Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview.

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.

Pitfalls of Cost-Effectiveness Analysis in Practice: A TRD Case Example in the United States with Esketamine Versus Oral Antidepressants.

DISCLOSURES: The writing of this letter was supported by Janssen Scientific Affairs. The authors are employees of Janssen Scientific Affairs or Janssen Global Services (Johnson & Johnson).

Practical considerations for managing breakthrough psychosis and symptomatic worsening in patients with schizophrenia on long-acting injectable antipsychotics.

With more long-acting injectable (LAI) antipsychotics available for treating schizophrenia, each with variable durations of action (2 weeks to 3 months), it is important to have clear management strategies for patients developing breakthrough psychotic symptoms or experiencing symptomatic worsening on LAIs. However, no treatment guidelines or clinical practice pathways exist; health-care providers must rely on their own clinical judgment to manage these patients. This article provides practical recommendations-based on a framework of clinical, pharmacokinetic, and dosing considerations-to guide clinicians' decisions regarding management of breakthrough psychotic symptoms. Management options include ruling out/addressing medical illness or substance abuse/misuse as a contributing factor, addressing stressors, optimizing nonpharmacologic treatments, treating medical/psychiatric comorbidities, ensuring proper LAI administration technique, addressing missed LAI doses or lack of steady-state attainment, and increasing LAI dose directly or indirectly by shortening the injection interval (off-label). If these strategies do not work sufficiently with frequent monitoring, the LAI could be supplemented with a low dose of the corresponding oral formulation for fast symptom control (off-label). However, caution should be exercised with this strategy, because data on the safety of concomitant use of LAI and oral antipsychotics (OAPs) are limited, especially over extended periods. If symptoms abate, therapy optimization could be continued and slow discontinuation of the OAP could be considered. For persistent/worsening symptoms, the OAP should be increased to optimum effective dose while intensifying the initial steps used before it was added. If this fails, switching the OAP or LAI could be considered. We believe that these strategies will help clinicians manage breakthrough psychotic symptoms during LAI treatment and improve overall outcomes among those who can benefit from LAIs.

Body mass index and metabolic parameters in patients with schizophrenia during long-term treatment with paliperidone palmitate.

BACKGROUND: There is a strong association between weight gain and metabolic events in patients with schizophrenia receiving many of the second-generation antipsychotic agents. We explored the relationship between body mass index (BMI) and metabolic events in patients with schizophrenia receiving long-acting injectable paliperidone palmitate (PP) in a long-term trial. METHODS: We conducted a post hoc analysis of data from a PP study that included a 33-week open-label transition (TR) and maintenance phase; a variable duration, randomized, double-blind (DB), placebo-controlled phase and a 52-week open-label extension (OLE) phase. Overall, 644 patients received PP continuously from study entry through discontinuation or study completion and were grouped by baseline BMI (kg/m2): underweight (BMI <19; n = 29, 4.5%), normal-weight (BMI 19- < 25; n = 229, 35.6%), overweight (BMI 25- < 30; n = 232, 36.0%) and obese (BMI ≥ 30; n = 154, 23.9%). Metabolic treatment-emergent adverse events (TEAEs) and changes in related laboratory results from TR baseline were analyzed. RESULTS: PP exposure was similar across BMI groups; overall mean (SD) dose/month was 70.3 (17.17) mg eq. [109.6 (26.78) mg]; median duration of exposure was 204 days (6 to 1009 days). Occurrences of metabolic TEAEs overall by group were 0% (underweight), 14.9% (normal-weight), 14.7% (overweight), and 24.0% (obese). The most common (≥ 2%) metabolic TEAE were weight gain and elevated blood levels of glucose, lipids, and insulin. Mean BMI and weight increased in normal-weight and overweight groups at DB endpoint, and in underweight, normal-weight and overweight groups at OLE endpoint (p ≤ 0.05). No consistent trend for increased metabolic-related laboratory values by baseline BMI group was observed. Homeostatic model assessments for insulin resistance indicated preexisting insulin resistance at baseline, with minimal changes at OLE endpoint across baseline BMI groups. CONCLUSION: Occurrences of metabolic-related TEAEs trended with greater BMI status in patients with schizophrenia treated with PP; consistent trends in metabolic-related laboratory values were not observed. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT 00518323).

Paliperidone palmitate and risperidone long-acting injectable in subjects with schizophrenia recently treated with oral risperidone or other oral antipsychotics.

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.

Long-term tolerability of once-monthly injectable paliperidone palmitate in subjects with recently diagnosed schizophrenia.

BACKGROUND: A post hoc analysis from a multiphase trial with open-label transition and maintenance phases, a double-blind relapse prevention phase, and an optional open-label extension examined the long-term tolerability with continuous once-monthly injectable paliperidone palmitate 39, 78, 117, or 156 mg (25, 50, 75, or 100 mg equivalents [mg eq] of paliperidone) in subjects with recently diagnosed (≤5 years; n = 216) versus chronic illness (>5 years; n = 429) schizophrenia. METHODS: Adverse events reported at a ≥2% margin between subgroups were identified. Relative risks (in the recently diagnosed compared with the chronically ill) and 95% confidence intervals (CI) were determined, and CI not including 1 were considered potentially significant. RESULTS: In both subgroups, the mean monthly dose was 109 mg (69.9 mg eq). Continuous mean exposures were 333.9 ± 271.9 and 308.7 ± 278.3 days in the recently diagnosed and chronic illness subgroups, respectively. Using the criteria outlined in the methods, nasopharyngitis was a potentially significant event reported in more chronically ill than recently diagnosed subjects at months 6, 9, 12, and endpoint (7.2% versus 2.8%; relative risk 0.384; 95% CI 0.163-0.907). Influenza (2.8% versus 0.7%; relative risk 3.9; 95% CI 1.003-15.730) and amenorrhea (3.2% versus 0.9%; relative risk 3.476; 95% CI 1.029-11.744) at endpoint were potentially significant events in more recently diagnosed than chronically ill subjects. Mean weight changes, sedation/somnolence, any extrapyramidal symptom-related or glucose-related events were generally similar between the groups. The mean prolactin level increased in both sexes in both subgroups (changes from baseline of +41.8 ng/mL and +26.5 ng/mL in recently diagnosed and chronic illness females and +12.3 ng/mL and +15.1 ng/mL in recently diagnosed and chronic illness males, respectively), and were higher in females with recently diagnosed illness than in females who were chronically ill (P = 0.0002 at endpoint). Prolactin-related events were reported by 7.9% of recently diagnosed subjects with schizophrenia and 3.5% of those who were chronically ill. CONCLUSION: The long-term tolerability of paliperidone palmitate was generally similar in recently diagnosed schizophrenia subjects and those with more chronic illness, with the exception of some prolactin-related measures.

Management of antipsychotic treatment discontinuation and interruptions using model-based simulations.

BACKGROUND: Medication nonadherence is a well described and prevalent clinical occurrence in schizophrenia. These pharmacokinetic model-based simulations analyze predicted antipsychotic plasma concentrations in nonadherence and treatment interruption scenarios and with treatment reinitiation. METHODS: Starting from steady state, pharmacokinetic model-based simulations of active moiety plasma concentrations of oral, immediate-release risperidone 3 mg/day, risperidone long-acting injection 37.5 mg/14 days, oral paliperidone extended-release 6 mg/day, and paliperidone palmitate 117 mg (75 mg equivalents)/28 days were assessed under three treatment discontinuation/interruption scenarios, ie, complete discontinuation, one week of interruption, and four weeks of interruption. In the treatment interruption scenarios, pharmacokinetic simulations were performed using medication-specific reinitiation strategies. RESULTS: Following complete treatment discontinuation, plasma concentrations persisted longest with paliperidone palmitate, followed by risperidone long-acting injection, while oral formulations exhibited the most rapid decrease. One week of oral paliperidone or risperidone interruption resulted in near complete elimination from the systemic circulation within that timeframe, reflecting the rapid elimination rate of the active moiety. After 1 and 4 weeks of interruption, minimum plasma concentrations were higher with paliperidone palmitate than risperidone long-acting injection over the simulated period. Four weeks of treatment interruption followed by reinitiation resulted in plasma levels returning to predicted therapeutic levels within 1 week. CONCLUSION: Due to the long half-life of paliperidone palmitate (25-49 days), putative therapeutic plasma concentrations persisted longest in simulated cases of complete discontinuation or treatment interruption. These simulations may help clinicians better conceptualize the impact of antipsychotic nonadherence on plasma concentrations, and the impact of medication-specific reinitiation strategies after intermittent nonadherence.

Effects of acute paliperidone palmitate treatment in subjects with schizophrenia recently treated with oral risperidone.

OBJECTIVE: To examine efficacy and safety of acute treatment with paliperidone palmitate in subjects with schizophrenia whose disease remained symptomatic despite recent treatment with oral risperidone. METHODS: Post hoc analysis of a 13-week, double-blind, placebo-controlled study of subjects with symptomatic schizophrenia randomized to paliperidone palmitate 39, 156, or 234 mg (25, 100, or 150 mg equivalents of paliperidone) or placebo. Paliperidone palmitate subjects received a 234-mg day 1 dose, followed by their assigned dose on day 8 and monthly thereafter. Subjects treated with oral risperidone within 2 weeks before randomization regardless of duration were included. ASSESSMENTS: PANSS, CGI-S, PSP scores; AEs. ANCOVA models with LOCF methodology evaluated treatment group differences. RESULTS: 216 subjects received prior oral risperidone (paliperidone palmitate 39 mg, n=53; 156 mg, n=58; 234 mg, n=48; placebo, n=57). Median prior risperidone use was 22 days. Significant improvement was observed with paliperidone palmitate 156-mg or 234-mg versus placebo in least-squares mean (SE) score change at end point in PANSS total (156 mg, -15.8 [3.0], p=0.0001; 234 mg, -17.6 [3.2], p=0.0001), CGI-S (156 mg, -0.9 [0.2], p=0.0068; 234 mg, -1.1 [0.2], p=0.0003), and PSP (156 mg, 10.7 [2.3], p=0.0061; 234 mg, 12.9 [2.4], p=0.0009). Most common AEs (≥10%) in any paliperidone palmitate group were insomnia, anxiety, and headache. CONCLUSIONS: In subjects with schizophrenia who recently received oral risperidone but who remained symptomatic, acute treatment with monthly doses of 156-mg and 234-mg paliperidone palmitate significantly improved clinical symptoms, global illness ratings, and functioning compared with placebo, with no unexpected safety findings.

Are the long-acting intramuscular formulations of risperidone or paliperidone palmitate associated with post-injection delirium/sedation syndrome? An assessment of safety databases.

Long-acting injectable (LAI) formulations of antipsychotics are valuable treatment alternatives for patients with psychotic disorders, and understanding their safe use is critical. Post-injection delirium/sedation syndrome (PDSS) has been reported following treatment with one atypical antipsychotic LAI. Clinical databases of risperidone LAI and paliperidone palmitate were explored to identify if cases of PDSS had been observed. No cases of PDSS were identified in 15 completed trials of 3,164 subjects (approximately 115,000 injections) or the postmarketing safety database of risperidone LAI. Only one case of PDSS was identified among 10 completed trials (3,817 subjects, 33,906 injections) of paliperidone palmitate-that case having been reported in a patient randomized to treatment with placebo. Examination of these prospective databases finds no evidence that risperidone LAI and paliperidone palmitate are associated with PDSS and suggest that findings seen with another antipsychotic LAI are not generalizable.

Tolerability of initiation doses of once-monthly paliperidone palmitate in patients with recently diagnosed schizophrenia in an acute treatment trial.

OBJECTIVE: To examine the tolerability of the recommended initiation doses for once-monthly injectable paliperidone palmitate in patients who have recently been diagnosed with schizophrenia and for whom high doses may pose tolerability concerns. METHODS: A post hoc analysis from a 13-week double-blind study of patients with schizophrenia randomized 1:1:1:1 to placebo or paliperidone palmitate at 25, 100, or 150 mg equivalents (mg eq) of paliperidone (corresponding to 39, 156, or 234 mg respectively). This analysis focused on the recently diagnosed subgroup (≤5 years; N = 146) who received the recommended initiation dosage of paliperidone palmitate [150 mg eq on day 1 (n = 109) followed by 100 mg eq on day 8 (n = 39)] or placebo (n = 37). Adverse events (AEs), reported in ≥2% of patients receiving paliperidone palmitate during days 1-7 or ≥5% during days 8-36, and in a higher percentage of patients receiving paliperidone palmitate than placebo, were identified. AE relative risks (RRs) and 95% confidence intervals (CIs) were determined. A RR was considered potentially significant when its 95% CI did not include 1. RESULTS: Overall, day 1-7 AE rates were 37.6% (41 of 109) and 29.7% (11 of 37) with paliperidone palmitate and placebo respectively; injection site pain (5.5% versus 2.7%, RR 2.0; 95% CI 0.25 to 16.37), agitation (4.6% versus 2.7%; RR 1.7; 95% CI 0.21 to 14.06), and headache (3.7% versus 0.0%; RR 3.1; 95% CI 0.17 to 56.41) met the ≥2% criteria. Day 8-36 AE rates were 41.0% (16 of 39) and 37.8% (14 of 37) with paliperidone palmitate and placebo respectively; anxiety (5.1% versus 0.0%; RR 4.8; 95% CI 0.24 to 95.76) met the ≥5% criteria. Key limitations were that some patients may have been ill for a significant time before formal diagnosis and that the number of patients is low in this subgroup, limiting the ability to detect statistical significance for AE RRs. CONCLUSIONS: Paliperidone palmitate initiation doses (150 mg eq day 1, 100 mg eq day 8) were tolerated in this subgroup of patients who were recently diagnosed with schizophrenia, with no unexpected findings. Although the same size was small, these data identified AEs that may be encountered during the week and month after initiation dosing. These findings may assist clinicians when paliperidone palmitate is considered an appropriate treatment choice for these patients.