which should continue to show a
`curve made up of many peaks. In addition, the bioavailability
`during the eight hours of testing was lower for the MPH-SR
`than for the standard MPH.
`MPH saliva levels after ingestion of the standard-release
`MPH tablet followed a course similar to that of the plasma
`levels. One child chewed the SR tablet slightly, giving a falsely
`high saliva level (3485.30 ng), so his saliva and plasma data
`had to be excluded. This subject's plasma levels were the
`highest levels reached (19.6 ng/rnl). This subject's peak was
`reached at 2.87 hours, suggesting that more MPH may have
`been released earlier with the other subjects. One must be
`careful about subject's chewing their medications in studies
`like this one, and thus saliva level measurements have proven
`helpful (Roose and Licamele, 1984). The remaining 9 males
`reached MPH peak concentrations in saliva that ranged be(cid:173)
`tween 10 ng/ml to 78.80 ng/mI. The plasma and saliva MPH
`level measures did not correlate (r = 0.22, p < 0.44). Although
`one cannot predict plasma levels from saliva MPH measure(cid:173)
`ment, the saliva method has promise as a compliance check.
`The drop in motor steadiness error rates (time out of 180
`seconds making errors on the Gardner Steadiness Test) and
`change in gross motor activity levels measured by the acto(cid:173)
`meter (ACfDIF) showed the greatest changes within the first
`3 hours after taking MPH-SR. Maximum change in activity
`levels over the first 3 hours (baseline mean count = 2690.88
`± 2013.48; 3-hour mean count = 2840.11 ± 2105.11) corre(cid:173)
`lated with change in MPH plasma concentrations during the
`same period (r = 0.6841, P < 0.0 I). Baseline steadiness errors
`(touch-time) for the MPH-SR group averaged 29.78 ± 9.72,
`and fell to 20.33 ± 11.77 by 180 minutes; the correlation
`between the drop in error rate and rise in plasma levels during
`absorption was significant (r = 0.414, P < 0.44). The Purdue
`Form board showed no significant correlation with MPH-SR
`levels.
`The other group on standard MPH showed higher plasma
`levels, probably caused by the difference in dosage (see Fig.
`2). As a result, the standard short-acting MPH's peak plasma
`levels (Cm ..) were significantly higher than those reported here
`
`8
`
`7
`
`6
`
`5
`
`4
`
`•
`
`EC
`
`i>
`5.
`Gi
`
`~.
`
`.
`
`5..
`
`0:
`
`o
`
`3+---~-~-~-~-~-~-~~
`2
`3
`4
`5
`6
`7
`8
`Time (hours)
`
`FIG. I. Plasma level meth ylphenidate: Patient 7 nonlin fit.
`
`MYLAN EX 1039 Page 3
`
`

`

`SUSTAINED RELEASE METHYLPHENIDATE
`
`771
`
`Instead of a contrast group, with different ages and on differ(cid:173)
`ent doses, the same boys would have been the best group to
`also be given identical doses of standard MPH. The standard
`MPH could have been given in the normal
`twice-per-day
`dosing pattern, morning and noon, rather than one large
`loading dose, as with the contrast group. Also, no control
`periods or groups are available to help interpret the perform(cid:173)
`ance measures. The ADDH males were not followed over
`time on MPH-SR, so these data cannot truly be used to study
`the decrease in efficacy of MPH-SR over time reported by
`Fried et al. (1987). The authors also had no measure of gastric
`emptying time, which could greatly affect absorption. The
`correlations between the peak MPH-SR plasma levels and
`maximum change on the Gardner Steadiness Test were found
`only for the first 3 hours. The lack of correlation between
`activity measures and plasma levels may have been due to
`the very high variability in these measures for a very small
`sample of subjects.
`This descriptive report agrees with published work on
`MPH-SR (Pelham et aI., 1987), which indicates that sus(cid:173)
`tained-release vehicle produces a delayed plasma peak MPH
`concentration. This may have implications for the clinical
`efficacy of MPH. Earlier work suggests that stimulants exert
`their major attention-enhancing action during absorption
`(Brown et aI., 1980; Greenhill et aI., 1983). It is not clear,
`however, whether the rate of absorption or simply the peak
`plasma (or brain) concentrations alone accounts for MPH's
`efficacy in a given child. This might be interpreted as a
`"threshold" model (peak reached) or "ramp effect" model
`(rate of absorption driven kinetics) of drug action.
`However, preliminary descriptive comments can be made
`about MPH-SR pharmacokinetics. The flattened curve of
`MPH plasma concentrations after MPH-SR ingestion (Fig. 2)
`resembles that seen with long-acting dextroamphetamine sul(cid:173)
`fate by Brown et al. (1980). This prolonged, stable level raises
`a question about whether MPH-SR may be more prone to
`tachyphylaxis, similar to that seen using a sympathomimetics
`with longer half-lives than standard MPH, such as the am(cid:173)
`phetamines (Nedergaard et aI., 1988) or inhaled beta adrener(cid:173)
`gic agonists (Pauwels, 1988).
`
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`
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