Bioavailability of modified-release methylphenidate: influence of high-fat breakfast when...

Received 15 November 2002Revised 15 February 2003

Copyright # 2003 John Wiley & Sons, Ltd. Accepted 28 February 2003

BIOPHARMACEUTICS & DRUG DISPOSITIONBiopharm. Drug Dispos. 24: 233–243 (2003)

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/bdd.358

Bioavailability of Modified-release Methylphenidate:Influence of High-fat Breakfast when Administered Intactand when Capsule Content Sprinkled on Applesauce

Lucy Leea,*, Joanne Kepplea, Yibin Wanga, Stephen Freestoneb, Ray Bakhtiarc,Yanfeng Wanga and Mohammad Hossaind

aNovartis Pharmaceuticals, East Hanover, NJ, USAb Inversek Research, Edinburgh, UKcMerck Research Laboratories, Rahway, NJ, USAdGlaxo SmithKline, King of Prussia, PA, USA

ABSTRACT: Ritalin1, an immediate release form of racemic methylphenidate hydrochloride, hasbeen available in the USA since 1955 and is used for the treatment of ADHD. The objective of thisstudy was to evaluate the pharmacokinetics of modified-release methylphenidate (highest singledose), Ritalin1 LA, when administered under fasting condition, with a high-fat breakfast, andwhen sprinkled on applesauce in healthy adult subjects. Blood samples were drawn for 24 hfollowing a 40mg oral administration. Most subjects appeared to produce a bimodalmethylphenidate plasma concentration profile. In all three treatment groups, methylphenidatewas rapidly absorbed with an initial average tmax(0–4) of 1.3–2.4 h and an average peak plasmaconcentration [Cmax(abs)] of 14.4–15.2 ng/ml. On average, both the rate [Cmax(abs) and tmax(abs)] andthe extent of absorption (AUC0–1) of methylphenidate were similar when the capsule was givenwith a high fat breakfast and when the capsule contents were sprinkled onto applesauce, comparedwith the fasting state. No dose dumping was observed when the capsule was given with a high fatbreakfast or when sprinkled onto applesauce. The dose was safe and generally well tolerated.Coadministration of a single oral dose of 40mg methylphenidate capsule whether administeredintact with a high-fat breakfast or sprinkled on applesauce did not affect the overall rate or extent ofabsorption of methylphenidate compared with the fasted condition. Copyright # 2003 John Wiley& Sons, Ltd.

Key words: Ritalin; food effect; bioavailability; methylphenidate; modified-release

Introduction

Attention-deficit hyperactivity disorder (ADHD)is a recognized medical problem characterizedby symptoms of inattention, hyperactivity andimpulsivity. Ritalin1, an immediate release (IR)

form of racemic methylphenidate hydrochloride(MPH), has been available in the USA since1955 and is used for the treatment of ADHD.A drawback of the current market form ofRitalin1 arises from its short half-life of 2–3 hwhich necessitates a dosing regimen of at leasttwice daily to ensure adequate treatment effectthroughout the day. For school-age childrenwho must take the drug, this can represent anadditional burden on school staff. Further,some schools have policies forbidding suchmedicine to be administered by school staff,

*Correspondence to: Translational Medicine, Oncology BusinessUnit, One Health Plaza, Bldg 105 2W078F, Novartis Pharmaceu-tical, East Hanover, NJ 07936, USA.E-mail: [email protected]

leaving the children to manage their ownmid-day dose. This scenario encourages non-compliance and therapeutic failure. The socialstigma associated with taking this medicationat a young age can also have a powerfulpsychological impact that can lead to lapses incompliance [1].

Previously, to eliminate the problems asso-ciated with a mid-day dose, sustained releaseformulations of MPH (Ritalin SR1, marketedby Novartis) and dextroamphetamine (DexedrinSpansules) were developed and are available insome countries for the treatment of ADHD.However, concerns relating to a delayed onsetof action compared with the immediate releaseformulations have prevented health care provi-ders from embracing these formulations [1].Recent studies have also indicated that sustainedplasma levels of MPH may not be associatedwith maintenance of efficacy [2–6]. As a result ofthese findings, it is suspected that maintainingefficacy throughout the day may likely beassociated with the two peak concentra-tion produced by the twice daily dosing ofMPH IR rather than a sustained plasma concen-tration produced by the once daily dosing ofMPH SR.

In an attempt to address this drug deliveryissue, Ritalin1 LA, an alternative once dailymodified-release formulation of MPH was devel-oped using the spheroidal oral drug absorptionsystem (SODAS1). SODAS is a registered trade-mark of Elan Corporation. Instead of providingthe traditional zero-order controlled-release ofMPH, Ritalin1 LA provides a bimodal releaseof methylphenidate characterized by a quickinitial release followed by a second, later release.This release profile mimics the pharmacokineticeffects of two doses of Ritalin1 administered4 h apart, and is thus more likely to producethe two peak concentration that is asso-ciated with the pharmacodynamic effects. Thelarger clinical studies have indeed confirmedthe efficacy and safety of Ritalin1 LA in thetreatment of ADHD when compared with place-bo. As a result, the unique release profileproduced by Ritalin1 LA provides a rapidonset with a longer lasting effect after only asingle dose, alleviating the need for a mid-daydose.

Modified-release dosage forms are primarilydeveloped to reduce the dosing frequency andimprove compliance for chronically administereddrugs. In the case of sustained-release formula-tions, their use also decreases maximum drugconcentrations for medications with concentra-tion-related side effects. However, such dosageforms are at risk of pharmacokinetic interac-tions which affects the absorption process espe-cially in the case of concomitant food intake.Such food effects are often not predictable fromthe in vitro characteristics of the dosage form,although several investigations have demon-strated a high probability of food interactionsin formulations with pH-dependent releaseproperties [7].

It was shown in a previous study that thebioavailability of methylphenidate is not affec-ted by the presence or absence of food [8].However, as a newly formulated modified-release product, investigating the effect of foodon drug absorption is of particular importancein order to assure consistent drug delivery. Foodcan induce numerous changes in the gastroin-testinal physiology including delayed gastricemptying, stimulation of bile flow, changesin pH, and splanchnic blood flow [9]. Any ofthese physiological changes may lead to anincreased or decreased methylphenidate expo-sure (AUC), and thus alter the toxicity orefficacy profile. For this reason, it is importantto study the effect of a high-fat breakfast onthe pharmacokinetics of Ritalin1 LA. The feasi-bility of opening the capsule and having itscontent sprinkled onto applesauce was alsostudied for children as young as 6 years oldwho have trouble swallowing intact capsules.Applesauce was chosen as the semi-solid foodof choice for this study because: (1) it is acceptedby FDA for studying sprinkleability of a for-mulation (e.g. Carbatrol1, registered trademarkof Shire US Inc.) and (2) applesauce is fat-free(�79 Kcal per 213 g (�1 cup serving)). Currently,the use of methylphenidate is approved fordoses up to 60mg per day, and the highestsingle dose of 40mg was studied. This dose isconsistent with the FDA guidelines on foodeffect studies, which recommends that studiesof this nature be carried out using the highestanticipated dose [10].

Copyright # 2003 John Wiley & Sons, Ltd. Biopharm. Drug Dispos. 24: 233–243 (2003)

L. LEE ET AL.234

Methods

Drug products

Ritalin1 LA modified release capsules are pro-duced using a dual bead fill system to allow forthe bimodal drug release profile. The dual beadfill system is composed of two types of beads onopposite ends of the capsules: immediate release(IR) beads and delayed release (DR) beads. TheIR beads were prepared by dissolving the drugsubstance and polyethylene glycol 6000 in pur-ified water, and subsequently coated onto sugarspheres. The DR beads were prepared using thesame methodology, and in addition were coatedwith an Eudragit RS/L suspension to allow for atime controlled release (i.e. 4 h post dosing). Thecapsules consist of 1:1 drug ratio of IR/DR beadsproviding three strengths of Ritalin1 LA cap-sules: 20mg (10mg/10mg), 30mg (15mg/15mg), and 40mg (20mg/20mg). As previouslymentioned, the highest strength of 40mg Rita-lin1 LA was used.

Analytical methods

Plasma samples were assayed using a high-performance liquid chromatography-tandemmass spectrometry (LC-MS/MS) that was devel-oped and validated for the quantification ofracemic methylphenidate in human plasma.Methylphenidate and its internal standard wereextracted from plasma by liquid–liquid extrac-tion (LLE) [11]. The method is suitable for theroutine analysis of racemic methylphenidate inhuman plasma with a validated limit of quantita-tion of 0.05 ng/ml using a sample volume of400 ml. Calibration was performed within therange of 50 pg/ml–100 ng/ml and correlationcoefficients were � 0.998. Mean accuracy ofcalibrator (standard) samples for 0.050 ng/ml–100 ng/ml were 96.5%–103%, and CVs 1.50%–9.52%. The intra- and inter-day accuracy andprecision values for the QC samples at LLOQ orabove are summarized below.

At LLOQ: intra-day accuracy within the rangeof 82.6%–100%, intra-day precision within therange of 5.29%–9.08%. Above LLOQ: intra-dayaccuracy within the range of 88.9%–105%, intra-day precision within the range of 0.797%–5.00%.At LLOQ: inter-day accuracy 93.2%, inter-day

precision 10.6%. Above LLOQ: inter-day accu-racy within the range of 95.5%–102%, inter-dayprecision within the range of 3.79%–7.46%.Stability studies at room temperature are re-ported in the previous enantiomeric method [12].

Clinical study

This study was performed in accordance withstandard operating procedures of the sponsor(formerly Sandoz/formerly Ciba/Novartis), op-erating at the time of the study. These weredesigned to ensure adherence to GCP and toensure the protection of the subjects, as requiredby the following directives in operation at thetime:

1. Declaration of Helsinki, concerning medicalresearch in humans (‘RecommendationsGuiding Physicians in Biomedical ResearchInvolving Human Patients’, Helsinki 1964,amended Tokyo 1975, Venice 1983, HongKong 1989, Somerset West, 1996).

2. Directive 91/507/EEC: The Rules GoverningMedicinal Products in the European Com-munity.

3. US 21 Code of Federal Regulations dealingwith clinical studies, parts 50 and 56,concerning Informed Patient Consent andIRB approval.

This study used an open label, single dose,three treatment, six sequence, three-period, ran-domized crossover design with 20 healthy adultsubjects. The three treatments were: 40mgRitalin1 LA with high fat breakfast (A), 40mgRitalin1 LA sprinkled onto applesauce (B), and40mg Ritalin1 LA under fasting condition (C).The six sequences were: ABC, BCA, CAB, ACB,BAC and CBA, with a 7 day interdose interval.Qualified healthy adult subjects reported to thestudy site at least 10 h prior to dosing for baselineevaluation. After an overnight fast, subjectswere randomized to one of the six treatmentsequences. For each treatment period, pharma-cokinetic (PK) samples were drawn 24 h postdose and safety evaluations were performed atspecified times. End of study evaluations weretaken after the final PK sample and prior todischarge from the study site in the final period.


FOOD EFFECT ON MODIFIED-RELEASE METHYLPHENIDATE 235

Subjects were confined to the study centre forat least 12 h before administration of and until24 h post dose for PK sampling. No strenuousphysical exercise (e.g. weight training, aerobics,football) was allowed for 7 days before dosingand until after the study completion evaluation.No alcohol was allowed for 72 h before dosingand until after the study completion evaluation.Intake of xanthine (e.g. caffeine) containing foodor beverages was discontinued 48 h before dosingand during each treatment period.

For the fasted treatment group, a single 40mgdose was administered between 07:30 and 09:00,after a 10 h fast. For the high-fat breakfasttreatment group, a single 40mg dose wasadministered by the study centre personnelbetween 07:30 and 09:00 immediately (within5min) after breakfast. The high-fat breakfastconsisted of 2 eggs fried in butter, 4 oz hashbrown potatoes, 2 slices of (white) toast withbutter, 2 strips of bacon and 8 oz (240ml) wholemilk (total of 150 protein calories, 250 carbohy-drate calories, 500–600 fat calories). For theapplesauce treatment group, the capsule wasopened and sprinkled onto �30ml of apple-sauce, which was consumed with a spoonfollowed by 200ml of water. Every subject’smouth was checked to ensure that the medicationwas swallowed.

The study population consisted of 20 healthyadult male and female volunteers of 18–45 yearsof age. Females of childbearing potential wereallowed providing they were surgically sterilizedat least 6 months prior to screening, post-menopausal with supporting documentation, orusing double barrier methods of contraception.Qualified subjects were determined by pastmedical history, physical examination, electro-cardiogram, laboratory tests and urinalysis. Allsubjects were non-smokers with a body weightwithin 15% of normal for their body type.Concomitant medications, with the exception ofparacetamol, were not allowed (e.g. corticoster-oids, antihistamines). Subjects with any medicalconditions that would interfere with the studyobjectives were also excluded.

When breakfast and blood draw times coin-cided, blood was drawn before consuming thebreakfast. Blood samples (7ml) of venous bloodwere taken by either direct venipuncture or an

indwelling cannula inserted in a forearm veinand were collected into heparinized green-topvacutainer tubes. Blood samples were taken atpredose, 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12,16 and 24 h post-dose. All samples were pro-cessed and kept frozen at ��208C pendinganalysis.

Pharmacokinetic and statistical evaluation

Sample size determination. Sample size was deter-mined based on the requirement that the two PKparameters Cmax and AUC should have at least80% chance to meet the equivalence criteria forfood effect assessment, i.e. the 90% confidenceinterval (CI) to fall within the range of 0.80–1.25for AUC and of 0.70–1.43 for Cmax. A sample sizeof 18 subjects was selected as this would allow atleast 0.89 probability with AUC (assuming anintra-subject CV of 0.20 and a test-reference ratioof 1.05), and 0.94 probability with Cmax (assum-ing an intra-subject CV of 0.25 and a test-reference ratio of 1.15); joint statistcal power isat least 0.84. The fasted treatment group isdefined as the ‘reference’ treatment with the fedtreatment groups (high-fast breakfast andsprinkled on applesauce) defined as the ‘test’treatments.

Pharmacokinetic data. All individual plasma methyl-phenidate concentrations were checked for consis-tency. Values below the limit of quantitation were setto 0 for pharmacokinetic analysis andmissing valueswere not included in the analysis. All subjects whocompleted at least one treatment period and had acomplete pharmacokinetic profile were included inthe pharmacokinetic data analysis. For each treat-ment period, the pharmacokinetic profiles wereanalysed by standard non-compartmental methodsusing theWinNonlin1 Professional pharmacokineticsoftware (version 3.1, Pharsight, Palo Alto, CA). Thefollowing pharmacokinetic parameters which de-scribe the bimodal profiles were determined formethylphenidate:

Primary PK parameters:Cmax(abs) (ng/ml) Absolute maximum (peak)

plasma drug concentrationafter single dose administra-tion.


L. LEE ET AL.236

AUC0–1 (ng.h/ml) AUC from time 0 to timeinfinity. This is calculated asAUC(0! t)+Ct/lz where Ct isthe concentration at time t,and lz is the terminal elimina-tion rate constant.

Secondary PK parameters:Cmax(0–4) (ng/ml) Maximum concentration ob-

served from time 0 to 4 h.Cmax(4–8) (ng/ml) Maximum concentration ob-

served from time 4 to 8 h.Cminp (ng/ml) Minimum plasma concentra-

tion between peaks, i.e. be-tween tmax(0–4) and tmax(4–8).

AUC(0–4) (ng.h/ml) AUC from 0 to 4 h, calculatedby linear trapezoidal rule.

AUC(4–8) (ng.h/ml) AUC from 4 to 8 h, calculatedby linear trapezoidal rule.

AUC0–t (ng.h/ml) AUC from time 0 to the lastmeasurable sampling timepoint, calculated by linear tra-pezoidal method.

tmax(abs) (h) Time to reach Cmax(abs) follow-ing drug administration.

tmax(0–4) (h) Time at which Cmax(0–4) occurs.tmax(4–8) (h) Time at which Cmax(4–8) occurs.tminp (h) Time at which Cminp occurs.

Statistical analysis. AUC0–1 and Cmax(abs) werethe primary pharmacokinetic parameters for theevaluation of the effect of food on the Ritalin1

LA capsules. Absence of a food-effect wasconcluded when the 90% C.I. for the true test-reference ratio fell within the ranges of 0.80–1.25for AUC0–1 and 0.70–1.43 for Cmax(abs).

An analysis of variance (ANOVA) was per-formed on log-transformed AUC0–1 andCmax(abs) data using the PROC MIXED SASprocedure. The sources of variation included inthe ANOVA model were sequence, subject(sequence), period, and treatment, with subject(sequence) as random effect. In the ESTIMATEstatement of the PROC MIXED SAS procedure,the test-reference contrast was constructed toobtain the p-value, the least squares mean of andthe 90% CI for the log-scale test-referencedifference. The anti-logs of least squares meandifference and its 90% CI constituted the ratio ofsample geometric means and the 90% CI for thetrue test-reference ratio [13].

For exploratory purposes, the statistical ana-lyses were also performed on the secondary PKparameters: Cmax(0–4), Cmax(4–8), Cminp, AUC(0–4),AUC(4–8), AUC(0–t), tmax(0–4), tmax(4–8), tmax(abs),and tminp. The ANOVA performed on the log-transformed Cmax(0–4), Cmax(4–8), Cminp, AUC(0–4),AUC(4–8), and AUC0–t, was in the same procedureas described for AUC(0–1) and Cmax(abs). Fortmax(0–4), tmax(4–8), tmax(abs), and tminp, statisticalanalysis was conducted based on the signed ranktest.

Results

Of 20 subjects who entered the study, 16 subjectscompleted all treatments and were evaluablefor food effect. Three subjects were withdrawnfor adverse events and one subject withdrew forpersonal reason. Three subjects took paracetamolfollowing screening and prior to baseline and onesubject took an oral contraceptive throughout theduration of the study. All 20 subjects who enteredthe study were Caucasian, there were 14 malesand 6 females. The age ranged from 18 to 45years with a mean (� SD) of 31 (� 7.75) years.The mean (� SD) height and weight were 171.2(� 8.82) cm and 74.3 (� 12.42) kg, respectively.No serious adverse events were reported duringthe study. The most commonly reported adverseevents were headache, lightheaded/dizzinessand anxiety, all of which have been previouslyreported with the use of methylphenidate.

The mean (� SD) plasma concentration-timeprofiles for all treatment groups are provided inFigure 1. Individual plasma concentration-timeprofiles for each treatment group are provided inFigures 2–4. In general, subjects from all threetreatments produced a bimodal plasma concen-tration vs. time profiles with two distinct peaks,with the exception of three subjects from thehigh-fat breakfast group. Due to the highlyvariable time to the second peak in the high-fatbreakfast group, the mean methylphenidateplasma concentration vs time profile did notdepict two peaks. All mean pharmacokineticparameters of methylphenidate following oraladministration of a single dose of 40mg Ritalin1

LA modified release capsules under fed (‘high-fat’ breakfast or sprinkled on applesauce) and



fasted conditions are provided in Table 1.Following a single oral administration of a40mg Ritalin1 LA capsule either in the fed(high-fat breakfast or sprinkled on applesauce) orfasted condition, methylphenidate was rapidlyabsorbed with an initial average tmax(0–4) of1.3–2.4 h and an average peak plasma concentra-tion [Cmax(abs)] of 14.41–15.23 ng/ml for all threetreatments.

On average, both the rate [Cmax(abs) andtmax(abs)] and the extent of absorption (AUC0–1)of methylphenidate were similar when Ritalin1

LA capsule was given with a high-fat breakfastor when the capsule contents were sprinkledonto applesauce (up to two teaspoons), com-pared with the fasting state. For the pri-mary pharmacokinetic parameters, AUC0– andCmax(abs), the 90% confidence interval (CI)fell, respectively, within the 80%–125% and

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Figure 1. Mean plasma concentration time profile of dl-methylphenidate after a single dose of Ritalin1 LA 40mgcapsule in the fasted and fed state. * n=18 high-fat breakfast;* n=17 sprinkled on applesauce; 4 n=18, fasted

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Figure 2. Individual plasma concentration time profile of dl-methylphenidate after a single dose of Ritalin1 LA 40mgcapsule in the fed state (‘high fat’ breakfast)

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Figure 3. Individual plasma concentration time profile of dl-methylphenidate after a single dose of Ritalin1 LA 40mgcapsule in the fed state (sprinkled on applesauce)

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Figure 4. Individual plasma concentration time profile of dl-methylphenidate after a single dose of Ritalin1 LA 40mgcapsule in the fasted state


L. LEE ET AL.238

70%–143% bioequivalence range. The 90% CI ofAUC0–1 were 98%–113% for the ratio of fed (highfat breakfast) treatment to fasted treatment, and89%–103% for the ratio of applesauce treatmentto fasted treatment. The 90% CI of Cmax(abs) were81%–100% for the ratio of fed (high-fat breakfast)treatment to fasted treatment, and 84%–104% forthe ratio of applesauce treatment to fastedtreatment (Table 2).

Exploratory analysis was also performed onthe secondary PK parameters. Average AUC,Cmax and tmax values over the 0–4 h and 4–8 hinterval also appeared comparable among thethree treatments, with the exception of AUC(4–8)

and Cmax(4–8) in the high-fat breakfast groupwhich were slightly lower (range: 14.7%–23%),and tmax(0–4) after high-fat breakfast, which wassomewhat longer (1.16 and 0.86 h), comparedwith the other two groups. The average mini-mum plasma methylphenidate concentrations(Cminp) between the peaks were also comparableamong the three treatments (range of means: 6.26to 6.85 ng/ml); however, tminp, the time at whichCminp occurs, was slightly prolonged in the high-fat breakfast group (mean value: 5.18 h) com-pared with the sprinkled on applesauce group(mean value: 3.94 h) and the fasting group (meanvalue: 3.92 h).

The statistical analysis using the secondary PKparameters in the high-fat breakfast group showthat the 90% CI for AUC0–t and Cmax(0–4) fell,respectively, within the 80%–125% and 70%–143% bioequivalence range and Cminp also fellwithin the 70%–143% range. The 90% CI were98%–112% for AUC0–t, 82%–115% for Cmax(0–4),and 92%–132% for Cminp. The 90% confidenceinterval for AUC(0–4) and AUC(4–8) fell outsidethe 80%–125% range and for Cmax(4–8) fell outsidethe 70%–143% range. The 90% CI were 74%–111%for AUC(0–4), 70%–87% for AUC4–8, and 67%–84%for Cmax(4–8). The difference in AUC(0–4) was notstatistically significant (p=0.42) but there was astatistically significantly lower AUC(4–8) andCmax(4–8) with the high fat breakfast comparedwith those with the fasted treatment (p50.001).The mean values were 31.5 ng.h/ml for AUC(4–8)

and 11.3 ng/ml for Cmax(4–8) with the high fatbreakfast, which were only 21% and 24% lowerthan the corresponding mean values with thefasted treatment. A statistically significantdelay of 1-h in tmax(0–4) (p=0.05) and tminp

(p=0.03) was observed compared with the fastedcondition.

The statistical analysis using the secondary PKparameters in the sprinkled on applesauce groupshowed that the 90% CI for AUC(0–t), and AUC(4–8)

Table 1. Mean (� SD) primary and secondary pharmacokinetic parameters of dl-methylphenidate following a single dose ofRitalin1 LA in the fasted and fed state in healthy subjects

40mg (fed)(high fat breakfast)n ¼ 18

40mg (fed)(applesauce)n ¼ 17

40mg (fasted)n ¼ 18

Primary PK parameterAUC0–t (ng.h/ml) 108.74� 15.77 100.82� 20.15 103.32� 19.42AUC0–1 (ng.h/ml) 111.33� 18.14 101.97� 20.56 105.72� 22.42Cmax(abs) (ng/ml) 14.41� 3.68 14.49� 2.76 15.23� 2.45tmax(abs) (h) 3.78� 2.95 3.56� 2.38 4.22� 2.02

Secondary PK parameterCminp (ng/ml) 6.85� 2.55a 6.41�1.78 6.26� 1.76tminp (h) 5.18� 1.41a 3.94� 0.88 3.92� 1.00AUC0–4 (ng.h/ml) 30.70� 12.10 33.16� 7.99 31.16� 6.94Cmax(0–4) (ng/ml) 12.75� 4.38 12.95� 3.56 12.47� 2.60tmax(0–4) (h) 2.42� 1.23 1.26� 0.31 1.56� 0.74AUC4–8 (ng.h/ml) 32.22� 9.32 38.16� 7.82 40.11� 7.15Cmax(4–8) (ng/ml) 11.42� 3.52 13.10� 2.84 14.84� 2.71tmax(4–8) (h) 5.33� 1.44 5.76� 0.59 5.44� 0.62

an ¼ 14 because Cminp and tminp could not be estimated in four subjects. Three of the four subjects did not show a bimodal concentration profile; the

other one patient showed a bimodal profile with the 2nd peak occuring at 16 h post dose with a tmin of 10 h.



fell within the 80%–125% bioequivalence rangeand Cmax(0–4), Cmax(4–8), and Cminp fell within the70%–143% range. The 90% CI were 90%–103% forAUC0–t, 84%–106% for AUC4–8, 84%–118% forCmax(0–4), 77%–97% for Cmax(4–8), and 89%–123%for Cminp. Only the 90% confidence interval forAUC(0–4) (86%–128%) fell slightly outside theupper limit of 80%–125% range. The difference(55%) in AUC0–4 between the two treatmentmeans was not statistically significant (p=0.71)when Ritalin1 LA capsule was sprinkled over

applesauce compared with that with the fastedtreatment. No statistically significant differencein tmax(0–4), tmax(4–8), tmax(abs) and tminp wereobserved compared with the fasted condition.

In addition, no dose dumping was observedwhen the Ritalin1 LA capsule was given with ahigh fat breakfast or with applesauce. This isconfirmed by the fact that both the AUC(0–4) andCmax(0–4) under the fed conditions (high-fat break-fast or applesauce) were similar to that observed forthe fasted condition (Table 1). The intersubject

Table 2. Statistical evaluation of food-effect on dl-methylphenidate pharmacokinetics following single oral administration of a40mg dose of Ritalin1 LA capsule in healthy subjects

Treatment n p-value Treatment ratio 90% CI for ratio

Primary PK parameterCmax(abs) (ng/ml) Breakfast 16 0.10 0.90 (0.81, 1.00)

Applesauce 16 0.27 0.93 (0.84, 1.04)Fasted 16

AUC0–t (ng.h/ml) Breakfast 16 0.20 1.05 (0.98, 1.12)Applesauce 16 0.35 0.96 (0.90, 1.03)Fasted 16

AUC0– (ng.h/ml) Breakfast 16 0.22 1.05 (0.98, 1.13)Applesauce 16 0.29 0.95 (0.89, 1.03)Fasted 16

tmax(abs) (h) (median) Breakfast 16 0.90 } }

Applesauce 16 0.83 } }

Fasted 16

Secondary PK parameterCminp (ng/ml) Breakfast 12 6.90 1.10 (0.92, 1.32)

Applesauce 16 6.30 1.04 (0.89, 1.23)Fasted 16 6.10

tminp (h) (median) Breakfast 12 0.03 } }


Fasted 16AUC0–4 (ng.h/ml) Breakfast 16 0.42 0.91 (0.74, 1.11)


Cmax(0–4) (ng/ml) Breakfast 16 0.76 0.97 (0.82, 1.15)Applesauce 16 0.93 0.99 (0.84, 1.18)Fasted 16

tmax(0–4) (h) (median) Breakfast 16 0.05 } }


Fasted 16AUC4–8 (ng.h/ml) Breakfast 16 50.001 0.78 (0.70, 0.87)


Cmax(4–8) (ng/ml) Breakfast 16 50.001 0.75 (0.67, 0.84)Applesauce 16 0.05 0.87 (0.77, 0.97)Fasted 16

tmax(4–8) (h) (median) Breakfast 16 0.47 } }


Fasted 16


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variability for the pharmacokinetic parameters waslow for methylphenidate. The coefficient of varia-tion (CV) ranged 14.5%–21.2% for AUC0–t andAUC0–1, and 16.1%–25.6% for Cmax(abs) (Table 1).

Discussion and Conclusion

Food–drug interaction can be associated withalterations in the pharmacokinetic and pharma-codynamic profile of various drugs that mayhave clinical implications. Mechanisms related tofood effects on drug absorption can be dividedinto four categories: those causing decreased,delayed, increased or accelerated absorption. If afood effect exists, the category in which it belongsis determined by the directional change in therate and extent of absorption as reflected in thestatistically significant differences in the primaryPK parameters, Cmax, tmax and AUC. Food mayinfluence drug absorption by altering tabletdisintegration, drug dissolution, gastric empty-ing time, gastrointestinal secretion and activetransport of drugs, or it may influence presys-temic clearance at some level between the gastricmucosa and the liver. Usually, the effect of food islargely a matter of the design of the pharmaceu-tical formulation. Although there is a vastamount of literature, there is still no rationalscientific basis to predict the effect of food for aparticular chemical entity or a chemical class oftherapeutic agents. Thus, a mechanistic under-standing of the effects of food may serve as a keyto the pharmacokinetic optimization of subjecttherapy [14].

Based on the evaluation of the primary PKparameter (AUC0–, Cmax(abs)), no food effect wasobserved following single dose administration ofa 40mg Ritalin1 LA capsule (highest strength,market formulation) with either a high-fat break-fast or applesauce (up to two teaspoons, 30ml),compared with the fasted condition. The absenceof a food effect is concluded since the 90%confidence intervals for the ratio of means for theprimary PK parameters of fed (high fat breakfastor applesauce) and fasted treatments fell withinthe 80%–125% for AUC0–1 and 70%–143%boundary for Cmax(abs).

Although not the major consideration for theeffect of food, the secondary PK parameters were

also evaluated. The same statistical evaluation forthe secondary PK parameters (Cmax(0–4), Cmax(4–8),Cminp, AUC0–4, AUC4–8, AUC0–t, tmax(0–4), tmax(4–8),tmax(abs), and tminp) indicates a certain amount ofdifferences in absorption between the fed andfasted states. A slightly longer tmax(0–4) after high-fat breakfast compared with the fasting treatmentreflects a moderate delay in absorption from thefirst release with high-fat breakfast. The delayedabsorption usually results from a slower gastricemptying range and/or increased gastric pHresulting from the ingestion of food. Slightlylower AUC(4–8) and Cmax(4–8) were also observedafter high-fat breakfast compared with the fastingtreatment, but this does not suggest a decreasedabsorption since AUC(abs) and Cmax(abs) were notsignificantly different between the two treatmentgroups. The average minimum plasma methyl-phenidate concentrations (Cminp) between thepeaks were comparable among the three treat-ments; however, tminp, the time at which Cminp

occurred, was slightly prolonged following ahigh-fat breakfast compared with when givenwith applesauce or under fasted treatment. In theapplesauce treatment, only AUC0–4 was slightlyhigher which reflects an increased extent ofabsorption in the first release. In the event thata delayed absorption is observed with food asdetermined by statistical boundaries, its rele-vance is further evaluated by the primaryconcern of reduced clinical efficacy. In anotherRitalin1 LA study in which school-aged childrenwith ADHD were given Ritalin1 LA capsulesapproximately 30min after a standard breakfast(e.g. one cup cereal with milk, juice), a signifi-cantly better behavioural and cognitive responserelative to placebo was observed during the 0–4 hevaluation period and was maintained over theentire 9-h evaluation period (i.e. 0–9 h post-dose).Thus, the observed moderate delay in absorptionwere determined to be clinically insignificant.

The majority of the diagnosis and treatment forADHD are still children and adolescents.Although healthy adult volunteers are the sub-jects for this study, the pharmacokinetic profilesof methylphenidate in adults and children wereobserved to be qualitatively similar with no age-related differences in absorption, distribution,metabolism, or excretion that would be expectedto alter the findings [15]. Enrollment of children



into clinical studies that require the use ofinvasive procedures is always a major concern.In this study, a relatively large number of bloodsamples (17) were required to be taken from eachsubject over three 24 h periods post administra-tion, and therefore adults were chosen as thesubjects of the study.

Compared with the previous sustained-releaseformulation of methylphenidate (Ritalin1 SR)which utilized the OROS (osmotic controlled-release system) drug delivery system, the SO-DAS1 technology has a significant advantagedue to the ease of administration as beads can besprinkled on food to eliminate difficulty inswallowing. This system consists of multipleparticles stored in a hard gelatin capsule. The1mm spheres result in a wide distribution withinthe GI tract and are surrounded by rate-control-ling polymers that allow dissolution and releaseto be independent of pH and food. Although theintent of the SODAS technology is to provide adrug delivery system that would release the drugwithout respect to fasting or fed state, the effect offood on each particular drug and formulationmust be investigated on a case by case basis.Studies on Verapamil SR, an anti-hypertensiveagent which utilizes the SODAS1 technology, havealso shown that food has no significant effect onthe peak plasma level and exposure [16].

Recently, two other controlled release methyl-phenidate formulations containing both the IRand DR components of MPH in a single dosageform were approved on the market: Metadate1

CD Extended-Release capsules (Celltech Phar-maceuticals), and Concerta1 tablets (Alza Cor-poration, Mountain View, CA). Similar toRitalin1-LA, these formulations were designedto allow the benefit of once-daily dosing byproviding a rapid onset and a longer duration ofaction. Metadate1 capsules contains 30% IRbeads and 70% DR beads, and when adminis-tered once daily produces a methylphenidateplasma concentration profile similar to that of IRmethylphenidate taken twice daily. The bioavail-ability of methylphenidate was not shown to bealtered when the capsules were administered bysprinkling their contents onto a small amount ofapplesauce [17]. Concerta1 tablets are coatedwith IR methylphenidate and contains an osmo-tic pumop (OROS) that gradually releases the

drug over a 10 h period. When administered oncedaily, it produces a methylphenidate plasmaconcentration profile similar to that of IR methyl-phenidate taken three times daily with lessfluctuation. The bioavailability was not signifi-cantly altered when taken with a high-fat break-fast [18,19].

The result of this Ritalin1 LA study showedthat food does not interfere significantly with theoverall rate and extent of absorption of methyl-phenidate delivered from the modified releasedosage form, although some minor effects on thebimodal concentration-time profiles were ob-served with high-fat breakfast. For subjects whoare unable to swallow the whole capsule, thecontents may be sprinkled onto applesauce andconsumed. Ritalin1 LA was well tolerated andno dose dumping was observed when capsuleswere given with either a high fat breakfast orwith applesauce. In conclusion, Ritalin1 LAprovides a unique modified release formulationwhich shows no influence on bioavailabilitywhen administered intact with a high-fat mealand when the capsule content was sprinkled onapplesauce.

References

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