Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2     Pharmacodynamics
Dexmethylphenidate is the more pharmacologically active d-enantiomer of racemic methylphenidate. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space.
Cardiac Electrophysiology
At the recommended maximum total daily dosage of 40 mg, Metadex XRdoes not prolong the QTc interval to any clinically relevant extent.

Pharmacokinetic Properties

12.3     Pharmacokinetics
Absorption dexmethylphenidate produces a bi-modal plasma concentration-time profile (i.e., 2 distinct peaks approximately 4 hours apart) when orally administered to healthy adults.
The initial rate of absorption for dexmethylphenidate is similar to that of dexmethylphenidate tablets as shown by the similar rate parameters between the 2 formulations, i.e., first peak concentration (Cmax1), and time to the first peak (tmax1), which is reached in 1.5 hours (typical range 1 to 4 hours). The mean time to the interpeak minimum (tminip) is slightly shorter, and time to the second peak (tmax2) is slightly longer for dexmethylphenidate given once daily (about 6.5 hours; range, 4.5 to 7 hours) compared to dexmethylphenidate tablets given in 2 doses 4 hours apart (see Figure 1), although the ranges observed are greater for dexmethylphenidate .
dexmethylphenidate given once daily exhibits a lower second peak concentration (Cmax2), higher interpeak minimum concentrations (Cminip), and fewer peak and trough fluctuations than dexmethylphenidate tablets given in 2 doses given 4 hours apart. This is due to an earlier onset and more prolonged absorption from the delayed-release beads (see Figure 1).
The ratio of geometric mean of AUC(0-inf) and Cmax after administration of dexmethylphenidate given once daily are 1.02 and 0.86 respectively, to the same total dose of dexmethylphenidate tablets given in 2 doses 4 hours apart. The variability in Cmax, Cmin, and AUC is similar between dexmethylphenidate and dexmethylphenidate immediate-release tablets with approximately a 3-fold range in each.
Approximately 90% of the dose is absorbed after oral administration of radiolabeled racemic methylphenidate. However, due to first pass metabolism, the mean absolute bioavailability of dexmethylphenidate when administered in various formulations was 22% to 25%.



Figure 1. Mean Dexmethylphenidate Plasma Concentration-Time Profiles After Administration 1 x 20 mg dexmethylphenidate (n = 24) Capsules and 2 x 10 mg dexmethylphenidate Immediate-Release Tablets (n = 25)


After single dose administration, dexmethylphenidate demonstrated dose proportional pharmacokinetics (PK) in the range of 5 mg to 40 mg.
For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and administered [see Dosage and Administration (2)].
Distribution
The plasma protein binding of dexmethylphenidate is not known; racemic methylphenidate is bound to plasma proteins by 12% to 15%, independent of concentration. Dexmethylphenidate shows a volume of distribution of 2.65 ± 1.11 L/kg.
Elimination
Plasma dexmethylphenidate concentrations decline monophasically fo lowing oral administration of dexmethylphenidate . The mean terminal elimination half-life of dexmethylphenidate was about 3 hours in healthy adults. Pediatric patients tend to have slightly shorter half-lives with means of 2 to 3 hours. Dexmethylphenidate was eliminated with a mean clearance of 0.40 ± 0.12 L/hr/kg after intravenous administration.
Metabolism
In humans, dexmethylphenidate is metabolized primarily via de-esterification to d-α- phenyl-piperidine acetic acid (also known as d-ritalinic acid). This metabolite has little or no pharmacological activity. There is no in vivo interconversion to the l-threo- enantiomer.
Excretion
After oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite of racemic dl- methylphenidate was dl-ritalinic acid, accountable for approximately 80% of the dose.
Urinary excretion of parent compound accounted for 0.5% of an intravenous dose.
Studies in Specific Populations
Male and Female Patients
After administration of dexmethylphenidate , the first peak (Cmax1), was on average 45% higher in women. The interpeak minimum and the second peak also tended to be slightly higher in women although the difference was not statistically significant, and these patterns remained even after weight normalization.
Racial or Ethnic Groups
There is insufficient experience with the use of dexmethylphenidate to detect ethnic variations in pharmacokinetics.
Pediatric Patients
The pharmacokinetics of dexmethylphenidate after dexmethylphenidate administration have not been studied in pediatrics less than 18 years of age. When a similar formulation of racemic methylphenidate was examined in 15 patients between 10 and 12 years of age, and 3 patients with ADHD between 7 and 9 years of age, the time to the first peak was similar, although the time until the between peak minimum, and the time until the second peak were delayed and more variable in pediatric patients compared to adults. After administration of the same dose to pediatric patients and adults, concentrations in pediatric patients were approximately twice the concentrations observed in adults. This higher exposure is almost completely due to smaller body size as no relevant age-related differences in dexmethylphenidate pharmacokinetic parameters (i.e., clearance and volume of distribution) are observed after normalization to dose and weight.
Patients with Renal Impairment
There is no experience with the use of dexmethylphenidate in patients with renal impairment. Since renal clearance is not an important route of methylphenidate elimination, renal impairment is expected to have little effect on the pharmacokinetics of Metadex XR.
Patients with Hepatic Impairment
There is no experience with the use of Metadex XRin patients with hepatic impairment. Drug Interaction Studies
Methylphenidate is not metabolized by cytochrome P450 (CYP) isoenzymes to a clinically relevant extent. Inducers or inhibitors of CYPs are not expected to have any relevant impact on methylphenidate pharmacokinetics. Conversely, the d- and l-enantiomers of methylphenidate did not relevantly inhibit CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A.
Clinically, methylphenidate coadministration did not increase plasma concentrations of the CYP2D6 substrate desipramine.