Long-acting Injection Research Articles

Med rec double check: Inpatient psychiatry medication errors identified on admission using Medicaid Web portals and electronic pharmaceutical claims data.

The role of pharmacists during medication reconciliation (MR) is well established, with a number of reports describing this in the context of psychiatric hospitalizations. However, medication errors (MEs) are common during transitions of care, with no exception during psychiatric hospitalizations. Our institution uses pharmacy-performed MR processes using patient interviews and reviewing objective sources, such as electronic pharmaceutical claims data (EPCD), which includes Medicaid Web portals. The inpatient psychiatric pharmacist reviews EPCD sources against previously pharmacy-completed MRs for new admissions, where if discrepancies are found, the patient is reinterviewed to identify and correct MEs. We performed a prospective quality improvement project during 28 days to evaluate the quantity and classification of MEs upon admission to a 22-bed inpatient psychiatry unit. Of 52 included patients, where a cumulative 426 medications were reviewed, a total of 29 MEs in 16 patients were identified. Eight patients had discrepancies on their home medication lists when compared to EPCD, where 7 of these had at least 1 ME due to inaccurate MR. Of all the MEs identified, the greatest quantity was found secondary to the EPCD "double-check" method. The most common MEs in all patients were the omission of home medications (34%), wrong frequency (28%), and ordering medication the patient is not taking (10%). All patients admitted on long-acting injection antipsychotics had errors in last dose received. No MEs resulted in patient harm, and they were identified and corrected by the psychiatric pharmacist 97% of the time.

Patient Education and Decision Support for Long-Acting Injectable HIV Antiretroviral Therapy: Protocol for Tool Development and Pilot Testing with Ryan White HIV/AIDS Program Medical Case Management Programs in New York.

Long-acting injectable (LAI) HIV antiretroviral therapy (ART) presents a major opportunity to facilitate and sustain HIV viral suppression, thus improving health and survival among people living with HIV and reducing the risk of onward transmission. However, realizing the public health potential of LAI ART requires reaching patients who face barriers to daily oral ART adherence and thus can clinically benefit from alternative treatment modalities. Ryan White HIV/AIDS Program Part A medical case management (MCM) programs provide an array of services to address barriers to HIV care and treatment among economically and socially marginalized people living with HIV. These programs have demonstrated effectiveness in improving engagement along the continuum of care, but findings of limited program impact on durable viral suppression highlight the need to further innovate and hone strategies to support long-term ART adherence. This study aims to adapt and expand Ryan White MCM service strategies to integrate LAI ART regimen options, with the larger goal of improving health outcomes in the populations that could most benefit from alternatives to daily oral ART regimens. In 3 phases of work involving patient and provider participants, this study uses role-specific focus groups to elicit perceptions of LAI versus daily oral ART; discrete choice experiment (DCE) surveys to quantify preferences for different ART delivery options and related supports; and a nonrandomized trial to assess the implementation and utility of newly developed tools at 6 partnering Ryan White HIV/AIDS Program Part A MCM programs based in urban, suburban, and semirural areas of New York. Findings from the focus groups and DCEs, as well as feedback from advisory board meetings, informed the design and selection of the tools: a patient-facing, 2-page fact sheet, including frequently asked questions and a side-by-side comparison of LAI with daily oral ART; a patient-facing informational video available on YouTube (Google Inc); and a patient-provider decision aid. Implementation outcomes, measured through provider interviews, surveys, and service reporting, will guide further specification of strategies to integrate LAI ART options into MCM program workflows. The study was funded in late April 2021 and received approval from the institutional review board in May 2021 under protocol 20-096. Focus groups were conducted in late 2021 (n=21), DCEs ran from June 2022 to January 2023 (n=378), and tools for piloting were developed by May 2023. The trial (May 2023 through January 2024) has enrolled >200 patients. This study is designed to provide evidence regarding the acceptability, feasibility, appropriateness, and utility of a package of patient-oriented tools for comparing and deciding between LAI ART and daily oral ART options. Study strengths include formative work to guide tool development, a mixed methods approach, and the testing of tools in real-world safety-net service settings. Clinicaltrials.gov NCT05833542; https://clinicaltrials.gov/study/NCT05833542. DERR1-10.2196/56892.

Design and Synthesis of New GS-6207 Subtypes for Targeting HIV-1 Capsid Protein.

HIV-1 capsid protein (CA) is the molecular target of the recently FDA-approved long acting injectable (LAI) drug lenacapavir (GS-6207). The quick emergence of CA mutations resistant to GS-6207 necessitates the design and synthesis of novel sub-chemotypes. We have conducted the structure-based design of two new sub-chemotypes combining the scaffold of GS-6207 and the N-terminal cap of PF74 analogs, the other important CA-targeting chemotype. The design was validated via induced-fit molecular docking. More importantly, we have worked out a general synthetic route to allow the modular synthesis of novel GS-6207 subtypes. Significantly, the desired stereochemistry of the skeleton C2 was confirmed via an X-ray crystal structure of the key synthetic intermediate 22a. Although the newly synthesized analogs did not show significant potency, our efforts herein will facilitate the future design and synthesis of novel subtypes with improved potency.

Rilpivirine and cabotegravir trough concentrations in people with HIV on long-term treatment with long-acting injectable antiretrovirals.

Large inter-individual variability in the pharmacokinetics of rilpivirine and cabotegravir has been reported in the first weeks after starting long-acting injectable (LAI) therapy. Here, we assessed the distribution of rilpivirine and cabotegravir trough concentrations in people with HIV (PWH) on long-term LAI treatment. Adult PWH treated with LAI for at least 32 weeks with an assessment of drug plasma trough concentrations were considered. The proportion of rilpivirine and cabotegravir plasma trough concentrations below four-times the protein-adjusted concentrations required for 90% inhibition of viral replication (4×PA-IC90) was estimated. Sixty-seven PWH were identified. LAI treatment duration was 216 ± 80 weeks (range 32-320 weeks). Cabotegravir concentrations were associated with lower inter-individual variability compared with rilpivirine (45% versus 84%; P < 0.05). No differences were found in rilpivirine (160 ± 118 versus 189 ± 81 ng/mL; P = 0.430) and cabotegravir (1758 ± 807 versus 1969 ± 802 ng/mL; P = 0.416) trough concentrations in males (n = 55) versus females (n = 12). A non-significant trend for lower cabotegravir concentrations was found in PWH with a body mass index >30 kg/m2 (n = 9) versus non-obese participants (1916 ± 905 versus 1606 ± 576 ng/mL; P = 0.131). Three out of the 67 PWH had at least one drug concentration <4×PA-IC90: 100% of PWH had undetectable HIV viral load. At steady state, optimal systemic exposure of cabotegravir and rilpivirine was found in most PWH; cabotegravir trough concentrations were associated with lower inter-individual variability compared with rilpivirine. The study was not powered to assess the contribution of sex and/or body weight on LAI exposure due to the small number of females and obese PWH included.

Antipsychotic Use and Psychiatric Hospitalization in First-Episode Non-affective Psychosis and Cannabis Use Disorder: A Swedish Nationwide Cohort Study.

There is a paucity of research on treatment outcomes of patients with psychosis and cannabis use disorder (CUD). We aimed to compare the effectiveness of antipsychotics in reducing the risk of hospitalization in patients with first-episode psychosis (FEP) and co-occurring CUD. We utilized a nationwide Swedish cohort of patients with longitudinal register data from the year 2006 to 2021. Participants were patients with FEP and co-occurring CUD (n = 1820, 84.73% men, mean age 26.80 years, SD 8.25 years). The main outcome was hospitalization due to psychotic relapse. Hospitalization due to any psychiatric disorder or substance use disorder (SUD) were examined as secondary outcomes. Within-individual Cox regression models were used to study these associations. Use of any antipsychotic was associated with a 33% risk reduction of psychotic relapse (aHR = 0.67; 95% CI 0.60-0.75). Clozapine (0.43; 0.29-0.64), long-acting injectable (LAI) formulations of risperidone (0.40; 0.22-0.71), aripiprazole (0.42; 0.27-0.65), and paliperidone (0.46; 0.30-0.69) were associated with the lowest risk of relapse. The association between the LAI formulation of olanzapine and hospitalization due to psychosis was statistically non-significant (0.61; 0.35-1.05). Clozapine was associated with an 86% risk reduction of hospitalization due to SUD (0.14; 0.05-0.44). Of oral non-clozapine antipsychotics, aripiprazole was associated with the lowest risk of hospitalization due to psychotic relapse (0.61; 0.45-0.83). These findings support the use of clozapine, LAI formulations of second-generation antipsychotics other than olanzapine, or oral aripiprazole to prevent hospitalization in FEP and co-occurring CUD.

Types of Medication Non-adherence & Approaches to Enhance Medication Adherence in Mental Health Disorders: A Narrative Review.

Medication non-adherence (MNA) presents a significant obstacle that negatively impacts treatment effectiveness in mental health disorders. The objective of this review is to study different types of MNA and interventions designed to enhance medication adherence among individuals with mental health disorders. We conducted an electronic search on PubMed and Google Scholar using keywords such as adherence, non-adherence, compliance, non-compliance, mental health disorders, psychotropic drugs, major depressive disorder (MDD), schizophrenia, anxiety disorders, and bipolar disorders (BD). From the search results, we selected studies pertinent to the objective of the review. Non-adherence can be categorized into primary nonadherence (not starting medication) and secondary non-adherence (not taking the medication as directed). Generally, we can group the reasons for non-adherence into unintentional and intentional. Unintentional non-adherence (UNA) arises when patients genuinely desire to comply with their prescribed course of therapy but are hindered by factors beyond their control. When addressing UNA, interventions should simplify medication regimens, utilize long-acting injectable (LAIs) medications, offer tools to manage medication and provide follow-up reminders. When a patient deliberately decides not to follow their treatment plan, this is known as intentional non-adherence. To improve intentional non-adherence, the focus should be on patient-centred care and shared decision-making, psychoeducation, effective doctor-patient communication, cognitive-behavioral strategies, and addressing concerns related to the side effects of psychotropic drugs. It is crucial to understand that there is no universal solution to address non-adherence in mental health disorders. Each patient has distinct needs and characteristics, making personalized strategies and interventions of utmost significance.

Population Pharmacokinetics of Cabotegravir Following Oral Administration and Long-Acting Intramuscular Injection in Real-World People with HIV.

Long-acting cabotegravir has been studied mainly in the stringent framework of clinical trials, which does not necessarily reflect the situation of people with HIV (PWH) in routine clinical settings. The present population pharmacokinetic analysis aims to build real-world reference percentile curves of cabotegravir concentrations, accounting for patient-related factors that may affect cabotegravir exposure. The second objective is to simulate whether dosing interval adjustments of cabotegravir could be considered in specific subpopulations. Overall, 238 PWH contributed to 1,038 cabotegravir levels (186 during the initial oral administration phase and 852 after intramuscular injection). Cabotegravir pharmacokinetics was best described using a one-compartment model with distinct first order-absorption for oral and intramuscular administrations, and identical volume and clearance. Our model showed almost 40% faster absorption and 30% higher clearance than previously reported, resulting in a time to steady-state of 8 months and an elimination half-life of 4.6 weeks for long-acting cabotegravir. Sex and body mass index significantly influenced absorption, and bodyweight affected clearance. Model-based simulations showed that cabotegravir trough concentrations in females were 25% lower 4 weeks after the intramuscular loading dose, but 42% higher during the late maintenance phase. Finally, simulations indicated that in females, despite significantly higher cabotegravir concentrations, longer intervals between injections may not consistently ensure levels above the 4-fold protein-adjusted 90% inhibitory target concentration.

Impact of drug compounds mechanical/deformation properties on the preparation of nano- and microsuspensions

The preparation of nano- and microsuspensions used for long-acting injectables include several advantages, where the ability to control the particle sizes of a drug compound, e.g., wet bead media milling, to obtain a desired release rate, has shown to be highly critical. Limiting factors, making the formulation screening process time-consuming, are both the grindability of a compound to obtain the desired particle size profile as well as the addition of a suitable stabilizer at a sufficient concentration to secure a long-term physical stability. Hence, the deformation properties of three different model compounds (i.e., cinnarizine, haloperidol, and indomethacin) were investigated in the present study by quantifying fragmentation after tableting followed by the preparation of nano- and microsuspensions with two different stabilizers (polysorbate 20 and poloxamer 188) and concentrations (1, 2, or 4%), as well as bead size (ø 0.5 or 1.0 mm), during processing. It was found that cinnarizine had brittle properties, haloperidol predominantly plastic properties, and indomethacin elastic properties. Distinct particle size profiles, after milling by the dual centrifugation approach, were achieved for the three model compounds, when prepared under the same manufacturing conditions. It was possible to obtain decreased sizes of cinnarizine particles, whereas the grindability for haloperidol was more restricted due to its plastic properties. The study further showed that higher concentrations of poloxamer 188 were needed to obtain smaller sizes of particles when compared to polysorbate 20. Short-term stability studies showed an increase in sizes of particles over 49 days stored at elevated temperatures, especially for indomethacin suspensions stabilized with the highest polysorbate 20 concentration, due to increased solubility from the stabilizer vehicle as confirmed by a solubility study. Sizes of haloperidol particles remained relatively stable when stabilized with the highest concentration of polysorbate 20, even with increased solubility, indicating a higher physical stability as compared to cinnarizine and indomethacin.

The impact of fluphenazine withdrawal: a mirror-image study.

Fluphenazine decanoate licenced as a long-acting injectable (LAI) first-generation antipsychotic (FGA) was withdrawn from sale in 2018. This study evaluates if its withdrawal resulted in increased relapse rates of psychosis in an Irish patient cohort and examines which prescribed alternative antipsychotic medications were associated with more optimal outcomes. Fifteen participants diagnosed with a psychotic disorder were included. A mirror-image study over 24-months' pre-and post-withdrawal of fluphenazine was conducted. Kaplan-Meier survival and proportional hazards analyses were conducted. The impact of alternate antipsychotic agents (LAI flupenthixol compared to other antipsychotic medications) was evaluated. Semi-structured interviews with participants examined subjective opinions regarding the change in their treatment. Seven participants (46.7%) relapsed in the 24-month period subsequent to fluphenazine discontinuation compared to one individual (6.7%) in the previous identical time-period (p = 0.035). Flupenthixol treatment was associated with reduced relapse rates compared to other antipsychotics (χ2 = 5.402, p = 0.02). Thematic analysis revealed that participants believed that the discontinuation of fluphenazine deleteriously impacted the stability of their mental disorder. The withdrawal of fluphenazine was associated with increased relapse rate in individuals previously demonstrating stability of their psychotic disorder. While acknowledging the limitation of small sample size, preliminary evidence from this study suggests that treatment with the first-generation antipsychotic (FGA) flupenthixol was associated with a lower risk of relapse compared to SGAs. Reasons for this lower risk of relapse are not fully clear but could be related to dopamine hypersensitivity with this treatment change.

Unlocking new dimensions in long-acting injectables using lipid mesophase-based beads

In this study, we explored the use of lipid mesophases (LMPs) as a biocompatible and biodegradable material for sustained drug delivery. Our hypothesis centered on leveraging the high surface-to-volume ratio of LMP-based beads to enhance strength, stability, and surface interaction compared to the LMP bulk gel. To modulate drug release, we introduced antioxidant vitamin E into the beads, influencing mesophase topologies and controlling drug diffusion coefficients. Four drugs with distinct chemical properties and intended for three different pathologies and administration routes were successfully loaded into the beads with a drug entrapment efficiency exceeding 80 %. Notably, our findings revealed sustained drug release, irrespective of the drugs' chemical properties, culminating in the development of an injectable formulation. This formulation allows direct administration into the target site, minimizing systemic exposure, and thereby mitigating adverse effects. Our approach demonstrates the potential of LMP-based beads for tailored drug delivery systems with broad applications in diverse therapeutic scenarios.

Weekly Oral Tenofovir Alafenamide Protects Macaques from Vaginal and Rectal Simian HIV Infection.

Pre-exposure prophylaxis (PrEP) with a weekly oral regimen of antiretroviral drugs could be a suitable preventative option for individuals who struggle with daily PrEP or prefer not to use long-acting injectables. We assessed in macaques the efficacy of weekly oral tenofovir alafenamide (TAF) at doses of 13.7 or 27.4 mg/kg. Macaques received weekly oral TAF for six weeks and were exposed twice-weekly to SHIV vaginally or rectally on day 3 and 6 after each dose. Median TFV-DP levels in PBMCs following the 13.7 mg/kg dose were 3110 and 1137 fmols/106 cells on day 3 and 6, respectively. With the 27.4 mg/kg dose, TFV-DP levels were increased (~2-fold) on day 3 and 6 (6095 and 3290 fmols/106 cells, respectively). Both TAF doses (13.7 and 27.4 mg/kg) conferred high efficacy (94.1% and 93.9%, respectively) against vaginal SHIV infection. Efficacy of the 27.4 mg/kg dose against rectal SHIV infection was 80.7%. We estimate that macaque doses of 13.7 and 27.4 mg/kg are equivalent to approximately 230 and 450 mg of TAF in humans, respectively. Our findings demonstrate the effectiveness of a weekly oral PrEP regimen and suggest that a clinically achievable oral TAF dose could be a promising option for non-daily PrEP.

Antiretroviral treatment for HIV infection and AIDS

Background: Antiretroviral therapy is the cornerstone treatment for people living with human immunodeficiency virus (HIV). Clinical practice guidelines for antiretroviral therapy have been developed.Current Concepts: After the introduction of zidovudine, more than 30 antiretroviral agents have been approved for the treatment of HIV infection. Since a controlled trial proved the efficacy and safety of combination antiretroviral therapy, virologic suppression, immune reconstitution, and long-term survival of people living with HIV have been achievable goals. Early antiretroviral treatment for all people living with HIV is an effective strategy to maintain individual health and prevent the transmission of HIV infection. Selecting an appropriate combination antiretroviral therapy requires careful consideration of various factors, including regimen characteristics, pretreatment viral load and CD4+ cell counts, comorbid conditions, and the anticipated level of compliance. Ongoing advances in antiretroviral treatment, such as the development of long-acting injectables and medications targeting multidrug-resistant HIV, address challenges in the treatment of HIV infection.Discussion and Conclusion: Although cure of HIV infection is impossible with current antiretroviral treatment, HIV infection has become a chronic disease with long-term survival. Hence, clinicians should have knowledge of antiretroviral treatment guidelines.

Continuous Microfluidic Antisolvent Crystallization as a Bottom-Up Solution for the Development of Long-Acting Injectable Formulations.

A bottom-up approach was investigated to produce long-acting injectable (LAI) suspension-based formulations to overcome specific limitations of top-down manufacturing methods by tailoring drug characteristics while making the methods more sustainable and cost-efficient. A Secoya microfluidic crystallization technology-based continuous liquid antisolvent crystallization (SCT-CLASC) process was optimized and afterward compared to an earlier developed microchannel reactor-based continuous liquid antisolvent crystallization (MCR-CLASC) setup, using itraconazole (ITZ) as the model drug. After operating parameter optimization and downstream processing (i.e., concentrating the suspensions), stable microsuspensions were generated with a final solid loading of 300 mg ITZ/g suspension. The optimized post-precipitation feed suspension consisted of 40 mg ITZ/g suspension with a drug-to-excipient ratio of 53:1. Compared to the MCR-CLASC setup, where the post-precipitation feed suspensions contained 10 mg ITZ/g suspension and had a drug-to-excipient ratio of 2:1, a higher drug concentration and lower excipient use were successfully achieved to produce LAI microsuspensions using the SCT-CLASC setup. To ensure stability during drug crystallization and storage, the suspensions' quality was monitored for particle size distribution (PSD), solid-state form, and particle morphology. The PSD of the ITZ crystals in suspension was maintained within the target range of 1-10 µm, while the crystals displayed an elongated plate-shaped morphology and the solid state was confirmed to be form I, which is the most thermodynamically stable form of ITZ. In conclusion, this work lays the foundation for the SCT-CLASC process as an energy-efficient, robust, and reproducible bottom-up approach for the manufacture of LAI microsuspensions using ITZ at an industrial scale.

Social determinants of choosing telemedicine for contraceptive care: A retrospective cohort study

ObjectivesCompare demographic characteristics and contraception choices among individuals seeking contraception care via telemedicine versus in-person. Study designRetrospective cohort study of contraception visits from June-September 2021 at Planned Parenthood of the Pacific Southwest. We assessed demographics and contraception choices. We used multivariable logistic regression to evaluate effect of language, age, income, having children, and insurance type on choosing telemedicine. ResultsWe included 16,855 patients: 2383 (14.1%) telemedicine visits and 14,472 (85.9%) in-person visits; 149/2383 (6.3%) non-English speakers used telemedicine compared to 1194/14,472 (8.3%) who used in-person care. A higher proportion of the telemedicine cohort had public insurance compared to the in-person cohort (2312/2383 [97.0%] telemedicine vs 11,646/14,472 [80.5%] in-person). Among the telemedicine cohort, a higher proportion of patients chose a barrier method (691/2363 [29.2%] telemedicine vs 1564/14,215 [11.0%] in-person) and short-acting method (1248/2363 [52.8%] telemedicine vs 5834/14,215 [41.0%] in-person) compared to in-person. A higher proportion of in-person patients chose long-acting reversible contraception (2681/14,215 [18.9%] in-person vs 179/2363 [7.6%] telemedicine) and injection (3779/14,215 [26.6%] in-person vs 115/2363 [4.9%] telemedicine) compared to telemedicine. Speaking Spanish was associated with decreased odds of choosing telemedicine after adjusting for covariates (aOR 0.53 [95% CI 0.44–0.64], p < 0.001). Older age, having children, lower income, and public insurance were associated with increased odds of choosing telemedicine. ConclusionsTelemedicine for contraception visits was associated with language, age, parity, income, and insurance. Despite small absolute difference in the proportion of patients that speak Spanish, in adjusted multivariate analysis speaking Spanish was associated with lower odds of choosing telemedicine. ImplicationsIncreasing access for people with limited technology as well as those who prefer non-English languages is essential to promote equitable reproductive care. Prospective research that focuses on patient experience and preferences is needed to better guide access to equitable, person-centered contraception care.

Miniaturized screening and performance prediction of tailored subcutaneous extended-release formulations for preclinical in vivo studies

Microencapsulation of active pharmaceutical ingredients (APIs) for preparation of long acting injectable (LAI) formulations is an auspicious technique to enable preclinical characterization of a broad variety of APIs, ideally independent of their physicochemical and pharmacokinetic (PK) characteristics. During early API discovery, tunable LAI formulations may enable pharmacological proof-of-concept for the given variety of candidates by tailoring the level of plasma exposure over the duration of various timespans. Although numerous reports on small scale preparation methods for LAIs utilizing copolymers of lactic and glycolic acid (PLGA) and polymers of lactic acid (PLA) highlight their potential, application in formulation screening and use in preclinical in vivo studies is yet very limited. Transfer from downscale formulation preparation to in vivo experiments is hampered in early preclinical API screening by the large number of API candidates with simultaneously very limited available amount in the lower sub-gram scale, lack of formulation stability and deficient tunability of sustained release.We hereby present a novel comprehensive platform tool for tailored extended-release formulations, aiming to support a variety of preclinical in vivo experiments with ranging required plasma exposure levels and timespans. A novel small-scale spray drying process was successfully implemented by using an air brush based instrument for preparation of PLGA and PLA based formulations. Using Design of Experiments (DoE), required API amount of 250 mg was demonstrated to suffice for identification of dominant polymer characteristics with largest impact on sustained release capability for an individual API. BI-3231, a hydrophilic and weakly acidic small compound with good water solubility and permeability, but low metabolic stability, was used as an exemplary model for one of the many candidates during API discovery. Furthermore, an in vitro to in vivo correlation (IVIVC) of API release rate was established in mice, which enabled the prediction of in vivo plasma concentration plateaus after single subcutaneous injection, using only in vitro dissolution profiles of screened formulations.By tailoring LAI formulations and their doses for acute and sub-chronic preclinical experiments, we exemplary demonstrate the practical use for BI-3231. Pharmacological proof-of-concept could be enabled whilst circumventing the need of multiple administration as result of extensive hepatic metabolism and simultaneously superseding numerous in vivo experiments for formulation tailoring.

PrEP for people who use opioids: A NIDA clinical trials network survey study in Southern U.S. cities where HIV incidence is high

BackgroundPeople who use opioids (PWUO) are at increased risk for HIV. Pre-exposure prophylaxis (PrEP) is effective but underutilized as HIV prevention among PWUO. This study examined predictors of willingness to take daily oral PrEP and long-acting injectable (LAI) PrEP among PWUO across eight Southern urban cities with high HIV incidence. MethodsHIV-negative PWUO (N = 308) seeking services in community-based programs participated in this cross-sectional survey study. Measures included demographics, sexual risk behavior, substance use frequency, and awareness of and willingness to take oral and injectable PrEP. Data were analyzed using mixed-effects models. ResultsWillingness to take daily oral and LAI PrEP was moderately high (69.16% and 62.02%, respectively). Half had heard of PrEP, but only 4% had ever taken it. Only education and condomless vaginal sex predicted willingness to take oral PrEP. Only education predicted willingness to take LAI PrEP. Polysubstance use was prevalent, with substantial proportions of PWUO reporting frequent use of injection drugs (opioids or stimulants, 79.5%), non-injection opioids (73.3%), non-injection stimulants (71.1%), cannabis (62.6%), and hazardous drinking (29.6%). About 20% reported past-year condomless anal sex, and one-third reported past-year condomless vaginal sex. ConclusionsPWUO in this study were amenable to PrEP, particularly in light of education and condomless vaginal sex. Careful consideration for matching PrEP messaging to the PWUO audience is needed. PrEP promotion should expand beyond men who have sex with men to include groups such as these predominantly heterosexual, polysubstance-using PWUO with HIV risk who were open to both formulations of PrEP.

Physiologically based Pharmacokinetic Model Validated to Enable Predictions Of Multiple Drugs in a Long-acting Drug-combination Nano-Particles (DcNP): Confirmation with 3 HIV Drugs, Lopinavir, Ritonavir, and Tenofovir in DcNP Products

Drug-Combination Nanoparticles (DcNP) are a novel drug delivery system designed for synchronized delivery of multiple drugs in a single, long-acting, and targeted dose. Unlike depot formulations, slowly releasing drug at the injection site into the blood, DcNP allows multiple-drug-in-combination to collectively distribute from the injection site into the lymphatic system. Two distinct classes of long-acting injectables products are proposed based on pharmacokinetic mechanisms. Class I involves sustained release at the injection site. Class II involves a drug-carrier complex composed of lopinavir, ritonavir, and tenofovir uptake and retention in the lymphatic system before systemic access as a part of the PBPK model validation. For clinical development, Class II long-acting drug-combination products, we leverage data from 3 nonhuman primate studies consisting of nine PK datasets: Study 1, varying fixed-dose ratios; Study 2, short multiple dosing with kinetic tails; Study 3, long multiple dosing (chronic). PBPK validation criteria were established to validate each scenario for all drugs. The models passed validation in 8 of 9 cases, specifically to predict Study 1 and 2, including PK tails, with ritonavir and tenofovir, fully passing Study 3 as well. PBPK model for lopinavir in Study 3 did not pass the validation due to an observable time-varying and delayed drug accumulation, which likely was due to ritonavir's CYP3A inhibitory effect building up during multiple dosing that triggered a mechanism-based drug-drug interaction (DDI). Subsequently, the final model enables us to account for this DDI scenario.

Accelerated and Biopredictive In Vitro Release Testing Strategy for Single Agent and Combination Long-Acting Injectables

The purpose of this study was to develop an in vitro release testing (IVRT) strategy to predict the pre-clinical performance of single agent and combination long acting injectable (LAI) suspension products. Two accelerated IVRT methods were developed using USP apparatus 2 to characterize initial, intermediate, and terminal phases of drug release. Initial and intermediate phases were captured using a suspension cup with moderate agitation to ensure a constant, low surface area exposure of the LAI suspension to the release media. The terminal phase was obtained by exposing the LAI suspension to a high initial paddle speed. This resulted in smaller suspension particulates with high cumulative surface area that were dispersed throughout the release media, enabling rapid drug release. The in vitro release profiles obtained with these two methods in 48 h or less were independently time scaled to reflect the in vivo time scale of approximately 1800 h. Level-A in vitro in vivo correlations (IVIVCs) were separately developed for each method and active pharmaceutical ingredient (API) using in vivo absorption profiles obtained by deconvolution of rat plasma concentration-time profiles. The IVIVCs were successfully validated for each API. This work provides a framework for evaluating individual phases of drug release of complex LAIs to ultimately predict their in vivo performance.

The Development of a Stable Peptide-Loaded Long-Acting Injection Formulation through a Comprehensive Understanding of Peptide Degradation Mechanisms: A QbD-Based Approach.

Quality by design (QbD) serves as a systematic approach to pharmaceutical development, beginning with predefined objectives and emphasizing an understanding of the product based on sound science and risk management. The purpose of this study is to utilize the QbD concept to develop a stable peptide-loaded long-acting injection formulation. An in-depth comprehension of peptide degradation mechanisms was achieved through forced degradation investigations, elucidating (acid) hydrolysis and oxidation as the primary degradation pathways for the peptide ACTY116. The quality built into the product was focused on risk assessment, for which the critical material attributes (CMAs) and critical process parameters (CPPs) associated with the critical quality attributes (CQAs) of each formulation were identified, leading to the development of the corresponding control strategies. CQAs for three LAI (long-acting injectable) formulations were enhanced by taking the right control strategies. The LAI formulation exhibiting the highest stability for ACTY116 was chosen for subsequent pharmacokinetic investigations in rats. The objective of addressing peptide chemical instability and in vivo long-acting release was achieved. For other molecules with susceptible functionalities like amide bonds, amino groups, and hydroxyl groups, the utilization of PLGA-based in situ gel as an LAI formulation for stabilizing molecules provides valuable insights.

Current advances in pharmacotherapy for schizophrenia

Background: Schizophrenia is a complex psychiatric disorder characterized by hallucinations, delusions, and cognitive deficits, often leading to functional decline. Pharmacotherapy has long played a central role in schizophrenia management with our evolving understanding shaping the treatment.Current Concepts: Antipsychotic agents are the mainstay of the pharmacological treatment of schizophrenia. Although second-generation antipsychotics (atypical) reduce extrapyramidal side effects, they give rise to metabolic concerns. Personalized treatment, guided by the response and side effects of the patient, determines suitable medications and dosages. Long-acting injectable antipsychotics have enhanced medication adherence, and the consideration of clozapine is warranted for treatment-resistant cases. In addition, potential combination therapies with other psychotropic medications could be explored to address specific symptoms or comorbidities.Discussion and Conclusion: Antipsychotics are pivotal in acute intervention and schizophrenia treatment maintenance. Individualized plans, accounting for drug response, side effects, and adherence, are essential when selecting specific antipsychotic agents. Long-acting injectables and clozapine with combination therapies for treatment resistance offer effective and tolerable management. Ongoing studies and novel antipsychotic development hold promise for improving schizophrenia treatment and patient life quality.