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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.

SUBMITTER: Correll CU

PROVIDER: S-EPMC7873121 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Correll Christoph U CU Kim Edward E Sliwa Jennifer Kern JK Hamm Wayne W Gopal Srihari S Mathews Maju M Venkatasubramanian Raja R Saklad Stephen R SR

CNS drugs 20210128 1

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 pharmacokineti ...[more]

PMID: 33507525

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Project description:Medication non-adherence in patients with schizophrenia continues to be a significant problem and threatens successful treatment outcomes. Medication non-adherence is often associated with negative consequences, including symptom exacerbation, more frequent emergency room visits, re-hospitalizations and relapse. Long-acting injectable (LAI) forms of antipsychotics allow for rapid identification of non-adherence, obviate the need for the patient to take the medication on a daily basis and increase adherence to some significant degree. Eli Lilly has developed a long-acting depot formulation of olanzapine, olanzapine pamoate, which has recently been approved by the FDA for the US market, and which will be reviewed here. Olanzapine LAI appears to be an effective antipsychotic at dosages of 210 mg every 2 weeks, 300 mg every 2 weeks and 405 mg every 4 weeks in patients with acute schizophrenia, and at 150 mg every 2 weeks, 300 mg every 2 weeks and at 405 mg every 4 weeks for the maintenance treatment of stable patients. Oral supplementation appears not to be needed, particularly not at the onset of treatment with the LAI as is necessary with risperidone LAI. Its efficacy is in general comparable to the efficacy seen with oral olanzapine at a corresponding dose. The side effect profile is also comparable to the side effects observed with oral olanzapine, including lower rates of extrapyramidal symptoms, prolactin elevation and cardiovascular side effects, but significant metabolic effects. The latter include significant weight gain, lipid abnormalities and glucose dysregulation. While the injection site adverse events are overall mild, the most significant serious adverse event is the post-injection delirium sedation syndrome (PDSS). While rare, this syndrome results from inadvertent intravascular injection of olanzapine LAI and can cause a range of olanzapine overdose-type of symptoms. Olanzapine LAI needs therefore to be administered by trained personnel in settings where a post-injection observation period for at least 3 hours by medical personnel is available. The overall use of olanzapine LAI will probably be limited by the possibility of a PDSS event. Patients who have a history of good response to oral olanzapine and are in need of assured medication administration may present a good indication for its use, provided that the appropriate mental health delivery setting is available.

Project description:ImportanceSchizophrenia is generally considered to be among the most severe psychiatric disorders because of the excessive mortality associated with it. Research to find means to reduce this excessive mortality is warranted.ObjectiveTo investigate associations of long-acting injectable antipsychotics (LAIs) with all-cause, natural-cause, and suicide mortality risks as well as the impacts of early use of LAIs in patients with newly diagnosed schizophrenia.Design, setting, and participantsThis cohort study used data from the Taiwan National Health Insurance Research Database to construct a population-based cohort of patients with schizophrenia who received oral antipsychotics (OAPs) from January 1, 2002, to December 31, 2017. Within this cohort, the LAI group was defined as patients who switched to LAIs and were prescribed LAIs at least 4 times within 1 year. The LAI group was propensity matched 1:1 to patients who continued receiving OAPs of the same compounds. All patients were followed up until switching the antipsychotic administration route, death, or the end of the study (December 31, 2018), whichever occurred first. Data analysis was performed from January 2002 to December 2018.Main outcomes and measuresAll-cause mortality, natural-cause mortality, suicide mortality, and suicide attempts.ResultsIn total, 2614 patients who switched to LAIs (median [interquartile range] {IQR} age, 30 [23-39] years) and 2614 who received OAPs (median [IQR] age, 30 [23-39] years) were included (1333 male patients [51.0%] in each group). During the 16-year follow-up period (median [IQR] follow-up of 14 [10-17] years), patients who switched to LAIs had lower risks of all-cause mortality (adjusted hazard ratio [aHR], 0.66; 95% CI, 0.54-0.81), natural-cause mortality (aHR, 0.63; 95% CI, 0.52-0.76), and suicide attempts (incidence rate ratio, 0.72; 95% CI, 0.55-0.93) compared with patients who received the corresponding OAPs. A 47% lower suicide mortality risk (aHR, 0.53; 95% CI, 0.30-0.92) was observed in patients who switched to LAIs within the first 2 years of OAP initiation.Conclusions and relevanceThese findings suggest that LAI use in patients with newly diagnosed schizophrenia is associated with decreased all-cause mortality and suicide risk. Furthermore, early treatment with LAIs within the first 2 years of OAP initiation was associated with a decrease in suicide mortality risk. Thus, LAI use in the early stage of treatment should be actively considered for patients with newly diagnosed schizophrenia.

Project description:ImportanceEvidence for improved clinical outcomes with long-acting injectable antipsychotics (LAIAs) vs oral antipsychotics (OAs) is limited in Asian populations and special patient groups, including older people (>65 years), people with substance use, and early initiators of LAIAs.ObjectiveTo compare the risk of disease relapse, health care use, and adverse events associated with the use of LAIAs vs OAs among people in Hong Kong with schizophrenia.Design, setting, and participantsIn this self-controlled case series study, individuals with a diagnosis of schizophrenia who were prescribed LAIAs and OAs between January 1, 2004, and December 31, 2019, were identified from the Clinical Database Analysis and Reporting System of the Hong Kong Hospital Authority. Data analysis was conducted from May to August in 2021.ExposuresUse of LAIAs vs OAs.Main outcomes and measuresRisk of disease relapse (hospitalizations for psychiatric disorders, hospitalizations for schizophrenia, and suicide attempts), health care use (all-cause emergency department visits and hospitalizations), and adverse events (hospitalizations for somatic disorders, hospitalizations for cardiovascular diseases, and extrapyramidal symptoms) between the period in which patients were treated with LAIAs and the period in which patients were treated with OAs were compared using Poisson regression.ResultsOf the 70 396 individuals with schizophrenia (37 200 women [52.8%]; mean [SD] age, 44.2 [15.8] years), 23 719 (33.7%) were prescribed both LAIAs and OAs. Compared with OAs, LAIAs were associated with a lower risk of hospitalizations for any cause (n = 20 973; incidence rate ratio [IRR], 0.63 [95% CI, 0.61-0.65]), hospitalizations for psychiatric disorders (n = 19 283; IRR, 0.52 [95% CI, 0.50-0.53]), hospitalizations for schizophrenia (n = 18 385; IRR, 0.53 [95% CI, 0.51-0.55]), and incident suicide attempts (n = 1453; IRR, 0.56 [95% CI, 0.44-0.71]). During full treatment with LAIAs, there was a reduction in hospitalizations for somatic disorders (n = 15 396; IRR, 0.88 [95% CI, 0.85-0.91]), hospitalizations for cardiovascular diseases (n = 3710; IRR, 0.88 [95% CI, 0.81-0.96]), and extrapyramidal symptoms (n = 22 182; IRR, 0.86 [95% CI, 0.82-0.91]) compared with full treatment with OAs. No significant difference was found for emergency department visits. Similar associations were observed during the subsequent treatment periods (beyond 90 days) and among older people and those with substance use, except for an increased risk of extrapyramidal symptoms among older people when initiating LAIAs (first 90 days). Compared with late initiators, early LAIA initiators had a greater reduction in these outcome events.Conclusions and relevanceThis self-controlled case series study of people in Hong Kong with schizophrenia suggests that LAIAs were associated with a lower risk of disease relapse and hospitalization than OAs, without an increased risk of adverse events. Clinicians should more broadly consider the long-term use of LAIAs for Chinese people with schizophrenia, especially early in the course of illness.

Dataset Information

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

Publications

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

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