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Percent D2 receptor occupancy as a function of plasma olanzapine concentrations at 4 Weeks after Injection of 300 mg OP Depot (N=14). The regression line has been fit to the rectangular hyperbole equation: occupancy=Emax (plasma concentration/(plasma concentration+EC50)), where Emax is the maximum receptor occupancy with an estimated EC50 (SD)=11.01.3 ng/ml.
Source publication
A long-acting depot formulation of olanzapine that sustains plasma olanzapine concentrations for over a month after a single injection is currently under development. This multicenter, open-label study explored D(2) receptor occupancy of a fixed dose of olanzapine pamoate (OP) depot given every 4 weeks. Patients (nine male, five female) with schizo...
Context in source publication
Context 1
... ¼ 14), reflecting the occupancy of the oral olanzapine dose of the study group (15.274.8 mg/day). Over the entire study period, an expected curvilinear asymptotic significant relationship was found between plasma olanzapine con- centrations and D 2 receptor occupancy (r ¼ 0.76, Pp0.001) (Figure 1). These data were fitted to the equation described in the Patients and Methods section to yield a concentration associated with 50% of maximal occupancy (EC 50 ) of 11.071.3 ...
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Despite the well-documented loss of brain dopamine activity with age, little is known about its functional consequences in healthy individuals. This study investigates the relationship between measures of brain dopamine D(2) receptors (molecules that transmit dopamine signals) and regional brain glucose metabolism (a marker of brain function) in he...
Citations
... TDM/A686). 28,32,[37][38][39][40][41][42] The first study was conducted in 1997 by Nyberg et al. 37 After the administration of single 10-mg oral doses, 3 healthy volunteers were scanned for D 2 and 5-HT 2 receptor occupancy. D 2 receptor occupancy was found to be between 59% and 63% (7 hours after intake), and 5-HT 2 receptor occupancy was 74%-92% (9.5 hours after drug intake), with drug levels of approximately 10-11 ng/mL. ...
... 39,42 Studies using a constrained model report a lower target concentration of 19.1-20.4 ng/ mL to achieve 65% D 2 receptor occupancy 38,39 ; 80% occupancy is reached above 41-44 ng/mL. Moreover, no clear correlation with EPS was reported. ...
... *Mean 6 SD plasma olanzapine concentrations; n, number of PET scans. 38 effective doses, from as low as 40 mg after single dosing to 120 mg following chronic dosing. Using chronic dosing regimens, phase II clinical efficacy studies found that 40 mg doses of ziprasidone were less effective than placebo. ...
Background
Positron emission tomography (PET) and single photon emission tomography (SPECT) of molecular drug targets (neuroreceptors and transporters) provide essential information for therapeutic drug monitoring–guided antipsychotic drug therapy. The optimal therapeutic windows for D 2 antagonists and partial agonists, as well as their proposed target ranges, are discussed based on an up-to-date literature search.
Methods
This part I of II presents an overview of molecular neuroimaging studies in humans and primates involving the target engagement of amisulpride, haloperidol, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, cariprazine, and ziprasidone. The systemic review particularly focused on dopamine D 2 -like and 5-HT 2A receptors. Target concentration ranges were estimated based on receptor occupancy ranges that relate to clinical effects or side effects (ie, extrapyramidal side effects). In addition, findings for other relevant receptor systems were included to further enrich the discussion.
Results
The reported reference ranges for aripiprazole and clozapine align closely with findings from PET studies. Conversely, for haloperidol, risperidone, and olanzapine, the PET studies indicate that a lowering of the previously published upper limits would be necessary to decrease the risk of extrapyramidal side effect.
Conclusions
Molecular neuroimaging studies serve as a strong tool for defining target ranges for antipsychotic drug treatment and directing therapeutic drug monitoring.
... (Modified from: Ross & Kenakin, 2001, with permission from McGraw-Hill Companies, Inc.) Example we focus mainly on its application to simulate target antagonism, as the majority of drugs are inhibitors (Copeland et al., 2007;Li et al., 2007){ 21,22}, and the accessibility of both ubiquitous CreER For example, opiate agonists etorphine and sufentanil have significant analgesic activity at very low receptor occupancy -approximately 2% at the ED50 (Rosenbaum et al., 1984);{18} and in another example, only 22% receptor occupancy is needed for half-maximal stimulation by PEG-TPOm, a mimetic peptide agonist in development for protection against chemotherapy-induced Thrombocytopenia (loss of blood platelets) (Samtani et al., 2009).{19} The antipsychotic dopamine D2 receptor antagonist olanzapine achieves optimal clinical efficacy at approximately 60% receptor occupancy (Mamo et al., 2007){20}. Similarly, genetic pharmacotherapy need not produce full target inhibition to elicit a response. ...
In current drug development, proof-of-concept—
determining whether a ligand engaging its target
is likely to be therapeutic—requires specific
ligands. This presents a catch-22, as the
motivation to develop ligands requires proof-of�concept studies that cannot be conducted
without ligands. A strategy we term genetic
pharmacotherapy—a refinement of genetic
blockade focused on drug-gable targets—
obviates the catch-22 by enabling proof-of�concept studies before the development of
specific ligands via genetic means in mouse
models. In this strategy, which could help avert
investment in molecular entities that will
ultimately prove therapeutically efficacious, a
gene is conditionally down-regulated via a
molecular switch in adult mice. Both the precise
temporal control of the intervention and the
consequent change in the target protein function
parallels the administration of drugs, with the
additional advantage of perfect specificity.
Moreover, genetic pharmacotherapy overcomes
the impediment of the blood-brain barrier, which
makes developing ligands for psychiatric
disorders particularly challenging
... It was found that oral supplementation was needed in half the patients for the first 4 months. 22 The authors concluded that this could indicate that oral supplementation of olanzapine or a higher dose or frequency of injections could be required. 22 It is notable that secondary care community mental health services refused to accept two patients (5%) prescribed OLAI at discharge from inpatient care, as they were not able to provide the required 3 h PIS monitoring, giving the clinician no option but to discontinue the otherwise effective OLAI. ...
... 22 The authors concluded that this could indicate that oral supplementation of olanzapine or a higher dose or frequency of injections could be required. 22 It is notable that secondary care community mental health services refused to accept two patients (5%) prescribed OLAI at discharge from inpatient care, as they were not able to provide the required 3 h PIS monitoring, giving the clinician no option but to discontinue the otherwise effective OLAI. As discussed, the incidence of PIS is reported as less than 0.1% in the Summary of Product Characteristics, supported by a study reporting a rate of 0.044%. ...
Background
Olanzapine pamoate has been shown to be an effective second-generation long-acting injection. Its popularity has possibly been adversely affected by the rare incidence of post-injection syndrome (PIS) and the associated requirement to monitor for 3 h after each injection.
Objective
This study aimed to collect and present data on the use of olanzapine long-acting injection (OLAI) over a 10-year period in a high-security forensic hospital in South East England.
Design
This was a non-interventional retrospective study collecting information from anonymised electronic patient and prescription records. As per hospital Trust guidelines, patient consent to access of hospital records was presumed unless explicitly withdrawn.
Method
All patients prescribed OLAI between the years 2009 and 2019 were identified. Data collected included date that OLAI was started, stopped, dose range, side effects and concomitant medication.
Results
Of 88 patients who were started OLAI, 45 (51%) continued at month 24. At 60 months, 22 of 70 (31%) patients for whom data were available continued with OLAI. Over 60% of continuers were on higher than recommended doses. Of almost 5000 injections administered, there was 1 episode of PIS.
Conclusion
OLAI is an effective treatment for schizophrenia and schizoaffective disorder, especially when used in patients have been able to tolerate the drug and were stabilised on it for 24 months. In over half the patients who continued OLAI, the doses were higher than that recommended by the manufacturer. The incidence of PIS in this study was very low in comparison with other studies.
Registration code
2049
... 21,22 Furthermore, the TEAEs reported were in line with those observed in previous studies with Risperidone ISM 4,5 and the overall dropout rate was also in agreement with those reported in other studies with antipsychotics. [23][24][25] Most treatment-related TEAEs reported were mild or moderate in severity, leading to study drug discontinuation in only two subjects (2.5%), one due to sedation whilst receiving oral treatment and one due to akathisia following a Risperidone ISM dose. ...
Introduction
This open-label, one-sequence study evaluated the steady-state comparative bioavailability of risperidone in situ microimplants (ISM®) and oral risperidone in patients stabilized on oral risperidone treatment.
Methods
Repeat oral administration of once daily 4 mg risperidone for 7 days was followed by 4 monthly (once every four weeks) intramuscular (IM) doses of risperidone ISM 100 mg. Mean steady-state concentration versus time profiles for risperidone, 9-OH risperidone, and risperidone active moiety was characterized.
Results
A total of 104 subjects were enrolled, 81 were included in the safety population and 58 completed the study. Intersubject variability for the steady-state concentrations versus time profiles for risperidone active moiety presented a greater variability range for oral risperidone versus risperidone ISM (% coefficient of variation [CV] range: 40–65% and 38–52%, respectively). Minimum plasma concentration at steady-state (Cmin, ss) and fluctuation in plasma concentrations (Fluc) of risperidone active moiety after risperidone ISM administration met bioequivalence criteria compared to the reference oral risperidone (geometric mean ratio [GMR] = 1.09 and 0.96, respectively; both 90% CIs were within 0.80–1.25). Area under the curve during the dosing interval (AUCtau), maximum plasma concentration at steady-state (Cmax, ss) and average plasma concentration (Cave) were only slightly higher (GMR [90% CI] = 1.25 [1.16–1.34], 1.17 [1.08–1.27], and 1.25 [1.16–1.34], respectively). Overall, once daily oral risperidone 4 mg and once monthly IM risperidone ISM 100 mg were generally safe and well tolerated in the participating subjects with schizophrenia previously stabilized with oral risperidone.
Conclusion
The rapid release of risperidone ISM allows the achievement of the desired levels similar to those observed at the steady-state after oral risperidone treatment. Therefore, direct switch after 24 hours from the last oral risperidone dose to risperidone ISM treatment can be done in schizophrenia patients with no time lag, maintaining steady-state levels of the active moiety throughout treatment and without the need for oral risperidone supplementation or loading doses.
... Furthermore, the D2 receptors occupancy was found to correlate directly with the plasma concentrations of olanzapine [40]. ...
... It was demonstrated that patients affected by schizophrenia and treated with antipsychotics have a good clinical response when the D2 occupancy rate is between 65 and 80%, while over 80% patients show extrapyramidal side effects and hyperprolactinemia [44,45]. D2 receptor occupancy in relation to LAI SGA plasma concentrations was mainly investigated by PET in small-sample studies of patients treated with risperidone [34][35][36], with the exception of the study by Mamo and collaborators [40] who tested olanzapine and also performed the longest follow-up. All the studies found a positive association between receptor occupancy and LAI SGA plasma concentrations [40] or dose [35,36]. ...
... D2 receptor occupancy in relation to LAI SGA plasma concentrations was mainly investigated by PET in small-sample studies of patients treated with risperidone [34][35][36], with the exception of the study by Mamo and collaborators [40] who tested olanzapine and also performed the longest follow-up. All the studies found a positive association between receptor occupancy and LAI SGA plasma concentrations [40] or dose [35,36]. Of note, Uchida and coauthors proposed a non-linear association between D2 receptor occupancy and LAI risperidone plasma concentrations [34]. ...
Atypical antipsychotic depot medications are currently recommended for patients with schizophrenia (SCZ) to prevent relapse and ameliorate the long-term prognosis of these patients. This review critically summarizes the available data about the association between the plasma concentrations of long-acting SecondGeneration Antipsychotics (SGAs) and the clinical effectiveness of these compounds in patients affected by SCZ or schizoaffective disorder. Our question is if the measurement of these concentrations can be helpful for clinicians in predicting treatment response and clinical stabilization of patients. Bibliographic research on the main databases was performed, and 13 studies were finally included in this review. Contrasting results were found between plasma concentrations of long-acting injectable (LAI) risperidone and clinical amelioration according to rating scale scores. Data are too scanty to draw conclusions for olanzapine and paliperidone. In contrast, despite small sample sizes, data are quite concordant in showing a relation between long-acting SGA plasma concentrations and D2 receptor occupancy. Despite the preliminary encouraging results, particularly for D2 receptor occupancy, future research with larger samples will have to confirm the clinical usefulness of measuring LAI SGA plasma concentrations to predict the clinical response of patients affected by severe mental conditions such as SCZ.
... Among SGAs, only PET studies including active drug concentrations in blood for olanzapine pamoate and risperidone microspheres were available. [79][80][81][82] For LAIs of novel compounds such as paliperidone and aripiprazole, researchers often extrapolated TDM findings supported by PET evidence from oral to LAI. 46,83 However, studies available for risperidone and olanzapine clearly illustrate a relationship between plasma concentrations and D 2 /D 3 receptor occupancy, which can ...
... Evidence from molecular imaging studies suggested that some patients could be adequately treated with 10-15 ng/mL, which would be slightly lower than recommended. 62,73 For olanzapine pamoate, only one trial was available, 80 which was conceptualized as a dosefinding study by the manufacturer; in this study, 14 patients stabilized on oral olanzapine were ...
Purpose:
The use of therapeutic drug monitoring (TDM) to guide treatment with long-acting injectable (LAI) antipsychotics, which are increasingly prescribed, remains a matter of debate. The aim of this review was to provide a practical framework for the integration of TDM when switching from an oral formulation to the LAI counterpart, as well as in maintenance treatment.
Methods:
The authors critically reviewed three types of data: 1) positron emission tomography (PET) data evaluating dopamine (D2/D3) receptor occupancy related to antipsychotic concentrations in serum or plasma; D2/D3 receptors are embraced as target sites in the brain for antipsychotic efficacy and tolerability, 2) pharmacokinetic studies evaluating the switch from oral to LAI antipsychotics, and 3) pharmacokinetic data for LAI formulations. Based on these data, indications for TDM and therapeutic reference ranges were considered for LAI antipsychotics.
Results:
Antipsychotic concentrations in blood exhibited interindividual variability not only under oral but also under LAI formulations, as these concentrations are affected by demographic characteristics such as age and sex, genetic peculiarities, and clinical variables, including co-medications and comorbidities. Reported data combined with PET evidence indicated a trend toward lower concentrations under LAI administration than under oral medications. However, the available evidence is insufficient to recommend LAI-specific therapeutic reference ranges.
Conclusions:
Although TDM evidence for newer LAI formulations is limited, this review suggests the use of TDM when switching an antipsychotic from oral to its LAI formulation. The application of TDM practice is more accurate for dose selection than the use of dose equivalents as it accounts more precisely for individual characteristics.
... mg/d in those whose PL are ,20 ng/mL and have not achieved a favorable response. Notably, there were studies [6][7][8][9] included in this review that were also separately cited by the AGNP guidelines. ...
... Some patients on the LAI required oral supplementation, but that need diminished when occupancy 60% was attained. 6 In the other study, 25 patients were studied to determine clinical efficacy and tolerability of OLZ LAI in relation to PL and clinical outcome in the maintenance phase of schizophrenia. Over 9 months, all patients received either 210, 300, or 405 mg every 4 weeks. ...
Introduction:
In addition to clozapine, there is a growing body of evidence that supports therapeutic drug monitoring (TDM) for additional antipsychotics commonly used in the United States.
Methods:
The Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) published TDM guidelines for several psychiatric medications. Sources were identified that the authors used to establish therapeutic reference ranges for haloperidol, fluphenazine, perphenazine, and olanzapine-4 antipsychotics commonly used in the United States with a "strong recommendation" for TDM. The sources were then reviewed for content and appropriateness for utilization in establishing the reference ranges.
Results:
Olanzapine had 15 citations, haloperidol had 9, perphenazine had 4, and fluphenazine had 2. The studies' methods were reviewed along with the proposed therapeutic reference ranges.
Discussion:
Several limitations of the guidelines were identified. Reference ranges were suggested based on studies of patients with various diagnoses; some patients had an acute exacerbation, and others were in a maintenance phase. An additional publication was identified that reviewed similar (and additional) TDM studies; those conclusions were in slight contrast with those of the AGNP guidelines. In the future, guidance should be given to those looking to conduct TDM studies to standardize methods and make meta-analysis of this data more feasible.
... Some patients who respond to first-line antipsychotic treatment experience diminished treatment efficacy over time (23), which can lead to treatment non-compliance and relapse (81). Diminished antipsychotic efficacy may also occur despite stable D 2 receptor occupancy (82). These dynamics are depicted in Figure 1. ...
... Some patients who respond to first-line antipsychotic treatment experience diminished treatment efficacy over time (23), which can lead to treatment non-compliance and relapse (81). Diminished antipsychotic efficacy may also occur despite stable D 2 receptor occupancy (82). These dynamics are depicted in Figure 1. ...
Antipsychotic treatment resistance in schizophrenia remains a major issue in psychiatry. Nearly 30% of patients with schizophrenia do not respond to antipsychotic treatment, yet the underlying neurobiological causes are unknown. All effective antipsychotic medications are thought to achieve their efficacy by targeting the dopaminergic system. Here we review early literature describing the fundamental mechanisms of antipsychotic drug efficacy, highlighting mechanistic concepts that have persisted over time. We then reconsider the original framework for understanding antipsychotic efficacy in light of recent advances in our scientific understanding of the dopaminergic effects of antipsychotics. Based on these new insights, we describe a role for the dopamine transporter in the genesis of both antipsychotic therapeutic response and primary resistance. We believe that this discussion will help delineate the dopaminergic nature of antipsychotic treatment-resistant schizophrenia.
... Olanzapine pamoate is a nearly insoluble salt designed for aqueous based injection, with multiple dosing options available. 38,39 The kinetic profile of various approaches to achieve a steady state on a dose of 300 mg/4 weeks is illustrated in Figure 8. 20 The expected steady state plasma level for 300 mg/4 weeks is approximately 30 ng/ ml, and for 205 mg/2 weeks or 410 mg/4 weeks is 45 ng/ ml. 40 Severe sedation often requiring hospitalization occurred in approximately 2% of patients in the clinical trials with onset 30-300 minutes after injection. ...
There has been increasing recognition that antipsychotic nonadherence is common across all stages of schizophrenia, starting from the first episode. Moreover, numerous meta-analyses of the existing literature indicate superiority of long-acting injectable (LAI) over oral antipsychotics when one adjusts for the greater illness severity and duration among patients in LAI antipsychotic trials. The increasing availability of LAI antipsychotic options has raised interest in converting patients from oral medication; however, the successful transition from oral to the comparable LAI antipsychotic requires an understanding of the current extent of antipsychotic exposure, the kinetics of the LAI preparation, and the expected plasma levels achieved by the LAI formulation. The purpose of this article is to provide, in a concise format, the essential information for converting patients to the LAI forms of haloperidol, fluphenazine, risperidone, paliperidone, olanzapine, and aripiprazole from the comparable oral medication, and how the use of plasma antipsychotic levels can be invaluable for this process.
