Rats and rabbits as pharmacokinetic screening tools for long acting intramuscular depots: case study with paliperidone palmitate suspension

1. Development of prodrug of 9-hydroxyrisperidone (paliperidone) long-acting intramuscular injection has enabled delivery over four-week time period with improved compliance.

2. The key aim of this work was to establish a reliable preclinical model which may potentially serve as a screening tool for judging the pharmacokinetics of paliperidone formulation(s) prior to human clinical work.

3. Sparse sampling composite study was used in rats, (Wistar/Sprague–Dawley (SD; n?=?10)) and a serial blood sampling study design was used in rabbits (n?=?4). Animals received intramuscular injection of paliperidone palmitate in the thigh muscle at dose of 16 (rats) and 4.5?mg/kg (rabbits). Samples were drawn in rats (retro-orbital sinus) and rabbits (central ear artery) and were analysed for paliperidone using liquid chromatography–mass spectrometry/ mass spectrometry (LC-MS/MS) assay. The plasma data was subjected to pharmacokinetic analysis.

4. Following intramuscular injection of depot formulation in Wistar/SD rats and rabbits, absorption of paliperidone was slow and gradual with median value of time to reach maximum concentration (T_max) occurring on day 7. The exposures (i.e. area under the curve (AUC; 0–28) days) were 18,597, 21,865 and 18,120?ng.h/mL, in Wistar, SD and rabbits, respectively. The clearance was slow and supported long half-life (8–10 days).

5. Either one of the two models can serve as a research tool for establishing pharmacokinetics of paliperidone formulation(s).

     

Non-oral contraception

Non-oral contraception is increasingly being promoted by contraceptive experts as a more convenient and, in many cases, safer and more efficacious alternative to short as acting methods such as oral contraception. Injectables, implants and intrauterine methods offer the advantage of being long-acting and less user dependent, factors which may potentially improve contraceptive compliance. Implants and intrauterine methods are also recognised to be more cost-effective, largely through the prevention of unintended pregnancy. Combined contraceptive methods in non-oral delivery forms [patches, gels and vaginal rings] offer a choice for women who find it difficult to adhere to daily use. The barrier methods, particularly the male and female condoms have the advantage of being user-controlled but they are vulnerable to misuse and can fail to protect against pregnancy and more importantly in the case of condoms, sexually transmitted infections. Male and female sterilisation offer irreversible contraception.     

Long-term outcome of depot neuroleptic maintenance treatment among chronic psychotic patients

A total of 51 chronic psychotic out-patients, with a median age of 51 years and median duration of psychosis of 23 years, treated with depot neuroleptics, entered a 5-year follow-up study with assessments of symptoms, side-effects and plasma concentration of the depot drug (follow-up (FU) patients). The outcome for 38 non-eligible (NE) patients was obtained from hospital case reports. The relapse rate was higher for NE than for FU patients (71% vs. 50%). The mortality rate was 9%, and the median age at death was 47 years. Half of the FU patients completed 3 years of treatment uneventfully. Of the total of 89 patients, only 18% remained stable over a period of 5 years. The depot dose was approximately the same after 3 years (median 255 mg, range 50–1018 mg chlorpromazine equivalents).     

Does drawing up technique influence patients’ perception of pain at the injection site?

Traditionally nurses have used one of two drawing up techniques for the administration of intramuscular (IM) injections. In the first, the injectable is drawn up using one needle, which is then discarded before administration using a new needle. Alternatively, the injectable is drawn up and administered without changing the needle. Advocates of the two‐needle technique suggest that this method reduces pain at the injection site. In the present study, 70 subjects completed an independently validated pain scale following administration of an IM depot neuroleptic. The conclusion, that there is a significant reduction in injection site pain, using the two‐needle technique, is not supported by the data obtained in this study.     

Advances in drug delivery to high grade gliomas

If cancer is hard to be treated, brain cancer is even more, caused by the inability of many effective drugs given systemically to cross the blood brain and blood tumor barriers and reach adequate concentrations at the tumor sites. Effective delivery of drugs to brain cancer tissues is thus a necessary, albeit not sufficient, condition to effectively target the disease. In order to analyze the current status of research on drug delivery to high grade gliomas (HGG‐WHO grades III and IV), the most frequent and aggressive brain cancers, a literature search was conducted in PubMed using the terms: “drug delivery and brain tumor” over the publication year 2015. Currently explored drug delivery techniques for HGG include the convection and permeabilization‐enhanced deliveries, drug‐releasing depots and Ommaya reservoirs. The efficacy/safety ratio widely varies among these techniques and the success of current efforts to increase this ratio widely varies as well.     

<Emphasis Type="BoldItalic">In Vitro</Emphasis> and <Emphasis Type="BoldItalic">In Vivo</Emphasis> Drug Release from a Novel <Emphasis Type="BoldItalic">In Situ</Emphasis> Forming Drug Delivery System

Purpose The objective of this work was to investigate the influence of various preparation and formulation parameters on the in vitro and in vivo release of bupivacaine hydrochloride from an injectable in situ forming microparticle system (ISM). Methods The in vitro drug release of ISM was investigated as a function of various formulation and process parameters and was compared to the drug release from in situ forming implants and conventional microparticles. In vivo studies were carried out in male Sprague–Dawley rats. Results Upon contact with an aqueous medium, the internal polymer phase of the ISM system solidified and formed microparticles. The initial drug release from ISM systems was reduced with decreasing polymer phase/external oil phase ratio. An advantage of the ISM system compared to in situ implant systems was the significantly reduced burst effect, resulting in drug release profiles comparable to microparticles prepared by conventional methods. The in vivo drug release studies were in good agreement with the in vitro drug release. With the ISM system, the analgesic effect of the bupivacaine hydrochloride was prolonged when compared to the injection of a drug solution or drug-polymer solution. Conclusions ISM are an attractive alternative for parenteral drug delivery systems.     

Synthesis and characterization of a thermally-responsive tumor necrosis factor antagonist

Numerous antagonists of tumor necrosis factor alpha (TNFα) have been developed to attenuate inflammation and accompanying pain in many disease processes. Soluble TNF receptor type II (sTNFRII) is one such antagonist that sequesters TNFα away from target receptors and attenuates its activity. Systemic delivery of soluble TNF receptors or other antagonists may have deleterious side effects associated with immune suppression, so that strategies for locally targeted drug delivery are of interest. Elastin-like polypeptides (ELPs) are biopolymers capable of in situ drug depot formation through thermally-driven supramolecular complexes at physiological temperatures. A recombinant fusion protein between ELP and sTNFRII was designed and evaluated for retention of bivalent functionality. Thermal sensitivity was observed by formation of supramolecular submicron-sized particles at 32 °C, with gradual resolubilization from the depot observed at physiological temperatures. In vitro refolding of the sTNFRII domain was required and the purified product exhibited an equilibrium dissociation constant for interacting with TNFα that was seven-fold higher than free sTNFRII. Furthermore, anti-TNF activity was observed in inhibiting TNFα-mediated cytotoxicity in the murine L929 fibrosarcoma assay. Potential advantages of this ELP-sTNFRII fusion protein as an anti-TNFa drug depot include facility of injection, in situ depot formation, low endotoxin content, and functionality against TNFα.     

“Impact of drug‐reimbursement policies on prescribing: A case‐study of a newly marketed long‐acting injectable antipsychotic among relapsed schizophrenia patients”

Objective

To quantify and explain variation in use of long‐acting injectable antipsychotics (LAIs) in the United States, and understand the relationship between patient characteristics, drug reimbursement policies, and LAI prescribing after relapse.

Methods

A cohort of recently relapsed patients with schizophrenia ages 18 to 64, were identified immediately after discharge from a related inpatient hospitalization, partial hospitalization, or emergency room visit, drawn from 2004 to 2006 Medicaid claims, and followed for 90 days until LAI initiation. Data on state‐level Medicaid prior authorization (PA) policies for LAIs were collected. Sequential longitudinal Poisson regression models were developed to understand the relationship between patient and PA policy variables and LAI prescribing, including prior adherence to oral antipsychotics, demographics, clinical variables, and presence of PA policy for LAI.

Results

Among 36 282 patients, 3.1% received risperidone LAI, and 3.8% received a first‐generation (FGA) LAI with wide variation across states. Prior adherence ranged from 29% to 89% but was marginally associated with initiation and did not explain variation for LAI prescribing. FGA initiation was associated with geography and race/ethnicity but not PA policy. For risperidone LAI initiation, demographics and clinical factors explained, respectively, 5.0% and 3.0% of the variation; PA policy had a large negative association with initiation (RR = 0.41; 95%CI 0.20–0.87) and explained 8.4% of the variation.

Conclusions

PA policies may represent a major treatment barrier for risperidone LAI among relapsed patients. Non‐adherence plays a little role in predicting which patients receive LAIs. Policy makers and health insurers will need to consider these findings when guiding the use of LAIs. KEY POINTS

• Among a nationwide cohort of relapsed schizophrenia patients enrolled in US Medicaid, 3.1% received Risperdal Consta, a long‐acting injectable antipsychotic (LAI), and 3.8% initiated a first‐generation first‐generation LAI within 90 days after discharge.
• During 2004 to 2006, there was marked variation in 90 day post‐relapse initiation of Risperdal‐Consta—a newly marketed medication during this period—and also marked variation in 90 day post‐relapse initiation of any first‐generation LAI, which appeared to be associated with race/ethnicity and geography.
• Prior authorization policies were associated with substantially lower initiation of Risperdal Consta in this cohort of relapsed patients even after accounting for clinical indication (non‐adherence), relapse history, demographics, adjunctive medication, and mental health service use.

     

Clozapine augmentation with long-acting antipsychotic injections: A case series and systematic review

Background

Up to 30% of patients with a diagnosis of treatment-resistant psychosis remain symptomatic despite an optimal trial with the gold standard treatment, clozapine. Emerging evidence suggests the clinical utility of long-acting injections (LAI) in such clinical scenarios. In this study, we aimed to describe clozapine augmentation with LAIs in an inner London hospital and explore the literature on the clinical effectiveness of this treatment modality.

Methods

Patients prescribed clozapine, who were commenced on a LAI between 2007 and 2023 by the United Kingdom's largest mental health trust, were identified from electronic patient records. First, routine clinical data were used to describe the use, effectiveness, and safety of this augmentation strategy. Second, we conducted a literature search up to 1st June 2023 to identify published studies describing clinical outcomes after clozapine augmentation with a LAI. Clinical outcomes were collated and presented in a table, including hospitalisation rates and quantitative clinical assessments using validated scales.

Results

Of the 1248 patients prescribed clozapine in SLaM, three patients (0.2%) received augmentation with the following LAIs: olanzapine embonate, paliperidone palmitate and pipotiazine palmitate. This treatment strategy was clinically effective and generally well tolerated in all three cases. Twelve published studies between 2010 and 2022 were included in the review. Eight distinct LAIs were reported (4 first and 4 second generation antipsychotics), with risperidone and paliperidone most widely studied. All the identified studies were observational including mirror-image studies, case series and case reports. Duration of follow up varied from 3 months to 3 years. There was evidence that the use of LAIs with clozapine can significantly reduce clinical symptoms, hospitalisation rates and bed days. No serious adverse effects were reported.

Conclusion

This preliminary evidence suggests clinical utility of LAIs in alleviating residual symptoms and subsequently reducing hospitalisation rates in patients optimised on clozapine treatment. The current study warrants further investigations including a randomised controlled study to establish the clinical efficacy, tolerability, and place in therapy of this treatment modality.