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{"project":"2_test","denotations":[{"id":"24532028-18759645-22892240","span":{"begin":411,"end":413},"obj":"18759645"},{"id":"24532028-20814325-22892241","span":{"begin":1065,"end":1066},"obj":"20814325"},{"id":"24532028-20814325-22892242","span":{"begin":1304,"end":1305},"obj":"20814325"},{"id":"24532028-20814325-22892243","span":{"begin":2163,"end":2164},"obj":"20814325"},{"id":"24532028-20814325-22892244","span":{"begin":2567,"end":2568},"obj":"20814325"},{"id":"24532028-20814325-22892245","span":{"begin":3703,"end":3704},"obj":"20814325"},{"id":"24532028-18759645-22892246","span":{"begin":4529,"end":4531},"obj":"18759645"},{"id":"24532028-20814325-22892247","span":{"begin":5120,"end":5121},"obj":"20814325"},{"id":"24532028-19519257-22892248","span":{"begin":5507,"end":5509},"obj":"19519257"}],"text":"Comparative Pharmacokinetics of MTS Compared with Oral Methylphenidate Formulations\nThe differences between MTS and immediate- and extended-release oral methylphenidate formulations reside in their pharmacokinetic profiles. The pharmacokinetic profile of MTS was evaluated in a phase II, randomized, placebo-controlled laboratory classroom study involving 80 children aged 6–12 years who were treated for ADHD [25]. Doses were titrated to methylphenidate 10, 15, 20, or 30 mg delivered over a 9-h MTS wear time. Systemic exposure was proportional to dose, and the effectiveness was observed between the first observation at 2 h after patch application and 12 h after patch application. These observations were expanded in a second pharmacokinetic study—conducted in 35 children aged 6–12 years and 36 adolescents aged 12–16 years—that compared the pharmacokinetic profiles of d- and l-methylphenidate enantiomers following administration of single, multiple fixed, and escalating doses of MTS or osmotic release oral system (OROS) methylphenidate 18 mg once daily [5].\nThe pharmacokinetic profiles of methylphenidate following single and multiple MTS and OROS doses are shown in Fig. 2. Circulating levels of d-methylphenidate were higher in children than for adolescents for all dosing regimens tested [5]. For the single-dose determinations, all patients received MTS 10 mg/9 h or OROS methylphenidate 18 mg/day. Blood samples were taken before dosing and at 1, 2, 4, 6, 8, 9, 10, 12, 14, 24, and 30 h post-dosing. Following the single dose, the concentration of d-methylphenidate was not measureable at the 1- or 2-h sampling times, suggesting that absorption of methylphenidate with MTS administration is delayed by about 2 h. In contrast, serum concentrations of methylphenidate increased rapidly after administration of a single OROS methylphenidate dose. The mean time to maximum concentration (tmax) for d-methylphenidate was 10.0 h (range 8.00–12.0) in children and 10.0 h (range 6.00–12.0) in adolescents with MTS, whereas the tmax following a single OROS methylphenidate dose was 6.02 h (range 4–10) in children and 8.00 h (range 1–10) in adolescents [5]. The same dosing regimens were extended for 10 days for the multiple fixed-dose analyses. Accumulation (defined as the maximum concentration [Cmax] at steady state over the Cmax after a single dose) of d-methylphenidate was 34 % in children and 57 % in adolescents after 7 days of MTS 10 mg/9 h per day, and 13 % in children and 19 % in adolescents following 7 days of OROS methylphenidate 18 mg/day [5]. Consistent with these accumulation data, serum methylphenidate was measurable at the 1 and 2 h sampling times after multiple dosing. The concentration-time curves suggest that lower doses of methylphenidate administered by a transdermal patch compared with OROS methylphenidate could achieve the same plasma levels of d-methylphenidate. Trough concentrations at steady state (between days 7 and 14 of escalated dosing) were similar between MTS and OROS methylphenidate when compared across corresponding doses in the same age group. As shown in Fig. 2, with MTS administration, serum levels of d-methylphenidate increased and did not decline during the 9-h wear time following multiple doses. As expected with OROS methylphenidate administration, serum d-methylphenidate levels increased rapidly over the first 1–2 h, and continued to increase, reaching a mean tmax at 6 h (range 4–10) after single and 8 h (range 4.00–10.0) after multiple fixed doses in children 6–12 years of ages. The mean tmax in adolescents (13–17 years) was 8 h (range 1–10) after 1 day of OROS methylphenidate 18 mg/day dosing, and was similar after 7 days [5].\nFig. 2 Mean plasma concentration-time profiles from day 1 to 31 for d-methylphenidate after single and multiple doses of MTS and OROS MPH in children aged 6–12 years (a, c) and adolescents aged 13–17 years (b, d) in the pharmacokinetic population. MTS 10 mg (day 1) indicates a single dose; MTS 10 mg (day 10), multiple fixed dose for 7 days; MTS 10 mg (day 31), multiple fixed dose for 28 days; MTS 30 mg, multiple escalating dose for 28 days (10, 15, 20, and 30 mg for 7 days each); OROS MPH 18 mg (day 1), single dose; OROS MPH 18 mg (day 10), multiple fixed dose for 7 days; OROS MPH 54 mg (day 31), multiple escalating dose for 28 days (18, 27, 36, and 54 mg for 7 days each). MTS methylphenidate transdermal system, OROS MPH osmotic-release oral system methylphenidate. Reprinted with permission from Pierce et al. [25]\nAnother difference of potential clinical importance between the MTS and other methylphenidate formulations is exposure to l-methylphenidate, which appears to be higher with the MTS relative to other formulations of methylphenidate following single or multiple doses. Circulating levels of l-methylphenidate are negligible after single or multiple doses in patients treated with oral methylphenidate and, as a result, the effects of this enantiomer have not been well characterized. The clinical implications of l-methylphenidate absorption with the MTS, if any, remain to be elucidated [5].\nThe application site can affect the bioavailability and pharmacokinetic profile of drugs administered through the skin. A comparison of two sites found that application of MTS to the hip resulted in a significantly greater Cmax than application to the scapula (33.8 ± 10.2 vs. 26.2 ± 11.2 ng/mL, p = 0.01 hip vs. scapula) in boys and girls (aged 6–12 years) during a 16-h wear time [26]. The area under the curve from 0 to 16 h (AUC0–16) was also greater with hip placement, although the tmax was only slightly longer with hip placement."}

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