A comparison of continuous subcutaneous paliperidone infusion and repeated subcutaneous injection of risperidone free-base in rats

Abstract

It is proposed that to achieve a therapeutic effect in schizophrenia patients, dopamine D(2)-receptor occupancy by antipsychotics within the striatum must exceed 60-65%. However, at high levels of D(2)-receptor occupancy, the risk of extrapyramidal symptoms (EPS) is increased. Following oral dosing of antipsychotics, peaks and troughs in plasma drug concentrations may be mirrored by fluctuations in D(2)-receptor occupancy. Paliperidone, a novel antipsychotic available as extended-release tablets (paliperidone ER), is the major active metabolite of risperidone and exhibits a plasma pharmacokinetic profile with reduced peak-trough fluctuations and consistent D(2)-receptor occupancy compared with conventional oral antipsychotic formulations. Using formulations that resemble those in clinical practice, this study provides a preclinical evaluation of the pharmacological properties of paliperidone ER and risperidone immediate-release formulation in terms of consistent antipsychotic efficacy over time and extrapyramidal symptom liability. Significant fluctuations in inhibition of d-amphetamine-induced hyperlocomotion were observed for repeated subcutaneous (SC) risperidone injections, whereas stable inhibitory efficacy was demonstrated during continuous SC paliperidone infusion. Similarly, significant fluctuations in latency on-bar were observed with repeated SC risperidone injections, whereas significantly lower latency on-bar was demonstrated following continuous SC paliperidone infusion. These results in an animal model suggest that although risperidone and paliperidone demonstrate similar pharmacologic effects, continuous administration of paliperidone achieves more stable antipsychotic efficacy with reduced motor impairment, akin to the effects observed with paliperidone ER in clinical studies.

Flexible dosing with paliperidone ER in the treatment of patients with acutely exacerbated schizophrenia: results from a single-arm, open-label study

“…Currently, two oral atypical antipsychotics (paliperidone and quetiapine) are available in extended-release (ER or XR, respectively) formulations. Extended-release oral antipsychotics have been shown to have at least comparable efficacy and tolerability with immediate-release agents; however, adherence may be improved using extended-release therapy [2][3][4][5][6] . In an interesting animal study, single-dose injections with risperidone or paliperidone showed similar inhibition of amphetamine-induced hyperlocomotion 6 .…”

“…Extended-release oral antipsychotics have been shown to have at least comparable efficacy and tolerability with immediate-release agents; however, adherence may be improved using extended-release therapy [2][3][4][5][6] . In an interesting animal study, single-dose injections with risperidone or paliperidone showed similar inhibition of amphetamine-induced hyperlocomotion 6 . However, repeated risperidone injections resulted in fluctuating inhibition, while continuous paliperidone infusion produced a stable inhibitory effect suggesting that extended-release dosing might also result in improved tolerability.…”

Studies on Paliperidone in OROS Tablets: Extraction Procedure and Chromatographic Analysis

“…A series of studies have evaluated the pharmacodynamics, efficacy, and tolerability of paliperidone. The results obtained from randomized, double-blinded, placebo-controlled studies indicate that the drug is effective and safe at all doses, resulting in significant improvements in the symptoms of schizophrenia and related disorders [3,[12][13][14][15][16].…”

Stress Degradation Behavior of Paliperidone, an Antipsychotic Drug, and Development of Suitable Stability-Indicating RP-LC Method

“…It is also active as an antagonist at α 1 and α 2 adrenergic receptors and H 1 -histaminergic receptors. Paliperidone has one chiral centre but as the pharmacological profiles of the racemate and the two enantiomers are similar with respect to in vitro binding assays, in vitro receptor occupancy studies and in vivo functional interaction studies, hence, it is marketed in its racemic mixture [1][2][3][4][5][6][7][8]. Paliperidone is chemically designated as (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4Hpyrido [1,2-a]pyrimidin-4-one ( Figure 1).…”