PIII‐57

OBJECTIVES Assess pharmacokinetics, dopamine D 2 and serotonin 5‐HT 2A receptor occupancy of paliperidone immediate‐release 1mg (paliperidone IR; Study 1) and paliperidone extended‐release tablets 6mg (paliperidone ER; Study 2). METHODS Blood samples were collected pre‐dose and ≤24h (Study 1) and ≤48h (Study 2). Striatal D 2 receptor binding was measured using PET and 11 C‐raclopride pre‐dose and post‐dose at 2.5h (Study 1) and at 22h and 46h (predicted C max ; Study 2). Frontal cortex 5‐HT 2A receptor occupancy (Study 1) was assessed using[ 11 C]M100,907 ≥1 week pre‐dose and 4.5h post‐dose (C max ). The apparent dissociation constant (K D app =plasma concentration at which 50% of target receptor is occupied) was estimated using an E max model. RESULTS Formulation differences were reflected in t max and C max . Paliperidone ER 6mg corresponds to median D 2 occupancy of 64% at 22h post‐dose. Using the K D app , plasma concentrations corresponding to 70–80% D 2 occupancy were estimated: 15–25ng/mL (Study 1); 10–17ng/mL (Study 2). Using pooled data from both studies the in vivo K D app is estimated to be 4.9ng/mL. CONCLUSION Paliperidone occupies central D 2 and 5HT 2A receptors. D 2 receptor occupancy with paliperidone ER suggests 6mg will be an effective dose in the treatment of schizophrenia. (See Table)Measure Paliperidone IR 1mg *. Study 1 (n=3) Paliperidone ER 6mg *. Study 2 (n=4)Median C max (ng/mL) (range) 6.02 (5.34–6.14) 11.3 (7.73–16.5) Median t max (h) (range) 4.2 (4.1–8.1) 24.1 (23.1–29.0) Median % D 2 receptor occupancy (range) 48 (35–51)[2.5h post‐dose] 64 (56–79)[22h post‐dose]; 53 (40–62)[46h post‐dose] Calculated K D app for D 2 ‐receptor occupancy (ng/mL) 6.4 4.4 Median % 5‐HT 2A ‐receptor occupancy (range) 65 (65–71)[4.5h post‐dose] Not measured Corresponding plasma concentration range (mg/mL) 5.1–6.0[4.0h post‐dose] Not measuredInitial studies have shown that paliperidone ER has a bioavailability of approximately 33% of that of paliperidone IR.Clinical Pharmacology & Therapeutics (2005) 79 , P74–P74; doi: 10.1016/j.clpt.2005.12.265