Medikinet Mechanism of Action

Pharmacotherapeutic group: psychostimulants, agents used for ADHD and nootropics; centrally acting sympathomimetics. ATC Code: N06BA04.
Pharmacology: Pharmacodynamics: 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 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 neurones 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.
MEDIKINET MR was evaluated in two randomised, double-blind, placebo-controlled clinical studies in adult patients: 363 patients were evaluated in the EMMA study (1) using a treatment duration of 24 weeks. In the QUMEA study (2), 162 patients were treated for 20 weeks overall, with all patients having changed from an 8-week double-blinded phase to an open phase of 12 weeks, during which all patients were treated with MEDIKINET MR. Primary endpoint of both studies was a decrease in WRI score (Wender-Reimherr-Interview = WRAADS). Evaluation took place at week 24 (study 1) and week 8 (study 2).
The daily dose was titrated individually in weekly steps according to the observed efficacy and tolerability, starting with 10 mg per day (study 1) or with a dose of 0.5 mg/kg body weight (study 2). It was planned not to exceed a total daily dose of 60 mg (study 1) or 1 mg/kg body weight (study 2). At evaluation of the studies, methylphenidate was dosed lower in the first study, with the average value being 0.55 mg/kg body weight (administered daily dose: min. 10 mg, max. 60 mg), as compared to the second study, with the average value being 0.9 mg/kg body weight (administered daily dose: min. 20 mg, max. 120 mg). A higher effect size for the whole study population was calculated for the administration of a higher average dose (0.9 mg/kg body weight), as it was the case in the QUMEA study. The clinical studies rendered only limited experience with total daily doses of more than 80 mg, since only two patients were treated with daily doses of 120 mg/day.
Dose/gender effect: The results of the first study (EMMA) reveal that gender-specific differences in the response to methylphenidate and the possibility that women could benefit from lower doses cannot be ruled out. This study demonstrated efficacy in men solely in the highest dose range with MPH > 0.7 mg/kg body weight. In women, however, efficacy was demonstrated even in the low (< 0.3 mg/kg body weight) and mid dose range (0.3-0.7 mg/kg body weight). With respect to reduction in symptoms, women in the high dose group showed no significant effect and, with respect to response rate, efficacy was comparable with that in lower dose groups. In the second study (QUMEA) these gender-specific effects could not be confirmed reliably. This was because the low dose range was not administered and only a few patients were treated in the mid dose range. In the high dose group, the response rate in women was significantly higher in the comparison between verum and placebo. For men, a non-significant result was obtained. With respect to the main target parameter (WRI reduction in week 8), a significant score reduction when compared to placebo was obtained in both men and women.
The following data was obtained for the study population as a whole: With respect to reduction in the total WRI score in the EMMA study the change from baseline to week 24 was -18.88 on verum compared to -13.99 on placebo, giving an effect size of 0.39, 95% CI (0.18, 0.63, for effect size) p=0.002. (ANOVA using LOCF for missing values). In the QUMEA the change from baseline to week 8 was -13.2 on verum compared to -6.2 on placebo, giving an effect size of 0.54, 95% CI (0.22, 0.85, for effect size) p=0.0001. (ANOVA using LOCF for missing values). The recalculated responder rate was determined as: Responder: % patients with WRAADDS Score 30% reduction or more and without trial discontinuation, Non-Responder: Patients with less reduction in WRAADDS score or early trial discontinuation for every reason, which lead to missing values in week 24 or 8). In the EMMA trial the recalculated responder rate was 128 (53%) in the verum group vs. 44 (37%) in the placebo group (Week 24, fisher's exact test, two-sided, 0.0051. The recalculated responder rate in the QUMEA study in week 8 was 41 (49%) vs. 14 (18%) (verum versus placebo, fisher's exact test, two-sided, p<0.0001).
Pharmacokinetics: 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 an initial 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: C_max = 6.4 ng/ml, t_max = 2.75 h, AUC_inf = 48.9 ng*h*ml^-1 and t_½ = 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 (t_max) by approximately 1.5 hours. There is no difference in bioavailability of MEDIKINET MR given either with a normal or high calorie meal. The plasma curves show similar exposure regarding rate and extend of absorption.
It is necessary to take MEDIKINET MR with or after a meal. 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 C_max, t_max, 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 and in adults older than 65 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 plasma (57%) and 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.
Toxicology: Preclinical safety data: Reproductive toxicity: Methylphenidate is considered to be possibly teratogenic in rabbits. Spina bifida with malrotated hind limbs was observed in two separate litters at a dose of 200mg/kg/day.
Exposure (AUC) at this dose was approximately 5.1 times higher than the extrapolated exposure at the maximum recommended human dose (MRHD). Exposure at the next lower dose, wherein no spina bifida was found, was 0.7 times the extrapolated exposure at MRHD. A second study was conducted with a high dose of 300 mg/kg, which was considered maternally toxic. No spina bifida was seen, in 12 liters (92 fetuses) surviving. Exposure (AUC) at 300 mg/kg was 7.5 times the extrapolated exposure at MRHD.
Methylphenidate is not teratogenic in rats. Development fetal toxicity was noted at a high dose of 75 mg/kg (20.9 times higher than the exposure (AUC) at MRHD) and consisted of an increase of the instance of fetuses with delayed ossification of the skull and hyoid bones as well as fetuses with short supernumerary ribs.
Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted over two generations of mice continuously receiving methylphenidate doses of up to 160 mg/kg/day (about 90-fold^* higher than the MRHD on a mg/kg basis).
^*based on pediatric patient body weight of 35 kg and a MRHD of 60 mg/day.
When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day (about 26-fold higher than the MRHD on a mg/kg basis), offspring body weight gain was decreased at the highest dose, but no other effects on postnatal development were observed.
Carcinogenicity: In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas (a benign tumor) and, in males only, an increase in hepatoblastomas (a malignant tumor) at daily doses of approximately 60 mg/kg/day about 35-fold-higher than the MRHD on a mg/kg basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no overall increase in the number of malignant hepatic tumors. The mouse strain used is particularly sensitive to the development of hepatic tumors. It is thought that hepatoblastomas might be due to non-genotoxic mechanisms such as an increase in hepatic cell proliferation. This is consistent with the increase in liver weights observed in this mouse carcinogenicity study.
Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day (about 26-fold^* higher than the MRHD on a mg/kg basis).
^*based on pediatric patient body weight of 35 kg and a MRHD of 60 mg/day.