Post by Amtram on Mar 1, 2014 10:59:35 GMT -5
From rxlist:
Pharmacodynamics
Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer.
Pharmacokinetics
Absorption
Methylphenidate is readily absorbed. Following oral administration of CONCERTA® , plasma methylphenidate concentrations increase rapidly, reaching an initial maximum at about 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.
CONCERTA® once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily (see Figure 1). The relative bioavailability of CONCERTA® once daily and methylphenidate three times daily in adults is comparable.
Figure 1. Mean methylphenidate plasma concentrations in 36 adults, following a single dose of CONCERTA® 18 mg once daily and immediate-release methylphenidate 5 mg three times daily administered every 4 hours.
Mean methylphenidate plasma concentrations - Illustration
The mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of CONCERTA® 18 mg once daily and methylphenidate 5 mg three times daily are summarized in Table 6.
Table 6: Pharmacokinetic Parameters (Mean ± SD) After Single Dose in Healthy Adults
PARAMETERS CONCERTA® (18 MG ONCE DAILY)
(N=36) METHYLPHENIDATE (5 MG THREE TIMES DAILY)
(N=35)
Cmax (ng/mL) 3.7 ± 1.0 4.2 ± 1.0
Tmax (h) 6.8 ± 1.8 6.5 ± 1.8
AUCinf (ng•h/mL) 41.8 ± 13.9 38.0 ± 11.0
t½(h) 3.5 ± 0.4 3.0 ± 0.5
The pharmacokinetics of CONCERTA® were evaluated in healthy adults following single-and multiple-dose administration (steady state) of doses up to 144 mg/day. The mean half-life was about 3.6 hours. No differences in the pharmacokinetics of CONCERTA® were noted following single and repeated once-daily dosing, indicating no significant drug accumulation. The AUC and t½ following repeated once-daily dosing are similar to those following the first dose of CONCERTA® in a dose range of 18 to 144 mg.
Dose Proportionality
Following administration of CONCERTA® in single doses of 18, 36, and 54 mg/day to healthy adults, Cmax and AUC (0-inf) of d-methylphenidate were proportional to dose, whereas l-methylphenidate Cmax and AUC (0-inf) increased disproportionately with respect to dose. Following administration of CONCERTA® , plasma concentrations of the l-isomer were approximately 1/40 the plasma concentrations of the d-isomer.
In healthy adults, single and multiple dosing of once-daily CONCERTA® doses from 54 to 144 mg/day resulted in linear and dose-proportional increases in Cmax and AUCinf for total methylphenidate (MPH) and its major metabolite, α-phenyl-piperidine acetic acid (PPAA). There was no time dependency in the pharmacokinetics of methylphenidate. The ratio of metabolite (PPAA) to parent drug (MPH) was constant across doses from 54 to 144 mg/day, both after single dose and upon multiple dosing.
In a multiple-dose study in adolescent ADHD patients aged 13 to 16 administered their prescribed dose (18 to 72 mg/day) of CONCERTA® , mean Cmax and AUCTAU of d- and total methylphenidate increased proportionally with respect to dose.
Distribution
Plasma methylphenidate concentrations in adults and adolescents decline biexponentially following oral administration. The half-life of methylphenidate in adults and adolescents following oral administration of CONCERTA® was approximately 3.5 hours.
Metabolism and Excretion
In humans, methylphenidate is metabolized primarily by de-esterification to PPAA, which has little or no pharmacologic activity. In adults the metabolism of CONCERTA® once daily as evaluated by metabolism to PPAA is similar to that of methylphenidate three times daily. The metabolism of single and repeated once-daily doses of CONCERTA® is similar.
After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPAA, accounting for approximately 80% of the dose.
Food Effects
In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of CONCERTA® when administered after a high-fat breakfast. There is no evidence of dose dumping in the presence or absence of food.
Alcohol Effect
An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the CONCERTA® 18 mg tablet dosage form. At an alcohol concentration up to 40% there was no increased release of methylphenidate in the first hour. The results with the 18 mg tablet strength are considered representative of the other available tablet strengths.
Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer.
Pharmacokinetics
Absorption
Methylphenidate is readily absorbed. Following oral administration of CONCERTA® , plasma methylphenidate concentrations increase rapidly, reaching an initial maximum at about 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.
CONCERTA® once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily (see Figure 1). The relative bioavailability of CONCERTA® once daily and methylphenidate three times daily in adults is comparable.
Figure 1. Mean methylphenidate plasma concentrations in 36 adults, following a single dose of CONCERTA® 18 mg once daily and immediate-release methylphenidate 5 mg three times daily administered every 4 hours.
Mean methylphenidate plasma concentrations - Illustration
The mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of CONCERTA® 18 mg once daily and methylphenidate 5 mg three times daily are summarized in Table 6.
Table 6: Pharmacokinetic Parameters (Mean ± SD) After Single Dose in Healthy Adults
PARAMETERS CONCERTA® (18 MG ONCE DAILY)
(N=36) METHYLPHENIDATE (5 MG THREE TIMES DAILY)
(N=35)
Cmax (ng/mL) 3.7 ± 1.0 4.2 ± 1.0
Tmax (h) 6.8 ± 1.8 6.5 ± 1.8
AUCinf (ng•h/mL) 41.8 ± 13.9 38.0 ± 11.0
t½(h) 3.5 ± 0.4 3.0 ± 0.5
The pharmacokinetics of CONCERTA® were evaluated in healthy adults following single-and multiple-dose administration (steady state) of doses up to 144 mg/day. The mean half-life was about 3.6 hours. No differences in the pharmacokinetics of CONCERTA® were noted following single and repeated once-daily dosing, indicating no significant drug accumulation. The AUC and t½ following repeated once-daily dosing are similar to those following the first dose of CONCERTA® in a dose range of 18 to 144 mg.
Dose Proportionality
Following administration of CONCERTA® in single doses of 18, 36, and 54 mg/day to healthy adults, Cmax and AUC (0-inf) of d-methylphenidate were proportional to dose, whereas l-methylphenidate Cmax and AUC (0-inf) increased disproportionately with respect to dose. Following administration of CONCERTA® , plasma concentrations of the l-isomer were approximately 1/40 the plasma concentrations of the d-isomer.
In healthy adults, single and multiple dosing of once-daily CONCERTA® doses from 54 to 144 mg/day resulted in linear and dose-proportional increases in Cmax and AUCinf for total methylphenidate (MPH) and its major metabolite, α-phenyl-piperidine acetic acid (PPAA). There was no time dependency in the pharmacokinetics of methylphenidate. The ratio of metabolite (PPAA) to parent drug (MPH) was constant across doses from 54 to 144 mg/day, both after single dose and upon multiple dosing.
In a multiple-dose study in adolescent ADHD patients aged 13 to 16 administered their prescribed dose (18 to 72 mg/day) of CONCERTA® , mean Cmax and AUCTAU of d- and total methylphenidate increased proportionally with respect to dose.
Distribution
Plasma methylphenidate concentrations in adults and adolescents decline biexponentially following oral administration. The half-life of methylphenidate in adults and adolescents following oral administration of CONCERTA® was approximately 3.5 hours.
Metabolism and Excretion
In humans, methylphenidate is metabolized primarily by de-esterification to PPAA, which has little or no pharmacologic activity. In adults the metabolism of CONCERTA® once daily as evaluated by metabolism to PPAA is similar to that of methylphenidate three times daily. The metabolism of single and repeated once-daily doses of CONCERTA® is similar.
After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPAA, accounting for approximately 80% of the dose.
Food Effects
In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of CONCERTA® when administered after a high-fat breakfast. There is no evidence of dose dumping in the presence or absence of food.
Alcohol Effect
An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the CONCERTA® 18 mg tablet dosage form. At an alcohol concentration up to 40% there was no increased release of methylphenidate in the first hour. The results with the 18 mg tablet strength are considered representative of the other available tablet strengths.