MEDIKINET Tablet Ref.[27707] Active ingredients: Methylphenidate

Absorption

Medikinet is rapidly and almost completely absorbed. Owing to its pronounced “first-pass” metabolism the absolute bioavailability is low at only 30% (11-51%) of the dose. Absorption is accelerated when the medicinal product is taken with meals but has no effect on the total amount absorbed. Maximum plasma concentrations of 7 ng/ml are reached on average 1-2 hours after administration of 10 mg. The maximum plasma concentrations vary considerably interindividually.

There are considerable interindividual and intraindividual variations in the plasma concentrations which, however, provide little conclusive evidence of the therapeutic efficacy. The relatively short half-life correlates well with the duration of action of 1 to 4 hours.

Distribution

In the blood, methylphenidate and its metabolites become distributed in the plasma (57%) and the erythrocytes (43%). Methylphenidate and its metabolites have a low plasma protein-binding (10-33%). The volume of distribution after a single intravenous dose is 2.2 l/kg (2.65±1.1 l/kg for d-methylphenidate and 1.8±0.9 l/kg for l-methylphenidate).

Biotransformation

Biotransformation of methylphenidate is rapid and extensive. Peak plasma concentrations of 2-phenyl -2-piperidyl acetic acid (PPAA) are attained approximately 2 hours after administration of methylphenidate and are 30-50 times higher than those of the unchanged substance. The half-life of PPAA is roughly twice as long as that of methylphenidate and the mean systemic clearance is 0.17 l/h/kg. Only small amounts of hydroxylated metabolites (e.g. hydroxymethylphenidate and hydroxyritalinic acid) are detectable. Therapeutic activity seems to be principally due to the parent compound.

Elimination

Methylphenidate is eliminated from the plasma with an average half-life of approximately 2 hours. The mean clearance after an intravenous single dose is 0.565 l/h/kg (0.40±0.12 l/h/kg for d-methylphenidate and 0.73±0.28 l/h/kg for l-methylphenidate). After oral administration, approximately 78-97% of the dose is excreted within 48 to 96 h via the urine and 1 to 3% via the faeces in the form of metabolites. Only small amounts (<1%) of unchanged methylphenidate appear in the urine. A large proportion of an intravenous dose (89%) is eliminated in the urine within 16 hours, presumably regardless of the pH value, as ritalinic acid.

There is apparently no difference in the pharmacokinetics of methylphenidate between children with hyperkinetic disorders/ADHD and healthy adult test subjects. Pharmacokinetic properties of methylphenidate have not been studied in children below 6 years of age or in elderly above 65 years.

The renal elimination of ritalinic acid may decrease in the case of impaired renal function.

The bulk of the dose is excreted in the urine as 2-phenyl-2-piperidyl acetic acid (PPAA, 60-86%).

Characteristics in patients

There are no apparent differences in the pharmacokinetic behaviour of methylphenidate in hyperactive children and healthy adult volunteers.

Elimination data from patients with normal renal function suggest that renal excretion of the unchanged methylphenidate would hardly be diminished at all in the presence of impaired renal function. However, renal excretion of PPAA may be reduced.

Carcinogenicity

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.

Pregnancy-embryonal/foetal development

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.