Post by Amtram on Mar 1, 2014 12:50:46 GMT -5
This is from the manufacturer, Novartis:
Pharmacodynamics
Dexmethylphenidate hydrochloride is a central nervous system stimulant. Focalin, the more pharmacologically active enantiomer of the d- and l-enantiomers, is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known.
Effects on QT Interval
The effect of Focalin® XR on the QT interval was evaluated in a double-blind, placebo- and open label active (moxifloxacin)-controlled study following single doses of Focalin XR 40mg in 75 healthy
volunteers. ECGs were collected up to 12 hours post dose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was <5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident-exposure response relationship.
Pharmacokinetics
Absorption
Dexmethylphenidate hydrochloride is readily absorbed following oral administration of Focalin. In patients with ADHD, plasma dexmethylphenidate concentrations increase rapidly, reaching a maximum in the fasted state at about 1 to 1.5 hours post dose. No differences in the pharmacokinetics of Focalin were noted following single and repeated twice daily dosing, thus indicating no significant drug accumulation in children with ADHD.
When given to children as capsules in single doses of 2.5 mg, 5 mg, and 10 mg, Cmax and AUC0-inf of dexmethylphenidate were proportional to dose. In the same study, plasma dexmethylphenidate levels were comparable to those achieved following single dl-threo-methylphenidate HCl doses given as capsules in twice the total mg amount (equimolar with respect to Focalin).
Food Effects
In a single dose study conducted in adults, coadministration of 2 x 10 mg Focalin with a high fat breakfast resulted in a dexmethylphenidate tmax of 2.9 hours post dose as compared to 1.5 hours post dose when given in a fasting state. Cmax and AUC0-inf were comparable in both the fasted and non fasted states.
Distribution
Plasma dexmethylphenidate concentrations in children decline exponentially following oral administration of Focalin.
Metabolism and Excretion
In humans, dexmethylphenidate is metabolized primarily to d-α-phenyl-piperidine acetic acid (also known as d-ritalinic acid) by de-esterification. This metabolite has little or no pharmacological activity. There is little or no in vivo interconversion to the l-threo-enantiomer, based on a finding of minute levels of l-threo-methylphenidate being detectable in a few samples in only 2 of 58 children and adults. After oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was ritalinic acid, accountable for approximately 80% of the dose.
In vitro studies showed that dexmethylphenidate did not inhibit cytochrome P450 isoenzymes.
The mean plasma elimination half-life of dexmethylphenidate is approximately 2.2 hours.
Dexmethylphenidate hydrochloride is a central nervous system stimulant. Focalin, the more pharmacologically active enantiomer of the d- and l-enantiomers, is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known.
Effects on QT Interval
The effect of Focalin® XR on the QT interval was evaluated in a double-blind, placebo- and open label active (moxifloxacin)-controlled study following single doses of Focalin XR 40mg in 75 healthy
volunteers. ECGs were collected up to 12 hours post dose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was <5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident-exposure response relationship.
Pharmacokinetics
Absorption
Dexmethylphenidate hydrochloride is readily absorbed following oral administration of Focalin. In patients with ADHD, plasma dexmethylphenidate concentrations increase rapidly, reaching a maximum in the fasted state at about 1 to 1.5 hours post dose. No differences in the pharmacokinetics of Focalin were noted following single and repeated twice daily dosing, thus indicating no significant drug accumulation in children with ADHD.
When given to children as capsules in single doses of 2.5 mg, 5 mg, and 10 mg, Cmax and AUC0-inf of dexmethylphenidate were proportional to dose. In the same study, plasma dexmethylphenidate levels were comparable to those achieved following single dl-threo-methylphenidate HCl doses given as capsules in twice the total mg amount (equimolar with respect to Focalin).
Food Effects
In a single dose study conducted in adults, coadministration of 2 x 10 mg Focalin with a high fat breakfast resulted in a dexmethylphenidate tmax of 2.9 hours post dose as compared to 1.5 hours post dose when given in a fasting state. Cmax and AUC0-inf were comparable in both the fasted and non fasted states.
Distribution
Plasma dexmethylphenidate concentrations in children decline exponentially following oral administration of Focalin.
Metabolism and Excretion
In humans, dexmethylphenidate is metabolized primarily to d-α-phenyl-piperidine acetic acid (also known as d-ritalinic acid) by de-esterification. This metabolite has little or no pharmacological activity. There is little or no in vivo interconversion to the l-threo-enantiomer, based on a finding of minute levels of l-threo-methylphenidate being detectable in a few samples in only 2 of 58 children and adults. After oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was ritalinic acid, accountable for approximately 80% of the dose.
In vitro studies showed that dexmethylphenidate did not inhibit cytochrome P450 isoenzymes.
The mean plasma elimination half-life of dexmethylphenidate is approximately 2.2 hours.