Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview.
ABSTRACT: The availability of long-acting injectable (LAI) antipsychotics for the treatment of schizophrenia provides clinicians with options that deliver continuous drug exposure and may improve adherence compared with daily oral antipsychotics. However, all LAI antipsychotics have unique formulations and pharmacokinetic characteristics that have implications for medication selection, administration interval, and injection site. This review outlines key differences in drug formulations and pharmacokinetics among LAI antipsychotics. A systematic search of the PubMed database was conducted to identify physical and formulation properties and pharmacokinetic data of commercially available LAI antipsychotics, including flupentixol decanoate, fluphenazine decanoate, haloperidol decanoate, zuclopenthixol decanoate, aripiprazole monohydrate, aripiprazole lauroxil, olanzapine pamoate, paliperidone palmitate, risperidone microspheres, and risperidone polymeric microspheres. Additional information was obtained from package inserts and product monographs. Relevant data on drug properties, administration details, pharmacokinetic parameters, and oral dose equivalencies of LAI antipsychotics are summarized. Based on our analysis, formulation characteristics (e.g., vehicle medium) and administration characteristics (e.g., injection site) can affect rate of absorption and adverse effects and may factor into whether oral supplementation or an additional injection is needed. Dose adjustments may be necessary based on potential drug-drug interactions, and approximate dose equivalence with oral formulations can help inform titration when switching from oral to LAI formulations. Clinicians administering LAI antipsychotics should consider these formulation and pharmacokinetic factors to maximize clinical impact and to adjust to an individual patient's needs and treatment goals.
Project description:Given the complex nature of symptom presentation and medication regimens, psychiatric clinics may benefit from additional tools to personalize treatments. Utilizing pharmacogenetic information may be helpful in assessing unique responses to therapy. We report herein a case of wearing-off phenomena during treatment with aripiprazole long-acting injectable (LAI) and a proof of concept strategy of how pharmacogenetic information may be used to assess possible genetic factors and also hypothesize potential mechanisms for further study.A 51-year-old African American male with schizoaffective disorder was referred to a psychiatric clinic for medication management. After unsuccessful trials of multiple antipsychotics, oral aripiprazole was initiated (up to 30 mg/day) and transitioned to aripiprazole LAI with symptom improvement. At a high dose of aripiprazole LAI (400 mg Q3wks), the patient experienced breakthrough symptoms approximately 3 days prior to his next injection. Various considerations were examined to explain his atypical dose requirements, including but not limited to pharmacogenetic influences. Pharmacogenetic testing ruled out genetic influences on drug metabolism but noted a -141C Del variant in the dopamine-D2 receptor (DRD2) gene associated in prior studies of poor-response to antipsychotics. At this time, a new formulation, aripiprazole lauroxil, was explored due to its availability in higher dose options. Transition to the new formulation (882 mg Q4wks) greatly improved and stabilized the patient's symptoms with no breakthrough psychosis. Comparable daily dose equivalents were achieved with two different formulations due to the Q3wks vs Q4wks dosing strategies, although the two agents have some differences in pharmacokinetic profiles.We report a case of a patient experiencing wearing-off symptoms with aripiprazole LAI who benefited from switching to aripiprazole lauroxil. Pharmacogenetic testing revealed normal activity for relevant metabolism pathways but a DRD2 -141C variant that may influence brain D2 expression and antipsychotic responsiveness. The clinical utility of DRD2 information and what to do with genotyping results has not been previously addressed, despite availability on clinical test panels. Our case report suggests further investigations of altered dosing strategies and receptor genotype sensitivities to pharmacokinetic factors may be helpful in understanding symptom re-emergence observed in some patients taking LAI antipsychotics.
Project description:Long-acting injectable (LAI) antipsychotics (LAI-APs) have several advantages over oral medications, but deaths reported in Japan during the early post-marketing phase vigilance period have raised safety concerns. We conducted a series of meta-analyses to assess whether LAI-APs affect the mortality of patients with schizophrenia. Three categorical meta-analyses of randomized controlled trials (RCTs) were performed to compare all-cause death (primary outcome) and death due to suicide: individual and pooled LAI-APs vs placebo, individual and pooled LAI-APs vs oral antipsychotics (OAPs), and head-to-head comparisons of LAI-APs. The risk ratios (RRs) and 95% CIs were calculated. We identified 52 RCTs (53 comparisons; total participants = 17 416, LAI-APs = 11 360, OAP = 3910, and placebo = 2146; mean study duration [wk]: LAI-APs vs placebo = 28.9, LAI-APs vs OAPs = 64.5). Neither pooled nor individual LAI-APs (aripiprazole, fluphenazine, olanzapine, paliperidone, and risperidone) differed from the placebo regarding the incidences of all-cause death (pooled LAI-APs: RR = 0.64, P = .37) and death due to suicide (pooled LAI-APs: RR = 0.98, P = .98). However, in a subgroup meta-analysis of only short-duration RCTs (?13wk), pooled LAI-APs exhibited a trend toward lower incidence of all-cause death than placebo (RR = 0.29, P = .08). Pooled LAI-APs (aripiprazole, fluphenazine, haloperidol, olanzapine, paliperidone, risperidone, and zuclopenthixol) did not differ from pooled OAPs regarding all-cause death (pooled LAI-APs: RR = 0.71, P = .30) and death due to suicide (pooled LAI-APs: RR = 0.94, P = .91). Individual LAI-APs and OAPs were associated with similar risks of death. Data for head-to-head comparisons of individual LAI-APs were insufficient. In conclusion, there was no significant difference between LAI-APs and placebo or OAPs regarding all-cause death and death due to suicide.
Project description:<h4>Background</h4>The analysis of prescribing patterns in entire catchment areas contributes to global mapping of the use of antipsychotics and may improve treatment outcomes.<h4>Objective</h4>To determine the pattern of long-term antipsychotic prescription in outpatients with schizophrenia in the province of Tarragona (Catalonia-Spain).<h4>Methods</h4>A naturalistic, observational, retrospective, non-interventional study based on the analysis of registries of computerized medical records from an anonymized database of 1,765 patients with schizophrenia treated between 2011 and 2013.<h4>Results</h4>The most used antipsychotic was risperidone, identified in 463 (26.3%) patients, followed by olanzapine in 249 (14.1%), paliperidone in 225 (12.7%), zuclopenthixol in 201 (11.4%), quetiapine in 141 (8%), aripiprazole in 100 (5.7%), and clozapine in 100 (5.7%). Almost 8 out of 10 patients (79.3%) were treated with atypical or second-generation antipsychotics. Long-acting injectable (LAI) formulations were used in 44.8% of patients. Antipsychotics were generally prescribed in their recommended doses, with clozapine, ziprasidone, LAI paliperidone, and LAI risperidone being prescribed at the higher end of their therapeutic ranges. Almost 7 out of 10 patients (69.6%) were on antipsychotic polypharmacy, and 81.4% were on psychiatric medications aside from antipsychotics. Being prescribed quetiapine (OR 14.24, 95% CI 4.94-40.97), LAI (OR 9.99, 95% CI 6.45-15.45), psychiatric co-medications (OR 4.25, 95% CI 2.72-6.64), and paliperidone (OR 3.13, 95% CI 1.23-7.92) were all associated with an increased likelihood of polypharmacy. Being prescribed risperidone (OR 0.54, 95% CI 0.35-0.83) and older age (OR 0.98, 95% CI 0.97-0.99) were related to a low polypharmacy probability.<h4>Conclusions</h4>Polypharmacy is the most common pattern of antipsychotic use in this region of Spain. Use of atypical antipsychotics is extensive. Most patients receive psychiatric co-medications such as anxiolytics or antidepressants. Polypharmacy is associated with the use of quetiapine or paliperidone, use of a LAI, younger age, and psychiatric co-medication.
Project description:Until relatively recently, long-acting injectable (LAI) formulations were only available for first-generation antipsychotics and their utilization decreased as use of oral second-generation antipsychotics (SGA) increased. Although registry-based naturalistic studies show LAIs reduce rehospitalization more than oral medications in clinical practice, this is not seen in recent randomized clinical trials. PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy) relapse prevention study incorporated efficacy and effectiveness features. At 8 US academic centers, 305 patients with schizophrenia or schizoaffective disorder were randomly assigned to LAI risperidone (LAI-R) or physician's choice oral SGAs. Patients were evaluated during the 30-month study by masked, centralized assessors using 2-way video, and monitored biweekly by on-site clinicians and assessors who knew treatment assignment. Relapse was evaluated by a masked Relapse Monitoring Board. Differences between LAI-R and oral SGA treatment in time to first relapse and hospitalization were not significant. Psychotic symptoms and Brief Psychiatric Rating Scale total score improved more in the LAI-R group. In contrast, the LAI group had higher Scale for Assessment of Negative Symptoms Alogia scale scores. There were no other between-group differences in symptoms or functional improvement. Despite the advantage for psychotic symptoms, LAI-R did not confer an advantage over oral SGAs for relapse or rehospitalization. Biweekly monitoring, not focusing specifically on patients with demonstrated nonadherence to treatment and greater flexibility in changing medication in the oral treatment arm, may contribute to the inability to detect differences between LAI and oral SGA treatment in clinical trials.
Project description:Adherence to antipsychotic medications is a major challenge in schizophrenia. Long-acting injectable antipsychotics have been shown to offer advantages over oral formulations. A new extended release formulation of risperidone for subcutaneous injection was developed to address issues of non-adherence. The aim of this manuscript was to compare the new subcutaneous formulation to currently available formulations of injectable risperidone and paliperidone to determine whether the novel delivery by subcutaneous injection may provide substantial benefits. A literature search was conducted using PubMed, OVID, and Cochrane Library electronic databases to assess the advantages and disadvantages of long-acting formulations of risperidone. Potential advantages of risperidone for subcutaneous injection include a simplified dosing and ease of administration. Potential disadvantages include injection site pain and medication cost.
Project description:Maintaining therapeutic plasma concentrations of an antipsychotic agent is essential in preventing relapse of symptoms in schizophrenia. Long-acting injectable (LAI) formulations provide extended exposure to antipsychotic therapy and have been useful in addressing treatment nonadherence. Aripiprazole is an atypical antipsychotic used in the treatment of schizophrenia and is available in 2 chemically different (aripiprazole monohydrate and aripiprazole lauroxil [AL]) and pharmaceutically different LAI formulations (aripiprazole once-monthly 400 mg [AOM 400] and AL). The pharmaceutical difference is that AL, unlike AOM 400, is a prodrug that requires additional metabolic steps to form the active drug aripiprazole. We present data demonstrating that aripiprazole plasma concentrations are similar for AOM 400 and the 882 mg dose of AL when administered once every 4 weeks and that both provide similar therapeutic plasma concentrations of aripiprazole when compared with therapeutic oral doses.
Project description:BACKGROUND:This post hoc subgroup analysis of a randomized, double-blind trial evaluated the response to treatment with two long-acting injectable atypical antipsychotics, ie, paliperidone palmitate and risperidone long-acting injectable (RLAI), in subjects with schizophrenia experiencing clinically significant symptoms despite recent treatment with oral risperidone only or other oral antipsychotics. METHODS:Adult subjects were eligible for the 13-week, double-blind, double-dummy trial (NCT00589914) if they had an established diagnosis of schizophrenia for at least one year and a Positive and Negative Syndrome Scale (PANSS) total score of 60-120 inclusive at screening. Subjects received either paliperidone palmitate (234 mg, day 1; 156 mg, day 8; then once-monthly flexible dosing) or RLAI (25-50 mg biweekly, with oral risperidone supplementation on days 1-28), plus matched placebo injections/tablets. RESULTS:This post hoc analysis reports data on 747 subjects who, within 2 weeks of starting double-blind study medication, had reportedly received oral risperidone only (paliperidone palmitate group, n = 126; RLAI group, n = 107), other oral antipsychotics (paliperidone palmitate group, n = 199; RLAI group, n = 203), or no antipsychotic (paliperidone palmitate group, n = 56; RLAI group, n = 56). Mean PANSS total scores improved significantly at end point across all subgroups (mean change from baseline ranged from -17.5 to -19.5, all P < 0.0001). Clinical Global Impression-Severity and Personal and Social Performance scale measures also significantly improved from baseline (all P < 0.0001). CONCLUSION:Treatment with paliperidone palmitate or RLAI resulted in a significant reduction in the symptoms of schizophrenia irrespective of previous recent treatment with oral risperidone only or other oral antipsychotics. For subjects who had previously received oral risperidone only, the difference in formulation was the main change in the intervention because the molecule delivered remained the same or similar. These data support the contribution of a long-acting formulation to improving the treatment response and suggest that nonadherence may be a significant contributor to inadequate efficacy of oral formulations in subjects with schizophrenia.
Project description:Treatment with long-acting injectable (LAI) antipsychotic medication is an important element of relapse prevention in schizophrenia. Recently, the intramuscular once-monthly formulation of aripiprazole received marketing approval in Europe and the United States for schizophrenia.This study aimed to compare aripiprazole once-monthly with other LAI antipsychotics in terms of efficacy, tolerability, and safety.A systematic literature review was conducted to identify relevant double-blind randomized clinical trials of LAIs conducted in the maintenance treatment of schizophrenia. MEDLINE, MEDLINE In-Process, Embase, the Cochrane Library, PsycINFO, conference proceedings, clinical trial registries, and the reference lists of key review articles were searched. The literature search covered studies dating from January 2002 to May 2013.Studies were required to have ?24 weeks of follow-up. Patients had to be stable at randomization. Studies were not eligible for inclusion if efficacy of acute and maintenance phase treatment was not reported separately. Six trials were identified (0.5% of initially identified studies), allowing comparisons of aripiprazole once-monthly, risperidone LAI, paliperidone palmitate, olanzapine pamoate, haloperidol depot, and placebo.Data extracted included study details, study duration, the total number of patients in each treatment arm, efficacy, tolerability, and safety outcomes. The efficacy outcome contained the number of patients that experienced a relapse, tolerability outcomes included the number of patients that discontinued treatment due to treatment-related adverse events (AEs), and that discontinued treatment due to reasons other than AEs (e.g., loss to follow-up). Safety outcomes included the incidence of clinically relevant weight gain and extrapyramidal symptoms.Data were analyzed by applying a mixed treatment comparison competing risks model (efficacy) and using binary models (safety). There was no statistically significant difference between any study outcome, including the risk of relapse, the risk of discontinuations, and safety outcomes.Aripiprazole once-monthly is similarly efficacious to other LAIs with relatively low rates of discontinuation due to AEs and due to reasons other than AEs than other LAIs.
Project description:<h4>Background and objectives</h4>Aripiprazole is an atypical antipsychotic drug that is metabolized by cytochrome P450 (CYP) 2D6 and CYP3A4, which mainly form its active metabolite dehydro-aripiprazole. Because of the genetic polymorphism of CYP2D6, plasma concentrations are highly variable between different phenotypes. In this study, phenotype-related physiologically based pharmacokinetic models were developed and evaluated to suggest phenotype-guided dose adjustments.<h4>Methods</h4>Physiologically based pharmacokinetic models for single dose (oral and orodispersible formulation), multiple dose, and steady-state condition were built using trial data from genotyped healthy volunteers. Based on evaluated models, dose adjustments were simulated to compensate for genetically caused differences.<h4>Results</h4>Physiologically based pharmacokinetic models were able to accurately predict the pharmacokinetics of aripiprazole and dehydro-aripiprazole according to CYP2D6 phenotypes, illustrated by a minimal bias and a good precision. For single-dose administration, 92.5% (oral formulation) and 79.3% (orodispersible formulation) of the plasma concentrations of aripiprazole were within the 1.25-fold error range. In addition, physiologically based pharmacokinetic steady-state simulations demonstrate that the daily dose for poor metabolizer should be adjusted, resulting in a maximum recommended dose of 10 mg, but no adjustment is necessary for intermediate and ultra-rapid metabolizers.<h4>Conclusions</h4>In clinical practice, CYP2D6 genotyping in combination with therapeutic drug monitoring should be considered to personalize aripiprazole dosing, especially in CYP2D6 poor metabolizers, to ensure therapy effectiveness and safety.
Project description:Olanzapine, aripiprazole and risperidone are atypical antipsychotics or neuroleptics widely used for schizophrenia treatment. They induce various adverse drug reactions depending on their mechanisms of action: metabolic effects, such as weight gain and alterations of glucose and lipid metabolism; hyperprolactinemia and extrapyramidal effects, such as tremor, akathisia, dystonia, anxiety and distress. In this review, we listed polymorphisms associated with individual response variability to olanzapine, aripiprazole and risperidone. Olanzapine is mainly metabolized by cytochrome P450 enzymes, CYP1A2 and CYP2D6, whereas aripiprazole and risperidone metabolism is mainly mediated by CYP2D6 and CYP3A4. Polymorphisms in these genes and other enzymes and transporters, such as enzymes from the uridine 5'-diphospho-glucuronosyltransferase (UGT) family and ATP-binding cassette sub-family B member 1 (ABCB1), are associated to differences in pharmacokinetics. The three antipsychotics act on dopamine and serotonin receptors, among others, and several studies found associations between polymorphisms in these genes and variations in the incidence of adverse effects and in the response to the drug. Since olanzapine is metabolized by CYP1A2, a lower starting dose should be considered in patients treated with fluvoxamine or other CYP1A2 inhibitors. Regarding aripiprazole, a reduced dose should be administered in CYP2D6 poor metabolizers (PMs). Additionally, a reduction to a quarter of the normal dose is recommended if the patient is treated with concomitant CYP3A4 inhibitors. Risperidone dosage should be reduced for CYP2D6 PMs and titrated for CYPD6 ultrarapid metabolizers (UMs). Moreover, risperidone dose should be evaluated when a CYP2D6, CYP3A4 or ABCB1 inhibitor is administered concomitantly.