Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: psychostimulants, agents used for ADHD and nootropics; centrally acting sympathomimetics

ATC Code: N06BA04

Mechanism of action: MEDIKINET MR is a mild CNS stimulant with more prominent effects on mental than on motor activities. Its mode of action in man is not completely understood but its effects are thought to be due to cortical stimulation and possibly to stimulation of the reticular activating system.
The mechanism by which MEDIKINET MR exerts its mental and behavioural effects in children is not clearly established, nor is there conclusive evidence showing how these effects relate to the condition of the central nervous system. It is thought to block the re-uptake of norepinephrine and dopamine into the presynaptic neurone and increase the release of these monoamines into the extraneuronal space. MEDIKINET MR is a racemic mixture of the d- and l- threo enantiomers of methylphenidate. The d-enantiomer is more pharmacologically active than the l-enantiomer.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Absorption:
MEDIKINET MR has a plasma profile showing two phases of active substance release, with a sharp, initial, upward slope similar to a methylphenidate hydrochloride immediate-release tablet, and a second rising portion approximately three hours later, followed by a gradual decline.
When taken by adults in the morning after breakfast, the immediate-release portion of the hard capsule dissolves rapidly and results in a intial peak plasma concentration. After passing through the stomach and into the small intestine, the sustained-release portion of the hard capsule releases its methylphenidate hydrochloride. This results in the formation of a 3-4 hour plateau phase during which concentrations do not sink below 75% of the peak plasma concentration. The amount of methylphenidate hydrochloride absorbed when administered once daily is comparable with conventional immediate-release formulations administered twice daily.
MEDIKINET MR combines the advantages of a fast onset of action with the build-up of an extended-duration plateau phase.
The following pharmacokinetic parameters were measured following a single daily dose of MEDIKINET MR 20 mg administered after breakfast: cmax = 6.4 ng/ml, tmax = 2.75 h, AUCinf = 48.9 ng.h.ml-1 and t½ = 3.2 h The area under the plasma concentration curve (AUC), as well as the peak plasma concentration, is proportional to the dose.

Food Effects:
Ingestion together with food with a high fat content delays its absorption (Tmax) by approximately 1.5 hour. There is no difference in bioevailability of MEDIKINET MR given either a normal or high calorie breakfast. The plasma curves show similar exposure regarding rate and extend of absorption.
It is necessary to take MEDIKINET MR with or after breakfast. The food influence takes effect and shows a significant and relevant retardation. This justifies the posology to be taken with food. A recommendation in relation of type of food is not necessary. Administration without food can have a risk of dose dumping.

Sprinkle Administration:
The Cmax Tmax and AUC of the sprinkled contents of the MEDIKINET MR capsule are similar (bioequivalent) to the intact capsule. MEDIKINET MR may, therefore, be administered either as an intact capsule, or the capsule may be opened and the contents swallowed, without chewing, immediately after sprinkling onto applesauce or other similar soft food.


Age:
The Pharmacokinetics of MEDIKINET MR have not been studied in children younger than 6 years of age.

Availability, systemic:
Owing to extensive first-pass metabolism its systemic availability amounts to approximately 30% (11-51%) of the dose.

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).

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.