CLINICAL PHARMACOLOGY
Pharmacodynamics
Methylphenidate hydrochloride, the active ingredient in Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, is a central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate 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. Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d - threo enantiomer is more pharmacologically active than the l-threo enantiomer.
Pharmacokinetics
Absorption
Ritalin LA produces a bi-modal plasma concentration-time profile (i.e., two distinct peaks approximately four hours apart) when orally administered to children diagnosed with ADHD and to healthy adults. The initial rate of absorption for Ritalin LA is similar to that of Ritalin tablets as shown by the similar rate parameters between the two formulations, i.e., initial lag time (Tlag), first peak concentration (Cmax1), and time to the first peak (Tmax1), which is reached in 1-3 hours. The mean time to the interpeak minimum (Tminip), and time to the second peak (Tmax2) are also similar for Ritalin LA given once daily and Ritalin tablets given in two doses 4 hours apart (see Figure 1 and Table 1), although the ranges observed are greater for Ritalin LA.
Ritalin LA given once daily exhibits a lower second peak concentration (Cmax2), higher interpeak minimum concentrations (Cminip), and less peak and trough fluctuations than Ritalin tablets given in two doses given 4 hours apart. This is due to an earlier onset and more prolonged absorption from the delayed-release beads (see Figure 1 and Table 1).
The relative bioavailability of Ritalin LA given once daily is comparable to the same total dose of Ritalin tablets given in two doses 4 hours apart in both children and in adults.
 Figure 1. Mean plasma concentration time-profile of methylphenidate after a single dose of Ritalin LA® 40 mg q.d. and Ritalin® 20 mg given in two doses four hours apart
Table 1. Mean ± SD and range of pharmacokinetic parameters of methylphenidate after a single dose of Ritalin LA® and Ritalin® given in two doses 4 hours apart | Population | Children | Adult Males |
Formulation
Dose | Ritalin ®
10 mg & 10 mg | Ritalin LA ®
20 mg | Ritalin ®
10 mg & 10 mg | Ritalin LA ®
20 mg |
| N | 21 | 18 | 9 | 8 |
| T lag (h) | 0.24 ± 0.44 | 0.28 ± 0.46 | 1.0 ± 0.5 | 0.7 ± 0.2 |
| 0 - 1 | 0 - 1 | 0.7 - 1.3 | 0.3 - 1.0 |
| T max1 (h) | 1.8 ± 0.6 | 2.0 ± 0.8 | 1.9 ± 0.4 | 2.0 ± 0.9 |
| 1 - 3 | 1 - 3 | 1.3 - 2.7 | 1.3 - 4.0 |
| C max1 (ng/mL) | 10.2 ± 4.2 | 10.3 ± 5.1 | 4.3 ± 2.3 | 5.3 ± 0.9 |
| 4.2 - 20.2 | 5.5 - 26.6 | 1.8 - 7.5 | 3.8 - 6.9 |
| T minip (h) | 4.0 ± 0.2 | 4.5 ± 1.2 | 3.8 ± 0.4 | 3.6 ± 0.6 |
| 4 - 5 | 2 - 6 | 3.3 - 4.3 | 2.7 - 4.3 |
| C minip (ng/mL) | 5.8 ± 2.7 | 6.1 ± 4.1 | 1.2 ± 1.4 | 3.0 ± 0.8 |
| 3.1 - 14.4 | 2.9 - 21.0 | 0.0 - 3.7 | 1.7 - 4.0 |
| T max2 (h) | 5.6 ± 0.7 | 6.6 ± 1.5 | 5.9 ± 0.5 | 5.5 ± 0.8 |
| 5 - 8 | 5 - 11 | 5.0 - 6.5 | 4.3 - 6.5 |
| C max2 (ng/mL) | 15.3 ± 7.0 | 10.2 ± 5.9 | 5.3 ± 1.4 | 6.2 ± 1.6 |
| 6.2 - 32.8 | 4.5 - 31.1 | 3.6 - 7.2 | 3.9 - 8.3 |
| AUC (0-∞) | 102.4 ± 54.6 | 86.6 ± 64.0a | 37.8 ± 21.9 | 45.8 ± 10.0 |
| (ng/mL x h-1) | 40.5 - 261.6 | 43.3 - 301.44 | 14.3 - 85.3 | 34.0 - 61.6 |
| t 1/2 (h) | 2.5 ± 0.8 | 2.4 ± 0.7a | 3.5 ± 1.9 | 3.3 ± 0.4 |
| 1.8 - 5.3 | 1.5 - 4.0 | 1.3 - 7.7 | 3.0 - 4.2 |
a N = 15
Dose Proportionality
After oral administration of Ritalin LA 20 mg and 40 mg capsules to adults there is a slight upward trend in the methylphenidate area under the curve (AUC) and peak plasma concentrations (Cmax1 and Cmax2).
Distribution
Binding to plasma proteins is low (10%-33%), and the apparent distribution volume at steady state with intravenous administration has been reported to be approximately 6 L/kg.
Metabolism
The absolute oral bioavailability of methylphenidate in children has been reported to be about 30% (range 10%-52%), suggesting pronounced presystemic metabolism. Biotransformation of methylphenidate is rapid and extensive leading to the main, de-esterified metabolite α-phenyl-2-piperidine acetic acid (ritalinic acid). Only small amounts of hydroxylated metabolites (e.g., hydroxymethylphenidate and hydroxyritalinic acid) are detectable in plasma. Therapeutic activity is principally due to the parent compound.
Elimination
In studies with Ritalin LA and Ritalin tablets in adults, methylphenidate from Ritalin tablets is eliminated from plasma with an average half-life of about 3.5 hours, (range 1.3 - 7.7 hours). In children the average half-life is about 2.5 hours, with a range of about 1.5 - 5.0 hours. The rapid half-life in both children and adults may result in unmeasurable concentrations between the morning and mid-day doses with Ritalin tablets. No accumulation of methylphenidate is expected following multiple once a day oral dosing with Ritalin LA. The half-life of ritalinic acid is about 3-4 hours.
After oral administration of an immediate release formulation of methylphenidate, 78%-97% of the dose is excreted in the urine and 1%-3% in the feces in the form of metabolites within 48-96 hours. Only small quantities (<1%) of unchanged methylphenidate appear in the urine. Most of the dose is excreted in the urine as ritalinic acid (60%-86%), the remainder being accounted for by minor metabolites.
Food Effects
Administration times relative to meals and meal composition may need to be individually titrated.
When Ritalin LA was administered with a high fat breakfast to adults, Ritalin LA had a longer lag time until absorption began and variable delays in the time until the first peak concentration, the time until the interpeak minimum, and the time until the second peak. The first peak concentration and the extent of absorption were unchanged after food relative to the fasting state, although the second peak was approximately 25% lower. The effect of a high fat lunch was not examined.
There were no differences in the pharmacokinetics of Ritalin LA when administered with applesauce, compared to administration in the fasting condition. There is no evidence of dose dumping in the presence or absence of food.
For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and administered (see DOSAGE AND ADMINISTRATION).
Special Populations
Age: The pharmacokinetics of Ritalin LA was examined in 18 children with ADHD between 7 and 12 years of age. Fifteen of these children were between 10 and 12 years of age. The time until the between peak minimum, and the time until the second peak were delayed and more variable in children compared to adults. After a 20-mg dose of Ritalin LA, concentrations in children were approximately twice the concentrations observed in 18 to 35 year old adults. This higher exposure is almost completely due to the smaller body size and total volume of distribution in children, as apparent clearance normalized to body weight is independent of age.
Gender: There were no apparent gender differences in the pharmacokinetics of methylphenidate between healthy male and female adults when administered Ritalin LA.
Renal Insufficiency: Ritalin LA has not been studied in renally-impaired patients. Renal insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity.
Hepatic Insufficiency: Ritalin LA has not been studied in patients with hepatic insufficiency. Hepatic insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body.
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