Long-acting Injectable Drugs Research Articles

Nomogram model for predicting medication adherence in patients with various mental disorders based on the Dryad database

ObjectiveTreatment compliance among psychiatric patients is related to disease outcomes. How to assess patient compliance remains a concern. Here, we established a predictive model for medication compliance in patients with...

Development of a physiologically-based pharmacokinetic model to simulate the pharmacokinetics of intramuscular antiretroviral drugs.

There is growing interest in the use of long-acting (LA) injectable drugs to improve treatment adherence. However, their long elimination half-life complicates the conduct of clinical trials. Physiologically-based pharmacokinetic (PBPK) modeling is a mathematical tool that allows to simulate unknown clinical scenarios for LA formulations. Thus, this work aimed to develop and verify a mechanistic intramuscular PBPK model. The framework describing the release of a LA drug from the depot was developed by including both the physiology of the injection site and the physicochemical properties of the drug. The framework was coded in Matlab® 2020a and implemented in our existing PBPK model for the verification step using clinical data for LA cabotegravir, rilpivirine, and paliperidone. The model was considered verified when the simulations were within twofold of observed data. Furthermore, a local sensitivity analysis was conducted to assess the impact of various factors relevant for the drug release from the depot on pharmacokinetics. The PBPK model was successfully verified since all predictions were within twofold of observed clinical data. Peak concentration, area under the concentration-time curve, and trough concentration were sensitive to media viscosity, drug solubility, drug density, and diffusion layer thickness. Additionally, inflammation was shown to impact the drug release from the depot. The developed framework correctly described the release and the drug disposition of LA formulations upon intramuscular administration. It can be implemented in PBPK models to address pharmacological questions related to the use of LA formulations.

Using in silico methods to determine optimal tapering regimens for decanoate-based long-acting injectable psychosis drugs.

Reducing the dose of psychosis drugs in a gradual hyperbolic manner may minimise withdrawal effects and risk of relapse. There is presently limited guidance on tapering decanoate-based long-acting injectable dopamine antagonists (LIDAs). We aimed to apply hyperbolic principles of tapering to the decanoate-based LIDAs flupentixol, zuclopenthixol and haloperidol to develop withdrawal regimens. We used in silico methodology to predict plasma drug levels and D2 occupancy for different LIDA regimens. Existing pharmacokinetic and receptor occupancy data from nuclear neuroimaging studies were used to power modelling. Abrupt discontinuation was examined as a potential strategy, and dose reduction was modelled with pre-defined constraints used in similar work of 10 (fast regimens), 5 (moderate) and 2.5 (slow) percentage points of D2 occupancy change per month. Abrupt discontinuation of decanoate-based LIDAs leads to excessive change in D2 occupancy which violated our pre-defined constraints, potentially resulting in withdrawal symptoms and increased risk of relapse. Reduction of LIDA dose allowed hyperbolic reduction in plasma level consistent with imposed constraints on receptor occupancy reduction rate. For equivalent per-weekly LIDA dosing, more frequent administration allowed a more gradual reduction of D2 occupancy. However, switching to oral forms is required to continue hyperbolic tapering to full discontinuation; reduction to zero using only LIDA produces too large a reduction in D2 occupancy. Guidance for reduction and cessation of LIDAs according to slow, moderate and fast criteria is provided. Abrupt cessation of decanoate LIDAs is not consistent with gradual hyperbolic tapering, despite their longer half-lives compared with oral formulations. Reduction to the point of full discontinuation can only be achieved by switching to oral therapy to complete the taper. These results are limited by the in silico and theoretical nature of the study, and there is a need to confirm these findings through real-world observational and interventional studies.

Assessment of satisfaction with antiretroviral drugs and the need for long-acting injectable medicines among people living with HIV in Japan and its associated factors: a prospective multicenter cross-sectional observational study

BackgroundLong-acting injectable formulations for HIV infection have been approved and are now available in Japan. Although not currently recommended as first-line drugs in Japanese or overseas guidelines, use of such formulations may increase, in accordance with patient conditions and preference. We determine the level of satisfaction with current anti-HIV drugs and analyzed the preferences of patients who favor long-acting injectable drugs based on their satisfaction level with the present anti-HIV drugs.MethodsPeople living with HIV (PLWH) who had received antiretroviral therapy (ART) for at least one month and consented to the study between 1 April and 31 December 2021 were included in a survey conducted using a self-administered questionnaire. The content of the survey included satisfaction with seven items (tablet size, ease and feeling when taking the medicine, color, taste, portability, daily oral therapy, and co-payment) related to the anti-HIV drugs they were taking and their need for future drugs (dosage form, frequency of dosing, long-acting injectable, etc.). In addition, factors related to the need for long-acting injectable medications were analyzed with regard to the relationship with satisfaction with anti-HIV drugs.ResultsOverall, 667 patients available for analysis were included in this study. Satisfaction with anti-HIV drugs was highest with regard to “co-payment” and lowest with “daily oral therapy”. Regarding the need for long-acting injectable medications, logistic regression analysis indicated that tablet size and daily oral therapy were significant predictors of patient preference for a once-every-eight-weeks intramuscular formulation in terms of their requirement for long-acting injectable medications (tablet size, OR = 2.14, 95%CI 1.030–4.430, p = 0.042; and daily oral therapy, OR = 1.75, 95%CI 1.010–3.030, p = 0.044).ConclusionsPatients currently receiving anti-HIV drugs who express dissatisfaction with tablet size and daily oral therapy may prefer a long-acting injectable formulation, taking into consideration patient age, employment status, ART history, frequency of daily dosage and concomitant medications other than ART.

Seventy Years of Treating Delusional Disorder with Antipsychotics: A Historical Perspective.

For many decades, delusional disorder (DD) has been considered a treatment-resistant disorder, with antipsychotics acknowledged as the best, though imperfect, treatment. It is possible that the discovery of the right drug could turn treatment resistance into treatment response. The goal of this narrative review is to provide a historical perspective of the treatment of DD since the introduction of antipsychotics 70 years ago. The following search terms were used to scan the literature: antipsychotics AND "delusional disorder". Findings were that therapy for DD symptoms has changed over time. Initial reports suggested that the drug of choice was the antipsychotic pimozide, and that this drug was especially effective for the somatic subtype of DD. Subsequent studies demonstrated that other antipsychotics, for instance, risperidone and olanzapine, were also highly effective. Treatment response may vary according to the presence or absence of specific symptoms, such as cognitive defect and depression. Clozapine, partial D2 agonists, and long-acting injectable drugs may be more effective than other drugs, but the evidence is not yet in. Because of the absence of robust evidence, treatment guidelines for the optimal management of DD are not yet available.

Target Product Profiles for Mosquito Gene Drives: Incorporating Insights From Mathematical Models

Mosquito-borne diseases such as malaria continue to pose a major global health burden, and the impact of currently-available interventions is stagnating. Consequently, there is interest in novel tools to control these diseases, including gene drive-modified mosquitoes. As these tools continue to be refined, decisions on whether to implement them in the field depend on their alignment with target product profiles (TPPs) that define product characteristics required to achieve desired entomological and epidemiological outcomes. TPPs are increasingly being used for malaria and vector control interventions, such as attractive targeted sugar baits and long-acting injectable drugs, as they progress through the development pipeline. For mosquito gene drive products, reliable predictions from mathematical models are an essential part of these analyses, as field releases could potentially be irreversible. Here, we review the prior use of mathematical models in developing TPPs for malaria and vector control tools and discuss lessons from these analyses that may apply to mosquito gene drives. We recommend that, as gene drive technology gets closer to field release, discussions regarding target outcomes engage a wide range of stakeholders and account for settings of interest and vector species present. Given the relatively large number of parameters that describe gene drive products, machine learning approaches may be useful to explore parameter space, and an emphasis on conservative fitness estimates is advisable, given the difficulty of accurately measuring these parameters prior to field studies. Modeling may also help to inform the risk, remediation and cost dimensions of mosquito gene drive TPPs.

Profile of patients with long-acting injectable antipsychotics drugs in outcome patients of the psychiatry services in a Galician regional hospital

Profile of patients with long-acting injectable antipsychotics drugs in outcome patients of the psychiatry services in a Galician regional hospital

Learning from the “tail end” of de-implementation: the case of chemical castration for localized prostate cancer

BackgroundMen with prostate cancer are often treated with the suppression of testosterone through long-acting injectable drugs termed chemical castration or androgen deprivation therapy (ADT). In most cases, ADT is not an appropriate treatment for localized prostate cancer, indicating low-value care. Guided by the Theoretical Domains Framework (TDF) and the Behavior Change Wheel’s Capability, Opportunity, Motivation Model (COM-B), we conducted a qualitative study to identify behavioral determinants of low-value ADT use to manage localized prostate cancer, and theory-based opportunities for de-implementation strategy development.MethodsWe used national cancer registry and administrative data from 2016 to 2017 to examine the variation in low-value ADT use across Veterans Health Administration facilities. Using purposive sampling, we selected high- and low-performing sites to conduct 20 urology provider interviews regarding low-value ADT. We coded transcripts into TDF domains and mapped content to the COM-B model to generate a conceptual framework for addressing low-value ADT practices.ResultsOur interview findings reflected provider perspectives on prescribing ADT as low-value localized prostate cancer treatment, including barriers and facilitators to de-implementing low-value ADT. We characterized providers as belonging in 1 of 3 categories with respect to low-value ADT use: 1) never prescribe 2); willing, under some circumstances, to prescribe: and 3) prescribe as an acceptable treatment option. Provider capability to prescribe low-value ADT depended on their knowledge of localized prostate cancer treatment options (knowledge) coupled with interpersonal skills to engage patients in educational discussion (skills). Provider opportunity to prescribe low-value ADT centered on the environmental resources to inform ADT decisions (e.g., multi-disciplinary review), perceived guideline availability, and social roles and influences regarding ADT practices, such as prior training. Provider motivation involved goals of ADT use, including patient preferences, beliefs in capabilities/professional confidence, and beliefs about the consequences of prescribing or not prescribing ADT.ConclusionsUse of the TDF domains and the COM-B model enabled us to conceptualize provider behavior with respect to low-value ADT use and clarify possible areas for intervention to effect de-implementation of low-value ADT prescribing in localized prostate cancer.Trial registrationClinicalTrials.gov, NCT03579680

Modulation of the clinically accessible gelation time using glucono-d-lactone and pyridoxal 5′-phosphate for long-acting alginate in situ forming gel injectable

The purpose of this study was to design alginate in situ forming gel (ISFG) injectable with clinically acceptable gelation time and controlled release of hydrophobic drug. Milled or unmilled paliperidone palmitate (PPP) was used. The gelation time was controlled by varying the ratios of glucono-d-lactone (GDL) and pyridoxal 5′-phosphate (PLP) in prefilled alginate solution mixtures (ASMs) containing PPP, CaCO3, GDL and PLP for clinically acceptable injectability. However, the gelation time was varied by the alginate type (M/G ratio), storage condition, and drug solubilizers. This ISFG exhibited 32.15 kPa of the maximal compressive stress without causing pain and stiffness. The ISFG containing conically milled PPP released PPP in a controlled manner without exhibiting any initial burst release for 4 weeks. The current alginate ISFG injectable using new combination of PLP and GDL could be used to deliver long-acting injectable drugs.

Safety and Pharmacokinetic Profiles of Long-Acting Injectable Antiretroviral Drugs for HIV-1 Pre-Exposure Prophylaxis: A Systematic Review and Meta-analysis of Randomized Trials.

Objectives: To investigate the safety and pharmacokinetic profiles of long-acting injectable pre-exposure prophylaxis (LAI PrEP), notably cabotegravir (CAB-LA) and rilpivirine (RPV-LA), for the prevention of human immunodeficiency virus-1 (HIV-1) infection. Methods: Eligible randomized trials of LAI PrEP in HIV-uninfected and/or healthy patients were included and assessed with the Revised Cochrane risk-of-bias tool for randomized trials. Where feasible, a meta-analysis was performed for safety outcomes by using a random-effects model with risk ratios and their 95% confidence intervals as the common effect measure. The protocol was registered with PROSPERO CRD42020154772. Results: Eight studies cumulating a total of 666 participants were included in this systematic review, including five (362 intervention-arm volunteers) and four trials (194 intervention-arm volunteers) that investigated CAB-LA and RPV-LA, respectively. We found that both CAB-LA and RPV-LA were generally well-tolerated as their safety profiles were similar to placebo in terms of any adverse event (AE), serious AE, and AE-related withdrawals. Furthermore, pharmacokinetic analyses revealed favorable prospects in viral inhibitory activity of CAB-LA and RPV-LA. Intramuscular (IM) injection of CAB-LA 600 mg Q8W was superior to CAB-LA 800 mg Q12W in male participants, while the same was true for RPV-LA 1200 mg IM Q8W over other dosing regimens. Although these results are promising, further research is required to confirm the findings on RPV-LA as current evidence is limited. Conclusion: CAB-LA and RPV-LA have promising safety and pharmacokinetic profiles. The preventive efficacy of these agents is being evaluated in Phase 3 trials.

Patterns of long acting injectable antipsychotic use and associated clinical factors in schizophrenia among 15 Asian countries and region.

Patterns of clinical use of long-acting injectable (LAI) antipsychotic drugs in many countries, especially in Asia, for treatment of patients diagnosed with chronic psychotic disorders including schizophrenia are not well established. Within an extensive research consortium, we evaluated prescription rates for first- (FGA) and second-generation antipsychotic (SGA) LAI drugs and their clinical correlates among 3557 subjects diagnosed with schizophrenia across 15 Asian countries and region. Overall, an average of 17.9% (638/3557; range: 0.0%-44.9%) of treated subjects were prescribed LAI antipsychotics. Those given LAI vs orally administered agents were significantly older, had multiple hospitalizations, received multiple antipsychotics more often, at 32.4% higher doses, were more likely to manifest disorganized behavior or aggression, had somewhat superior psychosocial functioning and less negative symptoms, but were more likely to be hospitalized, with higher BMI, and more tremor. Being prescribed an FGA vs SGA LAI agent was associated with male sex, aggression, disorganization, hospitalization, multiple antipsychotics, higher doses, with similar risks of adverse neurological or metabolic effects. Rates of use of LAI antipsychotic drugs to treat patients diagnosed with schizophrenia varied by more than 40-fold among Asian countries and given to an average of 17.9% of treated schizophrenia patients. We identified the differences in the clinical profiles and treatment characteristics of patients who were receiving FGA-LAI and SGA-LAI medications. These findings behoove clinicians to be mindful when evaluating patients' need to be on LAI antipsychotics amidst multifaceted considerations, especially downstream adverse events such as metabolic and extrapyramidal side effects.

Long-acting Injectable vs. Oral Antipsychotics: Adherence, Persistence and Switching over three Years of Real-life Analysis.

Persistence and adherence to treatment are considered efficacy outcomes in psychiatric disorders. One of the best ways to improve these values in patients with psychiatric disorders is to prefer Long-Acting Injectable (LAI) drugs to oral AP. The objective of this study is to evaluate adherence, persistence and switching of antipsychotics and compare in real life long-acting with oral formulations. This pharmacological, observational, retrospective and non-interventional study involved all patients of the ASL of Pescara treated in the front-line with AP in the period between January 2011 and February 2019. Adherence was measured using the ratio between the received daily dose and prescribed daily dose. Persistence to treatment with antipsychotics was calculated as the daily difference between the beginning and end of treatment. We examined 840 patients treated with aripiprazole, 130 patients treated with paliperidone and 925 patients treated with risperidone. Adherence was significantly better in long-acting formulations with values of 0.89 (aripiprazole) and 0.82 (paliperidone and risperidone) than in oral formulations with values of 0.78, 0.70 and 0.58, respectively (p> 0.999, p= 0.0091, p=< 0.0001). Threeyear persistence curves relating to three study drugs did not show a statistically significant difference (p = 0.3314). Persistence curves based on formulation have not shown a statistically significant difference (p= 0, 4658, p=0, 4794, p=0, 2199 for ariprazolo, paliperidone and risperidone, respectively). 7% of patients were treated with aripiprazole, 12% of patients were treated with risperidone and 28% of patients were treated with paliperidone switched therapy. In all the drugs of present study, adherence values were better in LAI than in OA, whereas no statistically significant difference was found in persistence values.

P.684 Potential benefit of polypharmacy of Long-acting injectable drugs: retrospective data from a psychiatry hospital

P.684 Potential benefit of polypharmacy of Long-acting injectable drugs: retrospective data from a psychiatry hospital

Long-Acting Injectable versus Oral Antipsychotics for Restoration of Competency to Stand Trial.

Treatment with antipsychotics is a mainstay of trial competency restoration, particularly given that most defendants deemed incompetent to stand trial have psychotic illnesses. We explored the association between competency restoration and antipsychotic type in a retrospective sample of defendants diagnosed with psychotic disorders and deemed incompetent to stand trial. Using regression models, we calculated the odds ratio of being competent to stand trial, adjusting for relevant confounders. We found that the use of long-acting injectable antipsychotics was not significantly associated with increased odds of restoration of trial competency. Our results highlight the need for larger, longitudinal studies to further explore the efficacy and tolerability of long-acting injectable drugs compared with oral antipsychotics. Future research will help develop treatment guidelines within the setting of trial competency restoration.

Modern Human Immunodeficiency Virus Therapy: Progress and Prospects

Safe and effective lifelong treatment to control human immunodeficiency virus (HIV) infection is one of the greatest scientific and public health achievements of the past century. The majority of infected individuals able to maintain a daily oral regimen now have a normal or near-normal life expectancy. More than 30 approved drugs and dozens of formulations have produced thousands of possible drug combinations used clinically in the past, but today most patients receive only a handful of high priority and rigorously tested regimens. Unique features of antiretroviral therapy include the need for lifelong treatment to control virus replication and the possibility of rapid emergence of permanent drug resistance if these agents are not properly used. Although three-drug combination oral regimens have radically altered the course of this epidemic, the future will include long-acting injectable and implantable drugs and devices to treat and prevent infection.

De-implementation of low value castration for men with prostate cancer: protocol for a theory-based, mixed methods approach to minimizing low value androgen deprivation therapy (DeADT)

BackgroundMen with prostate cancer are often castrated with long-acting injectable drugs termed androgen deprivation therapy (ADT). Although many benefit, ADT is also used in patients with little or nothing to gain. The best ways to stop this practice are unknown, and range from blunt pharmacy restrictions to informed decision-making. This study will refine and pilot two different de-implementation strategies for reducing ADT use among those unlikely to benefit in preparation for a comparative effectiveness trial.Methods/designThis innovative mixed methods research program has three aims. Aim 1: To assess preferences and barriers for de-implementation of chemical castration in prostate cancer. Guided by the theoretical domains framework (TDF), urologists and patients from facilities with the highest and lowest castration rates across the VA will be interviewed to identify key preferences and de-implementation barriers for reducing castration as prostate cancer treatment. This qualitative work will inform Aim 2 while gathering rich information for two proposed pilot intervention strategies. Aim 2: To use a discrete choice experiment (DCE), a novel barrier prioritization approach, for de-implementation strategy tailoring. The investigators will conduct national surveys of urologists to prioritize key barriers identified in Aim 1 for stopping incident castration as localized prostate cancer treatment using a DCE experiment design. These quantitative results will identify the most important barriers to be addressed through tailoring of two pilot de-implementation strategies in preparation for Aim 3 piloting. Aim 3: To pilot two tailored de-implementation strategies to reduce castration as localized prostate cancer treatment. Building on findings from Aims 1 and 2, two de-implementation strategies will be piloted. One strategy will focus on formulary restriction at the organizational level and the other on physician/patient informed decision-making at different facilities. Outcomes will include acceptability, feasibility, and scalability in preparation for an effectiveness trial comparing these two widely varying de-implementation strategies.DiscussionOur innovative approach to de-implementation strategy development is directly aligned with state-of-the-art complex implementation intervention development and implementation science. This work will broadly advance de-implementation science for low value cancer care, and foster participation in our de-implementation evaluation trial by addressing barriers, facilitators, and concerns through pilot tailoring.Trial registrationClinicalTrials.gov Identifier: NCT03579680, First Posted July 6, 2018.

Long-acting technologies for infectious diseases in LMICs

Imagine a child in the Sahel protected from malaria for an entire season after just one injection of chemoprophylaxis. Or a woman at risk of HIV in Zambia taking a single capsule every 2 weeks that slowly releases an antiretroviral drug to protect her from infection. Could the risk of resistance to medications for infectious diseases be reduced through the use of long-acting (LA) patches, implants, or injectable drugs?

Clinical and functioning outcomes of second-generation long-acting antipsychotics in a sample of schizophrenia patients during a follow-up period of 6 months

IntroductionSecond-generation long-acting injectable antipsychotics (LAIs) constitute a valuable alternative for the treatment of schizophrenia and combine advantages of both long-acting injectable drugs and atypical antipsychotics. Realistic, naturalistic studies are necessary to evaluate the impact of LAIs on specific cluster of symptoms.ObjectivesTo collect clinical and functioning outcomes in outpatients with schizophrenia treated with LAIs during a follow-up period of 6 months.AimsTo determine the impact on symptoms and functioning of second-generation LAIs.MethodsIt is a 6-month naturalistic, observational, prospective, non-interventional study of patients diagnosed with DSM-V schizophrenia disorder. Clinical data were assessed by the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF). For statistical analysis, we used the Wallwork's five-factor model of the PANSS.ResultsA total of 50 schizophrenia patients (70% male; mean age: 36.2 ± 10.4) referred to the Depot Clinic at Sant’Andrea Hospital in Rome was included. Eight patients received treatment with risperidone LAI (RLAI), 20 with paliperidone-palmitate LAI (PLAI), 10 with olanzapine-pamoate LAI (OLAI) and 12 with aripiprazole LAI (ALAI). LAIs were overall associated with improved functioning and positive symptoms; OLAI, ALAI e PLAI correlated with improved negative symptoms, RLAI, OLAI e PLAI with improved disorganised/concrete symptoms, OLAI e PLAI with improved excited symptoms; ALAI improved depressive symptoms.ConclusionOver the 6-month period, LAIs were associated with improved functioning and illness severity in schizophrenia patients with different symptoms profile. Treatment with PLAI and OLAI showed the major clinical advantages, whereas only ALAI correlated with improved depressive symptoms.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Long-acting injectable aripiprazole. Clinical experience in a case series

IntroductionThe use of long-acting injectable antipsychotics is useful in patients with low therapeutic compliance.ObjectiveTo present the demographic and clinical data of a case series in which long-acting injectable aripiprazole has been prescribed in an ambulatory Mental Health Center.MethodsSystematic review of the related literature and clinical history of patients in which long-acting injectable aripiprazole had been prescribed from January to March 2015 in a Mental Health Center.ResultsWe found 10 patients, whose diagnosis were schizophrenia (4), non-specified psychosis (2), personality disorder (1), bipolar disorder (1), schizoaffective disorder (2), of whom 7 were men and 3 women, with a mean age of 43.8 years old. The mean of years since diagnosis was 15.1 years. In 7 patients, we found concomitant treatment with another antipsychotic agent (low dose quetiapine in all of them); antidepressants in 1 patient, benzodiazepines in 6; mood stabiliser in 5 and biperidene in 1. In relation to previous antipsychotic drugs, we found: aripiprazole 15 mg/day oral (4); long-acting injectable paliperdidone 150 mg/28 days (2) paliperdone 6 mg/day oral (1); combination of paliperidone 6 mg/day oral plus olanzapine 5 mg/day oral (1). Only 4 patients had used long-acting injectable drugs previously in their lifetime. The reason of having initiated treatment with long-acting injectable aripiprazole was sexual disturbance (3); lack of compliance (4); clinical inestability (2) and motor side effects (1).ConclusionsIn our series, we can observe a chronic patient profile, predominantly men with diagnosis of psychotic spectrum.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Guidelines for the use of second-generation long-acting antipsychotics

Long-acting injectable antipsychotics constitute a valuable alternative for the treatment of psychotic disorders, mainly schizophrenia. They assure a more stable drug level, improve treatment compliance, and increase the chances for favorable and long-lasting improvement. Additionally, the long-acting second-generation antipsychotics combine the values of long-acting injectable drugs with the values of atypical antipsychotics. Four second generation long-acting antipsychotics have been described: risperidone, olanzapine, aripiprazole and paliperidone. The indications for their use, treatment strategy, tolerance, and potential interactions are discussed.