PIII-57Pharmacokinetics and dopamine D2 And serotonin 5-HT2A receptor occupancy of paliperidone in healthy subjects: Two open-label, single-dose studies

Abstract

OBJECTIVES Assess pharmacokinetics, dopamine D2 and serotonin 5-HT2A 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 D2 receptor binding was 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) was 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) was estimated using an Emax model. RESULTS Formulation differences were reflected in tmax and Cmax. Paliperidone ER 6mg corresponds to median D2 occupancy of 64% at 22h post-dose. Using the KDapp, plasma concentrations corresponding to 70–80% D2 occupancy were estimated: 15–25ng/mL (Study 1); 10–17ng/mL (Study 2). Using pooled data from both studies the in vivo KDapp is estimated to be 4.9ng/mL. CONCLUSION Paliperidone occupies central D2 and 5HT2A receptors. D2 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 Cmax (ng/mL) (range) 6.02 (5.34–6.14) 11.3 (7.73–16.5) Median tmax (h) (range) 4.2 (4.1–8.1) 24.1 (23.1–29.0) Median % D2 receptor occupancy (range) 48 (35–51)[2.5h post-dose] 64 (56–79)[22h post-dose]; 53 (40–62)[46h post-dose] Calculated KDapp for D2-receptor occupancy (ng/mL) 6.4 4.4 Median % 5-HT2A-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 measured a Initial 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