Source: Health Products Regulatory Authority (ZA) Revision Year: 2023 Publisher: Pharma Dynamics (Pty) Ltd, 1<sup>st</sup> Floor, Grapevine House, Steenberg Office Park, Silverwood Close, Westlake, Cape Town, 7945, South Africa
Pharmacotherapeutic group: centrally acting sympathomimetics
ATC code: N06BA04
Pharmacological classification: A 1.2 Psychoanaleptics (antidepressants)
Methylphenidate HCl is a mild central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate is thought to block the reuptake of noradrenaline and dopamine into the presynaptic neuron and increase the release of these monoamines into the extra-neuronal space. Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The disomer is more pharmacologically active than the l-isomer.
Methylphenidate is readily absorbed. Following oral administration of methylphenidate prolonged-release to adults, the tablet overcoat dissolves, providing an initial maximum concentration at about 1 to 2 hours. The methylphenidate contained in the two internal tablet layers is gradually released over the next several hours. Peak plasma concentrations are achieved at about 6 to 8 hours, after which plasma levels of methylphenidate gradually decrease.
Methylphenidate prolonged-release taken once daily minimises the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily. The extent of absorption of methylphenidate prolonged-release once daily is generally comparable to conventional immediate release preparations.
Following the administration of methylphenidate prolonged-release 18 mg once daily in 36 adults, the mean pharmacokinetic parameters were: Cmax 3,7 ± 1,0 (ng/mL), Tmax 6,8 ± 1,8 (h), AUCinf 41,8 ± 13,9 (ng.h/mL), and t½ 3,5 ± 0,4 (h).
No differences in the pharmacokinetics of prolonged-release methylphenidate were noted following single and repeated once daily dosing, indicating no significant drug accumulation. The AUC and t1/2 following repeated once daily dosing are similar to those following the first dose of prolonged-release methylphenidate.
Dose proportionality: Following administration of prolonged-release methylphenidate in single doses of 18, 36, and 54 mg/day to healthy adults, Cmax and AUC(0-inf) of methylphenidate were proportional to dose, whereas l-methylphenidate Cmax and AUC(0-inf) increased disproportionally with respect to dose. Following administration of prolonged release methylphenidate, plasma concentrations of the l-isomer were approximately 1/40th the plasma concentrations of the d-isomer.
In healthy adults, single and multiple dosing of once daily prolonged release methylphenidate 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, (alpha)-phenyl-piperidine acetic acid (PPAA). The single dose and steady state (Day 4) clearance and half-life parameters were similar, indicating that there was no time dependency in the pharmacokinetics of methylphenidate. The ratio of metabolite (PPAA) to parent medicine (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 ADHA patients aged 13–16 administered a dose of (18 to 72 mg/day) of prolonged release methylphenidate, mean Cmax and AUCTAU of methylphenidate increased proportionally with respect to the dose.
Plasma methylphenidate concentrations in adults decline biexponentially following oral administration. The half-life of methylphenidate in adults following oral administration of prolonged-release methylphenidate was approximately 3,5 h.
The rate of protein binding of methylphenidate and of its metabolites is approximately 15%. The apparent volume of distribution of methylphenidate is approximately 13 litres/kg.
In humans, methylphenidate is metabolised primarily by de-esterification to (alpha)-phenylpiperidine acetic acid (PPA, approximately 50-fold the level of the unchanged substance) which has little or no pharmacologic activity. In adults the metabolism of prolonged-release methylphenidate once daily as evaluated by metabolism to PPA is similar to that of methylphenidate three times daily. The metabolism of single and repeated once daily doses of prolonged-release methylphenidate is similar.
The elimination half-life of methylphenidate in adults following administration of prolongedrelease methylphenidate was approximately 3.5 hours.
After oral dosing of radiolabelled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPA, accounting for approximately 80% of the dose.
In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of prolonged-release methylphenidate when administered after a high fat breakfast on an empty stomach. There is no evidence of dose dumping in the presence of food.
In healthy adults, the mean dose-adjusted AUC(0-inf) values for prolonged-release methylphenidate were 36,7 ng.h/mL in men and 37,1 ng.h/mL in women, with no differences noted between the two groups.
In healthy adults receiving prolonged-release methylphenidate, dose-adjusted AUC was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics.
The pharmacokinetics of prolonged-release methylphenidate has not been studied in children younger than 6 years of age.
There is no experience with the use of prolonged-release methylphenidate in patients with renal insufficiency. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of prolonged-release methylphenidate.
There is no experience with the use of prolonged-release methylphenidate in patients with hepatic insufficiency.
In life-time rat and mouse carcinogenicity studies, increased numbers of malignant liver tumours were noted in male mice only. The significance of this finding to humans is unknown.
Methylphenidate did not affect reproductive performance or fertility at low multiples of the clinical dose.
Methylphenidate is not considered to be teratogenic in rats and rabbits. Foetal toxicity (i.e. total litter loss) and maternal toxicity was noted in rats at maternally toxic doses.
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