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. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-020-00779-5.

Controversies Surrounding the Use of Long-Acting Injectable Antipsychotic Medications for the Treatment of Patients with Schizophrenia

“…Clinicians may be hesitant to use LAIs for reasons including limited knowledge about drug pharmacokinetics and appropriate dose selection [15], an overestimation of patient adherence to OAs [14,56], and a lack of awareness of the benefits of SGA versus FGA-LAIs or versus OAs [42,76]. In addition, clinicians often appreciate the freedom to modify doses for patients, and limiting this ability with the use of LAIs could generate concerns.…”

“…Poor adherence is considered an important characteristic in determining whether a longacting injectable (LAI) antipsychotic medication will help a patient achieve their therapeutic goal, with LAI use and other strategies often being implemented as a means to help overcome low levels of adherence [8,12,13]. Firstgeneration antipsychotic (FGA) LAIs [14,15] (Table 1) were introduced over 50 years ago with the goals of improving adherence and reducing symptom exacerbation, relapse, and rehospitalization [16,17]. The concept of LAIs for schizophrenia was not initially well received by the medical community or patients because of concerns over increased side effects, lack of efficacy, and that psychiatrists were restricting patient freedom by imposing a treatment without due regard to patients' feelings or rights [10,18].…”

“…The concept of LAIs for schizophrenia was not initially well received by the medical community or patients because of concerns over increased side effects, lack of efficacy, and that psychiatrists were restricting patient freedom by imposing a treatment without due regard to patients' feelings or rights [10,18]. Although first-generation OAs and LAIs remain available, a series of second-generation antipsychotic (SGA) LAIs and OAs [14,15,19] have emerged (Table 1) with improved tolerability [16,20]. Despite recent evidence of the benefits of early LAI use [21,22], many barriers to their adoption exist, including the overestimation of patient adherence, patient refusal, and perceived coercion [23].…”

A systematic review and pooled, patient‐level analysis of predictors of mortality in neuroleptic malignant syndrome

“…First, our findings underscore the already undisputed notion that discontinuation of antipsychotics should be always considered when NMS arises 6,31 . A concern regarding this finding derives from the fact that LAIs cannot be discontinued immediately due to their prolonged medication release system, providing therapeutic antipsychotic blood levels during an injection interval that can last 2–12 weeks 17,32 . However, in this study, antipsychotic formulation was not a predictor of mortality.…”

“…In fact, the association of lack of antipsychotic discontinuation and mortality is driven by lack of OAP discontinuation (30.8 vs. 69.1%, p < 0.0001), yet not by lack of LAI discontinuation (53.9 vs. 56.0%, p = 0.8802). Further studies will be needed once longer‐acting formulations are more widely available, but these results could relate to the advantageous pharmacokinetic properties of LAIs, 32 that provide stable plasma drug concentrations and subsequently minimize fluctuations in receptor occupancy compared to their oral counterparts. These results are relevant, as they add important information about the safety of LAIs, 33 given the progressive expansion of their injection intervals, indications, and use 34‐37 .…”