A PET study examining dopamine transporter occupancy of repeat dosing of two formulations of methylphenidate in adults

Abstract

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Objectives: The rapid rise of plasma concentration and dopamine transporter (DAT) occupancy of immediate release methylphenidate (IR-MPH) is associated with greater abuse liability (detection/likability) than that of OROS-MPH which has a slow rise (Spencer et al. AJP 2006). However, the central nervous system pharmacokinetics of repeated administration are unknown. Methods: Eleven healthy volunteers underwent PET imaging with ¹¹C Altropane before and after repeat administration of oral doses of methylphenidate given at hour 0 and again at hour 4 in different sequences (OROS-OROS, OROS-IR, IR-IR & IR-OROS) on different days. The dose of IR-MPH was 20 mg and that of OROS-MPH, 36 mg. PET imaging occurred at 5 hours after initial dosing (1 hour after the second dose). Subjects were injected with 5 mCi of ¹¹C Altropane and serial images of the brain were acquired with a Siemens HR+ PET camera. Binding potential (BP,k3/ k4) was calculated from time-activity curves using the simplified reference region method with cerebellum as reference. Results: After repeat MPH dosing, DAT occupancy (right caudate) of IR-OROS sequence was lower than that of IR-IR (53.7±9 vs. 66.1±7, p<0.005) and OROS-IR (53.7±9 vs. 65.4±10, p<0.02). DAT occupancy (right caudate) of the OROS-OROS sequence was intermediate (62.8±11) and not statistically different from that of IR-IR or OROS-IR. Conclusions: To our knowledge this is the first study to document the pharmacokinetics of DAT receptor occupancy of repeated administration of therapeutic doses of a short and a long-acting formulation of MPH. Consistent with our hypotheses, the CNS DAT occupancies were greater at 5 hours in sequences with IR administrated second (at 4 hours) then the IR-OROS sequence. These preliminary results suggest that the abuse liability potential of delayed, repeated administrations of different formulations of MPH are moderated by the oral delivery system in which a slower onset may be safer than one with more rapid early release.

Research Support (if any): McNeil Inc.