Pharmacokinetics of CONCERTA

Summary

• CONCERTA (methylphenidate HCl) is an extended-release tablet designed to allow once daily dosing of methylphenidate (MPH).¹
• Following oral administration of CONCERTA, plasma MPH concentrations reached an initial maximum concentration at approximately 1 hour, followed by gradual ascending concentrations over the next 5 to 9 hours, after which a gradual decrease begins. Mean times to reach peak plasma concentrations across all doses of CONCERTA occurred between 6 and 10 hours.¹
• The mean half-life of MPH in adults and adolescents following oral CONCERTA administration was approximately 3.6 hours. There were no differences in the pharmacokinetics of CONCERTA following single and repeated once daily dosing, indicating no significant drug accumulation.¹
• In healthy adults, single and multiple doses (once daily) CONCERTA doses from 54 to 144 mg/day resulted in linear and dose-proportional increases in maximum concentration (C_max) and area under the concentration-time curve to infinite time (AUC_inf) for total MPH and its major metabolite, α-phenyl-piperidine acetic acid (PPAA).¹
• In humans, MPH is metabolized primarily by de-esterification to PPAA, which has little to no pharmacologic activity.¹ The primary location of presystemic metabolism of MPH is in the intestinal and/or gut wall.²
• No difference in the pharmacokinetic or pharmacodynamic performance of CONCERTA was observed when administered after a high-fat breakfast.¹
• Increase in pediatric age was associated with increased apparent oral clearance (CL/F) (58% increase in adolescents compared with younger pediatric patients). The use of CONCERTA is not recommended in pediatric patients younger than 6 years because they have higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage.¹
• There is no pharmacokinetic information on the use of CONCERTA in patients with renal or hepatic impairment.¹
• A coadministration study of guanfacine extended-release and CONCERTA did not result in significant pharmacokinetic drug-drug interactions.³

PRODUCT LABELING

Please refer to the following section of the enclosed Full Prescribing Information that is relevant to your inquiry¹: CLINICAL PHARMACOLOGY, Pharmacokinetics.

CLINICAL DATA

Modi et al (2000)⁴ studied the single- and multiple-dose pharmacokinetics of CONCERTA once daily in 36 healthy adults.

Two separate studies describe the pharmacokinetics and bioavailability of CONCERTA relative to immediate-release (IR) and sustained-release (SR) formulations of MPH, and to evaluate the single-dose and repeated-dose pharmacokinetics of CONCERTA. The most commonly reported adverse events (AEs) in both studies were headache, nausea, and dizziness.

Study 1

Study Design/Methods

• Open-label, randomized, 3-treatment, 3-period, 6-sequence crossover study in 36 healthy adults (mean age, 27.4 years).
• Rate and extent of absorption of CONCERTA were compared to that of IR and SR MPH.
• On 3 separate occasions, subjects received a single dose of CONCERTA 18 mg, a single dose of SR MPH 20 mg, and 3 doses of IR MPH 5 mg in random order.
• Blood samples for measuring plasma MPH and PPA/PPAA concentrations for CONCERTA and SR MPH were obtained predose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 17, 20, 24, and 30 hours postdose.
• Blood samples for measuring plasma MPH concentration for IR MPH were obtained predose and at 0.25, 0.5, 1, 1.5, 2, 4, 4.25, 4.5, 5, 5.5, 6, 8, 8.25, 8.5, 9, 9.5, 10, 12, 14, 17, 20, 24, and 30 hours postdose.

Results

• Thirty-six subjects were assigned to receive CONCERTA and SR MPH; 35 subjects were assigned to receive IR MPH 3 times a day.
• Following oral administration of CONCERTA, plasma MPH concentrations increased rapidly over the first 1 to 2 hours, followed by gradually ascending concentrations over the next 3 to 4 hours.
  • Mean time to reach peak plasma MPH concentration (T_max) was observed at approximately 6.7 hours.
• In contrast, following IR MPH administration, plasma MPH concentrations fluctuated with peak concentrations reached approximately 1 to 2 hours after each dose; T_max was observed 6.5 hours after dosing.
• Following SR MPH administration, plasma MPH concentrations increased rapidly with T_max occurring at 3.7 hours, after which plasma concentrations rapidly declined.
• Compared with IR MPH and SR MPH, C_max of MPH for CONCERTA was lower and T_max occurred later.
• The terminal half-lives for MPH for all 3 formulations were comparable (~3–4 hours).
• The relative bioavailability of MPH from CONCERTA relative to IR MPH was 91.4% and to SR MPH was 101%.
• Similar observations were made for the pharmacokinetic parameters of PPA.
  • C_max of PPA for CONCERTA was also lower and occurred later compared with that of IR MPH and SR MPH; t_1/2 of PPA for all 3 formulations was approximately 8 hours.

Study 2

Study Design/Methods

• Open-label study conducted to assess single- and repeated-dose pharmacokinetics of CONCERTA 18 mg.
• Thirty-two healthy adults (mean age, 29.7 years) were given a single oral dose of CONCERTA 18 mg on day 1, followed by a multiple-dose regimen on days 3–6.
• Blood samples for measuring plasma MPH concentrations were obtained predose and at predefined times for 36 hours following the single dose on day 1 and following multiple doses on day 6, in addition to predose on days 3–5.

Results

• Following single and repeated dosing of CONCERTA 18 mg, mean C_max, AUC_inf and t_1⁄2 of MPH for the 2 regimens were similar (C_max: 2.81±0.96 ng/mL vs 3.0±1.1 ng/mL, respectively; AUC_inf: 32.9±12 ng•h/mL vs 35.2±12 ng•h/mL, respectively; t_1⁄2: 3.9±0.73 hrs vs 3.9+0.76 hrs, respectively).
• Similarly, following repeated dosing, mean C_max, AUC_inf, and t_1⁄2 of PPA were comparable to the values after a single dose.
• Accumulation after repeated dosing was 13.7% for MPH and 17.5% for PPA, indicating the lack of clinically significant drug accumulation after repeated dosing.

Dose Proportionality

Modi et al (2000)² assessed the pharmacokinetics of d- and l-MPH and d- and l-PPA of CONCERTA 18, 36, and 54 mg in a randomized, open-label, 3-way crossover study.

Study Design/Methods

• Thirty-five healthy adults (22 men, 13 women), ages 18 to 45 years, were assigned to 1 of 6 treatment sequences to receive CONCERTA 18, 36, or 54 mg daily.
• Blood samples were collected over a 30-hour period to measure plasma MPH and PPA concentrations.

Results

• Following oral administration of CONCERTA, d- and l-MPH plasma levels increased rapidly for the first 1 to 2 hours, followed by gradual ascending concentrations over the next 3 to 4 hours.
• Peak plasma concentrations of d- and l-MPH were observed 6 to 8 hours postdose.
  • Plasma concentrations of l-MPH were only detected at certain time points and were lower than those of d-MPH.
• Plasma concentrations of d- and l-PPA were similar to one another and were higher than concentrations of d- and l-MPH.  
• There was a linear, dose-proportional increase in both C_max and AUC_inf of d- and l-MPH and of d- and l-PPA.
• The estimated t_1⁄2 for d-MPH was approximately 4 hours, but the estimated t_1⁄2 for l-MPH was not calculated due to the lack of detectable concentrations.
• The estimated t_1⁄2 for d-PPA and l-PPA were 9 and 7 hours, respectively.
• Following CONCERTA administration, plasma concentrations of l-MPH were approximately 40-fold lower than the plasma concentrations of d-MPH.

Safety

• The most commonly reported AEs were headache, nausea, and nervousness.

Food Effects

Wigal et al (2011)⁵ conducted a single-center, double-blind, double-dummy, randomized, crossover study to compare the pharmacokinetics and pharmacodynamics of CONCERTA with IR MPH after fasting state and different breakfast conditions in children with attention-deficit/hyperactivity disorder.

Study Design/Methods

• Thirty-one children (mean age, 10.1 years) were divided into 2 groups and then randomized into 1 of 3 treatment regimens in a 3-period crossover design with a minimum of 5 days in between treatments.
  • The 3 treatment regimens administered in group 1 included CONCERTA after a high-fat breakfast, CONCERTA in a fasted state, and IR MPH TID in a fasted state.
  • The 3 treatment regimens administered in group 2 included CONCERTA after a high-fat breakfast, CONCERTA after a normal breakfast, and IR MPH TID with first dose given after a normal breakfast.
• The normal breakfast had about 4 g of fat and the high-fat breakfast had about 34 g of fat.
• Patients were assigned to 1 of 3 dosage levels (CONCERTA 18, 36, and 54 mg once daily, and an assumed equivalent regimen of IR MPH 5, 10, and 15 mg given 3 times a day) based on their prestudy established clinical dose of IR MPH.
• Serial blood samples were collected at 0 (predose), 1.5, 2.5, 4, 5.5, 6.5, 8, 9.5, and 11.5 hours after the morning dose to measure the plasma concentrations of MPH and PPAA.
• Pharmacokinetic parameters were evaluated using noncompartmental analyses and a change in means by 20% was used as a criterion to evaluate food effect.

Results

• The pharmacokinetic values for MPH and PPAA after administration of CONCERTA under high-fat breakfast and fasting conditions were similar to those observed after administration of IR MPH under fasting conditions (group 1).
• The pharmacokinetic values for MPH and PPAA after administration of CONCERTA under high-fat and normal breakfast conditions were similar to those observed after administration of IR MPH after a normal breakfast (group 2).
• The drug-to-metabolite ratios for all CONCERTA and IR MPH treatments were similar.

Safety

• The most commonly reported AEs included headache, accidental injury, twitching, and anorexia.

Auiler et al (2002)⁶ conducted a single dose, open-label, randomized, crossover study to compare the effect of a high-fat breakfast on early drug exposure from a morning dose of CONCERTA and Adderall XR (mixed amphetamine salts [MAS]).

Study Design/Methods

• Thirty-six healthy subjects (mean age, 29 years) received either CONCERTA 36 mg or MAS 20 mg in the morning after an overnight fast (fasted) or 15 minutes after consuming a high-fat breakfast (fed).
• A high-fat breakfast included 2 eggs fried in butter, 2 slices of buttered toast, 2 bacon strips, 4 ounces of hash brown potatoes, and 8 ounces of whole milk.
• Blood samples were collected by venipuncture predose and at 1, 2, 2.5, 3, 3.5, 4, 5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 12, 15, 24, and 28 hours after the stimulant dose.
• The effect of food on each stimulant medication was assessed using AUC_inf and C_max.
  • Changes in either of these parameters within ±20% after consuming a high-fat breakfast indicated no food effect.
• The effects of early drug exposure using partial areas under the concentration-time curve from 0 up to 4, 6, and 8 hours (AUC_p4h, AUC_p6h, and AUC_p8h) was also assessed.

Results

• Results revealed that 32 out of 36 study subjects had a significant decrease (20% to 80%) in plasma amphetamine levels over the first 8 hours post-MAS dose after a high-fat breakfast (P<0.0001).
• Mean decreases of 55.5%, 42.5%, and 35% for MAS exposure over 4, 6, and 8 hours were significant compared to the mean increases of 3%, 9.2%, and 10% for CONCERTA exposure over the same time period (P<0.0001).
• Plasma levels of CONCERTA were unaffected by food over the first 8 hours of exposure.

Modi et al (2000)⁷ conducted 2 randomized, open-label, crossover studies to assess the effect of food on the pharmacokinetics of CONCERTA in healthy volunteers.

Study Design/Methods

• The first study involved 24 healthy males (aged 21 to 49 years), who received a single dose of CONCERTA 18 mg while the second study enrolled 36 healthy subjects (17 women, 19 men), between the ages of 18 and 45 years, who received a single dose of CONCERTA 36 mg.
• Subjects in both studies were administered CONCERTA in either a fasted state or in a fed state, within 30 minutes of consuming a high-fat breakfast containing 900-1000 calories.
• Blood samples were collected from each subject for up to 30 hours after dosing.

Results

Study 1: 18 mg

• All 24 subjects completed both the fast and fed treatments.
• Following the administration of CONCERTA 18 mg in the fast state, plasma MPH concentrations increased rapidly with an initial peak concentration observed at 1-hour postdose, followed by gradually ascending concentrations.
• T_max was observed at approximately 6.1 hours postdose.
• In the presence of food, the initial peak concentration of MPH was not observed; however, mean peak plasma concentrations were somewhat higher and T_max occurred later (at 7.2 hours) compared to the fasted state.

Study 2: 36 mg

• 31 subjects completed both the fast and fed treatments.
• Following the administration of CONCERTA 36 mg, the initial peak concentration was not evident in either the fasting or fed dosing condition. T_max in the fasted state was noted at approximately 6.5 hours postdose.
• As in the 18-mg dose group, peak MPH plasma concentrations were higher and T_max occurred later (at 7.4 hours) in the fed state.

Comparison of Fasted and Fed States

• When administered in the fed state, mean peak MPH concentrations were approximately 30% higher in the 18-mg dose group and 12% higher in the 36-mg dose group compared with administration in the fasted state.
• There was no evidence of dose dumping in the presence of food as the differences in initial MPH plasma concentrations between the fasted and the fed state were not significant.
• T_max was also noted approximately 1 hour later in the fed state compared to the fasted state.
• The plasma AUC was 20% higher in the fed state for both the 18- and 36-mg dose groups.
• The ratio of MPH AUC_inf to PPA AUC_inf was similar between the fast state and the fed state (0.021 and 0.025, respectively), indicating that food does not affect the metabolism of MPH.

Safety

• The most commonly reported AEs were headache, dizziness, somnolence, and nausea.

Coadministration Study

Roesch et al (2013)³ conducted a single-center, open-label, randomized, 3-period crossover, drug-drug interaction study to assess the pharmacokinetics of guanfacine extended release (GXR) 4 mg and CONCERTA 36 mg, alone and in combination in healthy volunteers.

Study Design/Methods

• Thirty-eight adults (mean age, 30.8 years) were randomly assigned to 1 of 6 different administration sequences; each sequence consisted of 3 treatment periods separated by a washout period of at least 7 days.
• Blood samples were collected predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 30, 48, and 72 hours postdose for each treatment period to measure plasma levels of guanfacine, d-MPH, and l-MPH.

Results

• Analyses of the 90% confidence intervals (CIs) for the geometric mean ratios (GMR) of the C_max and AUC_inf values for guanfacine following administration of GXR alone or in combination with CONCERTA met bioequivalence criteria (defined as 90% CIs within the interval of 0.80–1.25).
• Similarly, the analyses of 90% CIs for GMRs of the C_max and AUC_inf values for d-MPH following administration of CONCERTA alone or in combination with GXR met bioequivalence criteria.
• No significant differences in concentration of l-MPH were observed following administration of CONCERTA alone or in combination with GXR.
• The combination of GXR and MPH did not alter the pharmacokinetic parameters of either medication.

Safety

• The most common treatment-emergent AEs reported were headache, dizziness, and postural dizziness.

SELECTED ADDITIONAL REFERENCES

Data from animal studies suggest that the primary location of presystemic metabolism is in the intestinal and/or gut wall and not in the liver or lungs.² Additional comparative studies evaluating pharmacokinetics and/or bioavailability of MPH from CONCERTA relative to other MPH formulations are available.^8-11

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 03 February 2025.