Nanoparticle technology in cancer chemotherapy is a promising approach to enhance active ingredient pharmacology and pharmacodynamics. Indeed, drug nanoparticles display various assets such as ...extended blood lifespan, high drug loading and reduced cytotoxicity leading to better drug compliance. In this context, organic nanocrystal suspensions for pharmaceutical use have been developed in the past ten years. Nanocrystals offer new possibilities by combining the nanoformulation features with the properties of solid dispersed therapeutic ingredients including (i) high loading of the active ingredient, (ii) its bioavailability improvement, and (iii) reduced drug systemic cytotoxicity. However, surprisingly, no antitumoral drug has been marketed as a nanocrystal suspension until now. Etoposide, which is largely used as an anti-cancerous agent against testicular, ovarian, small cell lung, colon and breast cancer in its liquid dosage form, has been selected to develop injectable nanocrystal suspensions designed to be transferred to the clinic. The aim of the present work is to provide optimized formulations for nanostructured etoposide solutions and validate by means of in vitro and in vivo evaluations the efficiency of this multiphase system. Indeed, the etoposide formulated as a nanosuspension by a bottom-up approach showed higher blood life span, reduced tumor growth and higher tolerance in a murine carcinoma cancer model. The results obtained are promising for future clinical evaluation of these etoposide nanosuspensions.
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Checkpoints inhibitors anti-programmed death 1 (PD1) and anti-programmed death ligand 1 (PD-L1) restore immunity against tumour. By their mechanism of action, they could induce immune-related adverse ...events (irAEs) that can theoretically involve all organs. These irAEs, especially those that are rare, remain incompletely described. Immune-related eosinophilia has been described with ipilimumab and was interestingly associated with favourable response to immunotherapy. We report here the first series of patients who experienced immune-related eosinophilia due to anti-PDI or anti-PD-L1 antibodies. Immune-related eosinophilia is a new biological immune-related adverse effect with anti-PD-1 or anti-PD-Ll. To the best of our knowledge, we report here the first case series of immune-related eosinophilia with anti-PDl or anti-PD-Ll. Importantly, we show that kinetics of leukocyte changes was restricted to the eosinophil lineage. This immune-related eosinophilia was rare (estimated frequency of 2.9%), began at 3.0 months with a peak achieved at 6.4 months. Patients with immune-related eosinophilia remain asymptomatic. Larger prospective studies are required to search for a link with favourable anti-tumour response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Temozolomide (TMZ) is part of the therapeutic armamentarium used in managing pediatric cancers; however, available oral forms (capsules) are not adapted for use in children. Our aim was to assess the ...dose accuracy and stability of TMZ using capsule contents mixed with food compared with a novel, ready-to-use liquid formulation specifically developed for children (Ped-TMZ, brand name KIZFIZO). Dose accuracy and TMZ stability testing were performed with TMZ capsule contents (90 mg) mixed with food vehicles (apple juice, apple sauce, cream, milk, and mashed potatoes) and compared to an equivalent dose of Ped-TMZ. Acceptance criteria were predefined for TMZ (95.0-105.0%) and its degradation product amino-imidazole-carboxamide (AIC; <1%) content. The delivered dose was significantly higher using Ped-TMZ (96.6 ± 1.2%) and within the predefined criteria for TMZ content, whereas it was systematically under the lower specifications of 95% using capsule-derived preparations with apple juice (91.0 ± 1.5%) and apple sauce (91.6 ± 1.4%), respectively (
< 0.0001). In chemical stability tests, the four food vehicles (apple sauce, cream, milk, mashed potatoes) had a significant effect on TMZ stability (
= 0.0042), and the AIC significantly increased with time in three of the four vehicles (
< 0.0001). Only 1/72 of preparations from capsules met the predefined acceptance criteria, whereas Ped-TMZ showed no TMZ loss, and the AIC remained within specifications. In conclusion, mixing TMZ capsule content with food may result in significant underexposure, possibly even greater in routine practice, as complete food intake by the child is unlikely.
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Antiprogrammed death-1 (anti-PD1) and antiprogrammed death ligand-1 (anti-PD-L1) antibodies are effective checkpoint inhibitors that stimulate the immune system against many types of cancers. The ...flip side of these immunotherapies is the generation of immune-related adverse events, which can theoretically affect all organs. Among these side effects, lipase increase is frequently observed; however the meaning of this biological abnormality remains poorly understood. We investigate in this case study all the lipase increases greater or equal to grade 2 that occurred in patients receiving anti-PD-1 or anti-PD-L1 treatments, to determine their biological and clinical significance. Twenty-one patients were retained with lipase increase related to the immune checkpoint inhibitor. Most of them (71%) were treated for a metastatic melanoma. The peak of lipase increase was observed at a median of 2.8 (range, 0.4-11.4) months after the initiation of the anti-PD1 or anti-PD-L1 treatment, which correlates with cycle 5 of treatment. Three of 21 patients (14%) had a clinical or radiologic immune-related pancreatitis that led to a permanent discontinuation of the treatment. In 15 of 21 (71%) patients, the lipase increase was not considered as clinically significant, and the treatment was continued without complications. The 3 remaining patients discontinued the treatment for progressive disease. These data indicate that lipase increase related to anti-PD1 or anti-PD-L1 is not associated with a significant clinical event in most cases. On the basis of these data, we propose that lipase increase in an asymptomatic patient and without radiographic abnormalities of the pancreas can be reasonably regarded as a not clinically significant event, allowing the continuation of the anti-PD-1 or anti-PD-L1 treatment.
Objective
The development of oncology day-hospital activities contributes to increase quality of life of patients and consequently have changed their perception about waiting. The extemporaneous ...preparation of antineoplastic has become difficult to achieve given the increasing activity, and hospital pharmacists have taken up the challenge by the implementation of the antineoplastic preparation in anticipation. Because anticipation can lead to an important number of preparations to be discarded, we also develop a recycled process for other patients to limit these waste extra costs. We aim to demonstrate the positive balance of anticipated preparation in this 4-year study report.
Data sources: This prospective study was conducted in a major European oncology day-hospital from January, 2012 to December, 2015. The data were extracted from our software WinSimbad™ and updated as needed. The number and cost-associated of preparation ungiven chemotherapy doses (recycled or discarded) were compared to the global drug budget of our hospital in order to not exceed 2%.
Data summary: 303,100 antineoplastic have been prepared. Approximately 35% of them were anticipated with an average of 5,431±984 that were finally ungiven. Two-third was recycled and the cost of the ungiven preparations finally discarded represents 1.7±0.15% of the global drug budget.
Conclusions
This study assesses the drug wastage and its associated cost of this concept through a prospective study and discusses the cost of ungiven antineoplastic preparations. With prior consideration of the need to define the acceptable rate of discarded ungiven preparation, the hospitals with an high oncology day-hospital activity should implement this approach.
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Background Patient Derived Organoids (PDOs) emerged as the best technology to develop ex vivo tumor avatars. Whether drug testing on PDOs to identify efficient therapies will bring clinical utility ...by improving patient survival remains unclear. To test this hypothesis in the frame of clinical trials, PDO technology faces three main challenges to be implemented in routine clinical practices: i) generating PDOs with a limited amount of tumor material; ii) testing a wide panel of anti-cancer drugs; and iii) obtaining results within a time frame compatible with patient disease management. We aimed to address these challenges in a prospective study in patients with colorectal cancer (CRC). Methods Fresh surgical or core needle biopsies were obtained from patients with CRC. PDOs were established and challenged with a panel of 25 FDA-approved anti-cancer drugs (chemotherapies and targeted therapies) to establish a scoring method ('chemogram') identifying in vitro responders. The results were analyzed at the scale of the cohort and individual patients when the follow-up data were available. Results A total of 25 PDOs were successfully established, harboring 94% concordance with the genomic profile of the tumor they were derived from. The take-on rate for PDOs derived from core needle biopsies was 61.5%. A chemogram was obtained with a 6-week median turnaround time (range, 4-10 weeks). At least one hit (mean 6.16) was identified for 92% of the PDOs. The number of hits was inversely correlated to disease metastatic dissemination and the number of lines of treatment the patient received. The chemograms were compared to clinical data obtained from 8 patients and proved to be predictive of their response with 75% sensitivity and specificity. Conclusions We show that PDO-based drug tests can be achieved in the frame of routine clinical practice. The chemogram could provide clinicians with a decision-making tool to tailor patient treatment. Thus, PDO-based functional precision oncology should now be tested in interventional trials assessing its clinical utility for patients who do not harbor activable genomic alterations or have developed resistance to standard of care treatments. Keywords: Organoids, Precision medicine, Colorectal cancer, Chemogram
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Scarcity of age appropriate formulations for orally administered medicines for paediatric malignancies is a critical and ongoing issue which necessitates urgent solutions. According to JARC Survey ...27 % of oral medicines were never available in child-friendly formulations (Vassal et al., 2021 2). Pharmacists from the European Society of Oncology Pharmacy Global (ESOP) and the European Society for Pediatric Oncology (SIOPE) have collaborated to provide a document summarising literature data on this topic and a set of practical instructions on the preparation of extemporaneous oral liquid medicines.
Literature review was conducted for the preparation of oral medicines for paediatric cancer, through Pubmed 2.0. A table was drawn up with necessary information for medicine preparation. We adapted the classification model of the molecule stability ranking of the International database of stability for injectable drugs, Stabilis® (Class A–C).
A total of 126 articles were selected and analysed. All commercially available marketed liquid oral medications used in paediatric cancer were overviewed using globally accessible drug databases and compiled in a table with appropriate indications. Based on the literature review, 28 formulations for 13 different active ingredients for chemotherapy and 35 formulations for 16 different active ingredients for supportive therapy were compiled.
Development of child-appropriate formulations of anticancer medicines by the pharmaceutical industry should be incentivised towards marketing authorisation to enhance accessibility. The results of this study could help facilitate creation of European standards for extemporaneous preparation and persuade researchers in the field of paediatric oncology on the way forward.
•There is a significant lack of essential and novel medicines in paediatric oncology.•Many medicines require appropriate child-friendly formulations.•The compounding of child-friendly formulations of medicines relies on pharmacists.•Practices of extemporaneous preparation vary between countries across Europe.•The development of age appropriate formulations of medicines should be incentivised.
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Nirmatrelvir is an antiviral drug approved for the treatment of COVID-19. The available dosage form consists of tablets marketed under the brand name PAXLOVID®. Although knowledge of nirmatrelvir’s ...intrinsic stability may be useful for any potential development of other pharmaceutical forms, no data regarding this matter is available to date. Preliminary forced degradation studies have shown that the molecule is stable under oxidative and photolytic conditions, while hydrolytic conditions, both acidic and basic, have proven deleterious. Indeed, the molecule presents a priori several functions that can undergo hydrolysis, i.e., three amide moieties and a nitrile function. However, considering the degradation products formed under forced conditions and which were detected and identified by LC-UV-HRMSn, the hydrolysis process leading to their formation is selective since it involved only 2 of the 4 hydrolysable functions of the molecule. Ab initio studies based on density functional theory (DFT) have helped better understand these reactivity differences in aqueous media. Some hydrolyzable functions of nirmatrelvir differ from others in terms of electrostatic potential and Fukui functions, and this seems to correlate with the forced degradation outcomes.
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Glioblastoma is one of the most common and aggressive forms of brain tumor, a rare disease for which there is a great need for innovative therapies. ONC201, a new drug substance, has been used in a ...compassionate treatment program where the choice of dosage form and regimen have yet to be justified. The prior knowledge needed to anticipate ONC201 stability problems has recently been partially addressed, by (i) showing that ONC201 is sensitive to light and oxidation and (ii) identifying the molecular structures of the main degradation products formed. The aim of the work presented here was to improve our understanding of the degradation pathways of ONC201 using data from ab initio calculations and experimental work to supplement the structural information we already published. The C–H bonds located αto the amine of the tetrahydropyridine group and those located alpha to the imine function of the dihydroimidazole group exhibit the lowest bond dissociation energies (BDEs) within the ONC201 molecule. Moreover, these values drop well below 90 kcal.mol−1 when ONC201 is in an excited state (S1; T1). The structures of the photoproducts we had previously identified are consistent with these data, showing that they would have resulted from radical processes following the abstraction of alpha hydrogens. Concerning ONC201’s sensitivity to oxidation, the structures of the oxidation products matched the critical points revealed through mapped electrostatic potential (MEP) and average local ionization energy (ALIE). The data obtained from ab initio calculations and experimental work showed that the reactivity of ONC201 to light and oxidation conditions is highly dependent on pH. While an acidic environment (pH < 6) contributes to making ONC201 quantitatively more stable in solution in the face of oxidation and photo-oxidation, it nevertheless seems that certain chemical groups in the molecule are more exposed to nucleophilic attacks, which explains the variation observed in the profile of degradation products formed in the presence of certain antioxidants tested. This information is crucial to better understand the stability results in the presence of antioxidant agents and to determine the right conditions for them to act.
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Background
Imatinib is a protein-tyrosine kinase inhibitor which is currently only commercially available as a tablet dosage form in the strength of 100mg and 400mg. The elaboration of new oral ...liquid formulations is suitable in pediatrics and for patients who have difficulties to swallow, notably in the absence of commercial forms. This enables the adaptation of dosage and secure the administration.
Objectives
The formulation of an oral pediatric solution of imatinib at a concentration of 30 mg/mL and the evaluation of its stability for the treatment of pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia.
Methods
The physicochemical stability parameters: appearance, pH, osmolality, and drug content of formulation were evaluated for 30 days when stored at 2–8°C. Concentration of solution was measured with a validated method using high performance liquid chromatography (HPLC) coupled with an absorbance UV detector. Equally, microbiological stability was performed.
Results
The remaining imatinib concentration was at least 95% of the initial concentration after 30 days stored in fridge temperature. No changes were observed regarding the physical properties of the formulation during the study period.
Conclusions
The stability study showed that the imatinib oral solution at a concentration of 30 mg/mL provides an alternative option at the commercial tablet dosage forms for pediatric patients and patients who have difficulties to swallow.
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