Pharmacokinetics and dopamine d2 and serotonin 5-ht2a receptor occupancy of paliperidone in healthy subjects: two open-label, single-dose studies (PAL-115)

Abstract

Two open-label studies assessed pharmacokinetics, dopamine D2 and serotonin 5-HT2A receptor occupancy for paliperidone immediate-release 1mg (IR; Study 1) and extended-release 6mg (ER; Study 2). Blood was collected pre-dose and ≤24h (Study 1, n=3) and ≤48h (Study 2, n=4). Striatal D2 receptor binding measured using PET and 11C-raclopride pre-dose and post-dose at 2.5h (Study 1) and at 22h and 46h (predicted Cmax; Study 2). Frontal cortex 5-HT2A receptor occupancy (Study 1) assessed using [11C]M100,907 ≥1 week pre-dose and 4.5h post-dose (Cmax). The apparent dissociation constant (KDapp=plasma concentration at which 50% of target receptor is occupied) estimated via Emax model. Formulation differences reflected in tmax (median 4.2h for paliperidone IR 1mg vs. 24.1h for paliperidone ER 6mg) and Cmax (median 6.02ng/mL vs. 11.3ng/mL). Paliperidone ER 6mg had a median D2 occupancy of 64% at 22h post-dose (for paliperidone IR 1mg 48% at 2.5h post-dose). Calculated KDapp from pooled data was 4.9ng/mL. Using the KDapp, calculated plasma concentrations for 70–80%, D2 occupancy is 11–20/mL. The median 5HT2A occupancy for paliperidone IR 1mg was 65% at 4.5h post-dose, with a corresponding plasma concentration of 5.1–6.0mg/Ml, which indicates that the 5HT2A occupancy is substantially higher than D2at therapeutic doses. Paliperidone highly occupies central D2 and 5HT2A receptors. The D2 occupancy with paliperidone ER suggests that 6mg will be an effective dose in schizophrenia treatment.