Biomedical subjects

Erik Mannaert

Publications and source records attributed to Erik Mannaert.

7 recordsLinked to original sources

PubMed2006

A PET study evaluating dopamine D2 receptor occupancy for long-acting injectable risperidone.

OBJECTIVE: Long-acting injectable risperidone represents the first clinically available depot atypical antipsychotic. The present study used positron emission tomography (PET) to evaluate its dopamine D(2) binding profile at doses of 25, 50, or 75 mg administered every 2 weeks. METHOD: After achieving stabilization with one of the doses, nine patients with a diagnosis of schizophrenia or schizoaffective disorder underwent [(11)C]raclopride PET to measure D(2) occupancy. Participants were scanned twice during the 2-week injection interval: within 3 days after injection (postinjection) and within 5 days before the next injection (preinjection). At the same time, plasma was collected for measurements of risperidone plus 9-hydroxyrisperidone. RESULTS: Mean post- and preinjection D(2) occupancy levels for the 25-, 50-, and 75-mg doses were 71.0% and 54.0%, 74.4% and 65.4%, and 81.5% and 75.0%, respectively. There was a significant correlation between dose and plasma concentrations of risperidone plus 9-hydroxyrisperidone, and the estimated plasma concentration associated with 50% D(2) occupancy (ED(50)) was 11.06 ng/ml. Prolactin levels were not correlated with drug levels or D(2) occupancy. CONCLUSIONS: All three doses of injectable risperidone showed peak D(2) occupancy levels above the 65% threshold associated with optimal clinical response; the 75-mg dose approximated the 80% threshold linked to increased risk of extrapyramidal symptoms. Doses of 25 or 50 mg should provide therapeutic efficacy while minimizing the risk of extrapyramidal symptoms.

Adult↗

PubMed2005

Plasma antipsychotic concentration and receptor occupancy, with special focus on risperidone long-acting injectable.

Although effective plasma concentration ranges have been established for some antipsychotics, conventional and atypical, there is considerable inter-patient pharmacokinetic variation. Positron-emission tomography (PET) can be used to estimate D(2)-like receptor occupancy in the brain needed for an antipsychotic effect and the level above which extrapyramidal side effects (EPS) develop. For conventional antipsychotics, the window occupancy is approximately 70-80%. For the atypical antipsychotic risperidone, the antipsychotic effect starts at approximately 60% occupancy, with occupancy above 80% leading to EPS. The new formulation, risperidone long-acting injectable (RLAI), comprises risperidone in a biodegradable polymer. It is effective long-term at doses of 25 or 50 mg injected i.m. every 2 weeks. The constant and slow release of the long-acting formulation leads to less fluctuation in plasma levels and to a D(2)-like receptor occupancy which is below the threshold for EPS.

Antipsychotic Agents↗

PubMed2005

Pharmacokinetics and D2 receptor occupancy of long-acting injectable risperidone (Risperdal Consta) in patients with schizophrenia.

Thirteen patients with schizophrenia received injections of 25, 50, or 75 mg of long-acting risperidone every 2 wk. Brain D2 receptor occupancy was assessed with [11C]raclopride 2 wk after the last (fifth) injection (day 71) in seven subjects and 2 wk after the third injection (day 44) in one subject. Stable plasma concentrations were reached after the third injection and steady-state concentrations of the active moiety (risperidone + 9-hydroxyrisperidone) after the fourth injection. Steady-state plasma concentrations were maintained for 4-5 wk after the last injection and then declined rapidly. After injections of 25, 50 and 75 mg on day 44 or day 71, D2 receptor occupancy ranged from 25-48%, 59-83% and 62-72% respectively, while plasma active-moiety levels ranged from 4.4-8.8, 15.0-31.1 and 22.5-26.3 ng/ml respectively. The results indicate that brain D2 receptor occupancy at steady state after injections of long-acting risperidone was in the range found in patients effectively treated with 2-6 mg of oral risperidone.

Administration, Oral↗

PubMed2005

Pharmacokinetic profile and clinical efficacy of long-acting risperidone: potential benefits of combining an atypical antipsychotic and a new delivery system.

Continuous long-term antipsychotic therapy is required for patients with schizophrenia to optimise treatment benefits. The use of long-acting antipsychotic preparations can help to ensure compliance with therapy and has been shown to improve efficacy in relapse prevention when compared with oral agents. How- ever, the use of long-acting agents has been limited, since this approach to patient care has only been available with conventional drugs. The atypical antipsychotic agents have provided a new option for the treatment of schizophrenia. However, entwined with health system limitations, partial or non-compliance remains a problem with oral atypical antipsychotic agents. Combining the attributes of the atypical antipsychotic class with the pharmacokinetic profile and compliance advantages of a long-acting formulation could potentially be an important advance in the management of patients requiring continuous anti- psychotic therapy. This review considers the available clinical data supporting possible advantages for the only long-acting atypical agent currently available, long-acting risperidone, as a microsphere formulation. The drug-delivery technology employed provides a sustained therapeutic plasma level, with administration once every 2 weeks, and this is translated into improved symptom control and improved quality of life, even in patients already deemed clinically stable on an oral agent or on a conventional depot antipsychotic.

Antipsychotic Agents↗

PubMed2004

Pharmacokinetics and tolerability of long-acting risperidone in schizophrenia.

The pharmacokinetics and tolerability of long-acting risperidone (Risperdal Consta) were evaluated in a multicenter, prospective, open-label, 15-week study of 86 patients with schizophrenia. Subjects stabilized on 2, 4 or 6 mg of oral risperidone once daily for at least 4 weeks were assigned to receive i.m. injections of 25, 50 or 75 mg of risperidone, respectively, every 2 weeks for 10 weeks. The 90% confidence intervals for the i.m./oral ratios of the mean steady-state plasma-AUC, corrected for dosing interval, and of the average plasma concentration of the active moiety (risperidone plus 9-hydroxyrisperidone) were within the range of 80-125%, indicating bioequivalence of the i.m. and oral formulations. However, mean steady-state peak concentrations of the active moiety were 25-32% lower with i.m. than oral dosing (P < 0.05) and fluctuations in plasma active-moiety levels were 32-42% lower with the i.m. than oral regimen. Symptoms of schizophrenia continued to improve after switching from oral to i.m. dosing. Long-acting risperidone was well tolerated locally and systematically. Although overall bioequivalence of the two formulations was established, the differences in pharmacokinetic profiles between the two formulations indicate potential benefits for long-acting risperidone.

Administration, Oral↗

PubMed2004

In vitro effects of risperidone and 9-hydroxy-risperidone on human platelet function, plasma coagulation, and fibrinolysis.

BACKGROUND: Thrombotic events have been reported with the use of antipsychotic compounds, although the incidence, predisposing factors, and biological mechanisms associated with these events in psychiatric patients are subject to debate. OBJECTIVE: The in vitro actions of risperidone and its active metabolite 9-hydroxy-risperidone (9-OH-risperidone) on human platelet function, plasma coagulation, and fibrinolysis were examined to explore whether hematologic effects might be a mechanism for thrombotic events with these compounds. METHODS: Blood was donated by healthy white male subjects who were free of medications (particularly acetylsalicylic acid and nonsteroidal anti-inflammatory compounds). Platelet shape change and adhesion/aggregation reactions to risperidone and 9-OH-risperidone induced by adenosine diphosphate (ADP), collagen, epinephrine, and 5-hydroxytryptamine (5-HT) were tested in human platelet-rich plasma. Arachidonic acid metabolism was assessed in human platelets and rat aortic rings. Plasma coagulation was tested in human platelet-poor plasma. Fibrinolysis was measured in human whole blood. RESULTS: The 12 study subjects ranged in age from 20 to 40 years (median age 30 years). At concentrations of 1 x 10(-5) mol/L (approximately 4180 ng/mL), neither risperidone nor 9-OH-risperidone induced platelet shape change or aggregation, amplified reactions to ADP, or modified platelet adhesion/aggregation induced by collagen or ADP, but they did attenuate epinephrine-induced platelet aggregation (-50% in the case of 9-OH-risperidone; P < 0.05) and 5-HT-induced platelet aggregation (drug concentrations yielding 50% inhibition of 5-HT-induced platelet aggregation, 0.5 and 0.2 ng/mL, respectively). Cyclooxygenase, thromboxane A2 synthase, 12-lipoxygenase, prostacyclin synthase, plasma coagulation, and fibrinolysis were unaffected. CONCLUSIONS: Risperidone and 9-OH-risperidone reduced epinephrine- and 5-HT-induced human platelet aggregation but did not significantly alter other measures of platelet function, plasma coagulation, or fibrinolysis in vitro.

Adult↗

PubMed2003

Pharmacokinetic comparison of fast-disintegrating and conventional tablet formulations of risperidone in healthy volunteers.

BACKGROUND: Difficulties with and resistance to tablet-taking are common in all patient groups and can exacerbate compliance problems and undermine treatment efficacy. In recent years, rapidly dissolving oral drug formulations have been developed to overcome problems related to swallowing difficulties. OBJECTIVE: The goal of this study was to evaluate the bioequivalence of a fast-disintegrating oral tablet of risperidone and the conventional oral tablet. METHODS: This was a randomized, open-label, 2-way crossover trial in which healthy volunteers received two 0.5-mg tablets of a fast-disintegrating oral risperidone formulation and two 0.5-mg tablets of conventional oral risperidone, each in a single administration. Blood samples for pharmacokinetic analysis of the active moiety (risperidone + 9-hydroxy-risperidone), risperidone, and its active metabolite 9-hydroxy-risperidone were obtained during a 96-hour period after dosing. Safety assessments included monitoring of adverse events, hematology and biochemistry tests of the sampled blood, urinalysis, blood pressure measurements, and electrocardiography. RESULTS: The bioequivalence assessment was based on pharmacokinetic and statistical analysis of data from 37 subjects who completed both treatment periods. The plasma concentration-time profiles of the active moiety, risperidone, and 9-hydroxy-risperidone were similar after intake of the 2 formulations. The fast-disintegrating tablet and the conventional tablet showed bioequivalence with respect to the active moiety, risperidone, and 9-hydroxy-risperidone. The 90% CIs for the mean treatment ratios of the log-transformed peak plasma concentration, area under the plasma concentration-time curve (AUC) to the last quantifiable time point, and AUC extrapolated to infinity were all within the predefined equivalence range from 80% to 125%. Twenty-eight of 50 (56%) subjects originally randomized reported adverse events, with a similar incidence for both treatments. All adverse events were mild, with somnolence and headache being the most frequently reported. No clinically relevant changes were observed in physical, biochemical, hematologic, or urinalysis variables during the study. CONCLUSION: In this study in healthy subjects, a single administration of two 0.5-mg fast-disintegrating risperidone tablets was bioequivalent to a single administration of two 0.5-mg conventional risperidone tablets.

Adult↗