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Review
, 24 (1), 1-17

Evolution of Stimulants to Treat ADHD: Transdermal Methylphenidate

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Review

Evolution of Stimulants to Treat ADHD: Transdermal Methylphenidate

Kennerly S Patrick et al. Hum Psychopharmacol.

Abstract

Objective: The following comprehensive review describes the evolution of stimulant drug formulations used in the treatment of attention-deficit/hyperactivity disorder (ADHD). Emphasis is placed on the basic and clinical pharmacology of the dl-methylphenidate (MPH) transdermal system (MTS).

Methods: The pharmacokinetic and pharmacodynamic literature pertaining to MPH and amphetamine enantiomers was reviewed in the context of ADHD therapy and MTS as a treatment option.

Results: MTS incorporates MPH into an adhesive monolithic matrix, using the free base form of the drug to facilitate transdermal absorption. MTS technology minimizes contact dermatitis by eliminating to need for percutaneous penetration enhancers. After a lag time of approximately 2 h, plasma concentrations of the therapeutic d-MPH isomer become detectable, then continuously rise over the course of the recommended 9 h wear time. Concentrations of l-MPH typically attain 40-50% that of d-MPH (vs. 1-2% following oral MPH). Unauthorized MTS removal poses some misuse liability and over 50% of MTS drug content remains in the discarded system.

Conclusions: While liquid or chewable MPH formulations overcome potential swallowing difficulties, as do sprinkled once-daily extended-release (ER) MPH products, only MTS addresses swallowing difficulties while also offering a flexible individualized MPH exposure time in a once-daily MPH regimen.

Figures

Figure 1
Figure 1
Stereostructures of amphetamine enantiomers
Figure 2
Figure 2
Stereostructures of MPH enantiomers as assigned by chemical correlation (Shafi'ee and Hite, 1969) and by X-ray crystallography (Froimowitz et al., 1995). Adapted from Patrick et al. (1987)
Figure 3
Figure 3
Mean plasma MPH concentration-times profiles (n = 18) comparing branded and generic 20 mg conventional ER-MPH formulations (◆; ■) versus 10 mg IR-MPH (□) dosed on the twice-daily schedule
Figure 4
Figure 4
Estimate of relative mean plasma d-MPH concentrations from single doses of different biphasic/pulsatile (second generation) ER-MPH dosage forms when administered at doses that would provide approximately the same total exposure (AUC). In oral MPH pharmacokinetic analyses, virtually all detectable drug exists as the d-isomer due to the very extensive pre-systemic metabolism of l-MPH (See Historical perspective). Plasma Cmax values resulting from maintenance doses of ER-MPH formulations for most ADHD patients generally range from 10 to 20ng/ml. For specific values, see Markowitz et al. (2003a), Patrick et al. (2005a), Quinn et al. (2007), Markowitz and Patrick (2008), Reiz et al. (2008)
Figure 5
Figure 5
Plasma d-MPH and l-MPH (inset) concentration-time profiles for 12.5 (◇), 25 (□), and 37.5 cm2 (Δ) MTS compared to 54 mg Concerta® (X) (Andreason, 2005)

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