Extended physicochemical stability of cetuximab in opened vials and infusion bags when stored at 4°C and 25°C.

INTRODUCTION: This study aimed to determine the stability of cetuximab: (1) under "in-use" conditions after dilution to 1 mg/mL in 0.9% sodium chloride in polyolefin bags and (2) as an undiluted solution (5 mg/mL) repackaged in polypropylene bags or kept in the vial after opening. METHODS: Ready-to-use 500 mg/100 mL vials of cetuximab solution were diluted to 1 mg/mL in 100 mL bags of 0.9% sodium chloride or repackaged as a 5 mg/mL solution into empty 100 mL bags. Bags and vials were stored at 4°C for 90 days and 25°C for 3 days. A syringe sample of 7 mL was taken from each bag for the initial determinations. The sampled bags were weighed to determine their initial weight and placed under the planned storage conditions. The physicochemical stability of cetuximab was estimated using validated methods. RESULTS: No changes in turbidity, no protein loss, and no changes in cetuximab tertiary structure were observed after 30 days of storage or when subjected to a temperature excursion of 3 days at 25°C and when stored at 4°C for up to 90 days, regardless of the concentrations and batches. The colligative parameters did not change under any of the tested conditions. No evidence of microbial growth was found in bags after 90 days of storage at 4°C. CONCLUSION: These results support the extended in-use shelf-life of cetuximab vials and bags, which can be cost-effective for healthcare providers.

Formulation and Administration of Biological Medicinal Products".

Monoclonal antibody (Mabs) containing medicinal products are widely used in clinical practice. Prior to parenteral administration, licensed Mab containing medicinal products are transferred to the ready-to-administer (RTA) forms. Reconstitution and/or preparation should follow the guidelines for Good Reconstitution/Good Preparation Practice. Preparation in the pharmacy must take place within the framework of a suitable quality management system. The responsible pharmacist must apply a risk assessment on the process to ensure the appropriate quality of the RTA preparation, especially because the extent of quality testing is limited by batch size (often one single unit) and time restraints. In these cases, appropriate quality is to be assured by means of qualification activities, environmental monitoring, process validation with growth medium and in-process controls. Correct labelling of the Mab containing RTA preparations includes a suitable storage advice and a defined shelf life. Physicochemical stability of a given Mab preparation can be assessed based on a specific stability study (supplied by the manufacturer in the SmPC or scientific journals, study published by an expert in a peer-reviewed scientific journal). Physicochemical stability studies require the use of various orthogonal physicochemical methods to detect accurately the degradation changes that may result from the deamidation, oxidation, disulfide formation, aggregation or fragmentation during storage. Complementary, biological activity can be measured. Compatibility studies of Mabs and devices used for preparation and administration are still scarce. Microbiological stability of Mab preparations is related to the complexity of the preparation process, the growth supporting nature of the preparation and the integrity of the container or container/closure combination. In use viability tests revealed that the potential of Mab preparations to support microbial growth was similar to that of the pure vehicle solutions used as control solutions. The enumerated microbial counts varied according to the species utilized and the type of Mab preparation. If sterility testing of the individual preparation is impossible, maximum permitted shelf life can be assessed empirically with regard to the maximum shelf lives defined in the USP <797> monograph. Finally, microbiological and physicochemical stability are to be considered concurrently when determining the shelf life of an individual Mab preparation. In each case, shelf life should be limited according to the shorter period of proven stability, either derived from the microbiological or physicochemical stability data.

3D-Printed, Liquid-Filled Capsules of Concentrated and Stabilized Polyphenol Epigallocatechin Gallate, Developed in a Clinical Trial.

In vitro studies have shown that epigallocatechin gallate (EGCG), the most potent antioxidant of the green tea polyphenol catechins, is able to effectively prevent the formation of amyloid plaques and induce their clearance. However, its high chemical reactivity promotes high chemical instability, which represents a major obstacle for the development of pharmaceutical forms containing solubilized EGCG, an essential condition for a better systemic passage via the oral route. After discovering that EGCG forms a deep eutectic with choline chloride, we exploited this property to formulate and patent liquid-filled capsules containing 200-800 mg of soluble EGCG in easy-to-administer sizes. The gelatin envelopes used are of the conventional type and their filling has been achieved using 3D printing technology. Not only did the EGCG-choline complex allow the formulation of hydrophilic solutions with a high concentration of active substance but it also contributed significantly to its chemical stability, since after at least 18 months of storage at 25 °C/60% RH and one year at 40 °C/75% RH, the capsules show unchanged hardness, chromatographic profiles and antioxidant activity compared to T0. Preclinical studies in monkeys showed that bioavailability was increased by a factor of 10 compared to marketed capsules comprising EGCG powder. This pharmaceutical development was conducted in the context of upcoming clinical trials to evaluate EGCG alone or in combination when treating transthyretin and light-chain cardiac amyloidosis.

Simple Approach to Enhance Green Tea Epigallocatechin Gallate Stability in Aqueous Solutions and Bioavailability: Experimental and Theoretical Characterizations.

Because of its antioxidant, antimutagenic, and anti-infectious properties, epigallocatechin gallate (EGCG) is the most interesting compound among the green tea catechins polyphenols. However, its health effects are inconclusive due to its very low bioavailability, largely due to a particular instability that does not allow EGCG to reach the potency required for clinical developments. Over the last decade, many efforts have been made to improve the stability and bioavailability of EGCG using complex delivery systems such as nanotechnology, but these efforts have not been successful and easy to translate to industrial use. To meet the needs of a large-scale clinical trial requiring EGCG in a concentrated solution to anticipate swallowing impairments, we developed an EGCG-based aqueous solution in the simplest way while trying to circumvent EGCG instability. The solution was thoroughly characterized to sort out the unexpected stability outcome by combining experimental (HPLC-UV-mass spectrometry and infrared spectroscopy) and computational (density functional theory) studies. Against all odds, the EGCG-sucrose complex under certain conditions may have prevented EGCG from degradation in aqueous media. Indeed, in agreement with the ICH guidelines, the formulated solution was shown to be stable up to at least 24 months under 2-8 °C and at ambient temperature. Furthermore, considerable improvement in bioavailability in rats, against EGCG powder formulated in hard-gel capsules, was shown after gavage. Thus, the proposed formulation may provide an easily implementable platform to administer EGCG in the context of clinical development.

Investigation of the Physicochemical and Biological Stability of the Adalimumab Biosimilar CT-P17.

INTRODUCTION: CT-P17 (Celltrion, Inc., Incheon, Republic of Korea) is a biosimilar of reference adalimumab (Humira®; AbbVie Inc., North Chicago, IL, USA), which has recently received regulatory approval from the European Medicines Agency. METHODS: This analysis was designed to evaluate the stability profile of CT-P17 compared with reference adalimumab and the currently licensed adalimumab biosimilars ABP 501 (Amjevita®/Amgevita®; Amgen Inc., Thousand Oaks, CA, USA) and SB5 (Imraldi®; Biogen Inc., Cambridge, MA, USA) when stored at low temperature (5 °C) or room temperature (25 °C) with 60% relative humidity for up to 28 days. RESULTS: Multiple orthogonal and complementary tests demonstrated that CT-P17 was stable for 28 days under all tested conditions, as well as for protein concentrations tested (50 vs 100 mg/mL), type of delivery device (autoinjector vs prefilled syringe), and manufacturing date (recently manufactured vs aged for 17 months). There were slight differences among products in terms of charge variants, oxidation level, purity, and number of subvisible particles; however, overall, the quality of each product was maintained over 28 days. CONCLUSION: Our data suggest that CT-P17 may be used without any significant loss of stability when stored at 5 °C or 25 °C with 60% relative humidity for up to 28 days, and was not impacted by protein concentration tested and delivery device. Comparative stability data suggest that the appropriate maximum storage period for CT-P17 may be up to 28 days at room temperature with 60% relative humidity.

Development of microemulsion of mitotane for improvement of oral bioavailability.

BACKGROUND: Mitotane (o,p'-DDD) is considered to be the drug of choice in the treatment of nonresectable and metastasized adrenocortical carcinoma. However, mitotane has poor solubility in the gastrointestinal tract and very low bioavailability. Consequently, to achieve therapeutic plasma level, high cumulative doses (4-6 g/day) of mitotane were usually used during 3-5 months. To shorten this equilibration time and reduce gastrointestinal side effects, a self-microemulsifying drug delivery system (SMEDDS) of mitotane has been developed. METHOD: First time, the solubility of mitotane was determined in various oils and surfactants; then, the influence of oils, surfactants, and cosurfactants on the formation of SMEDDS was investigated by constructing ternary phase diagrams. SMEDDS was characterized by morphological observations and droplet size measurements. Intestinal drug permeation of SMEDDS of mitotane (3 mM) was assessed in an Ussing-type apparatus and the bioavailability was determined in a rabbit model. RESULTS: The optimum formulation consisted of a mixture of Capryol, Tween, and Cremophor EL (33:33:33). The formulation was found to pass through the intestinal barrier much faster than a solution of mitotane (14.85 +/- 0.8 versus 3.03 +/- 0.2 micromol/cm(2)). Moreover, after oral administration in rabbits, the relative bioavailability was 3.4, compared with that of the conventional form (Lysodren). CONCLUSION: This SMEDDS can now be considered as a very good candidate to optimize the administration of mitotane.

Speciation of arsenic in urine following intravenous administration of arsthinol in mice.

Recent investigations have shown that arsthinol, a trivalent organoarsenic compound (dithiarsolane), has been active in vitro on leukemia cell lines and offers a better therapeutic index than arsenic trioxide, as estimated by the ratio LD50/IC50. To complete our understanding of its urinary excretion, a sensitive method using liquid chromatography coupled with mass spectrometry (LC-MS) was used. Mice were injected intravenously with a single dose of arsthinol at 0.2 mmol/kg of body weight. The amount of total arsenic in tissues and body fluids was determined by a colorimetric method and urine metabolites were analyzed on a C18 Acclaim PepMap 100 A column by LC-MS. Our results showed that only three arsenic species (acetarsol, acetarsol oxide and arsthinol) were detected in the first 24-h urine. Overall, this study confirms that the hydrolysis of dithiarsolanes to arsenoxides (i.e. acetarsol oxide) can be followed by an oxidation in arsonic acids (i.e. acetarsol). All these compounds are excreted in the urine.

Physicochemical Stability of Monoclonal Antibodies: A Review.

Monoclonal antibodies (mAbs) are subject to instability issues linked to their protein nature. In this work, we review the different mechanisms that can be linked to monoclonal antibodies instability, the parameters, and conditions affecting their stability (protein structure and concentration, temperature, interfaces, light exposure, excipients and contaminants, and agitation) and the different analytical methods used for appropriate physicochemical stability studies: physical stability assays (aggregation, fragmentation, and primary, secondary, and tertiary structure analysis), chemical stability assays and quantitative assays. Finally, data from different published stability studies of mAbs formulations, either in their reconstituted form, or in diluted ready to administer solutions, was compiled. Overall, the physicochemical stability of mAbs is linked to numerous factors such as formulation, environment, and manipulations, and must be thoroughly investigated using several complementary analytical techniques, each of which allowing specific characterization information to be harvested. Several stability studies have been published, some of them showing possibilities of extended stability. However, those data should be questioned due to potential lacks in study methodology.

Cancer, immune suppression and Coronavirus Disease-19 (COVID-19): Need to manage drug safety (French Society for Oncology Pharmacy [SFPO] guidelines).

The Coronavirus disease (COVID-19) pandemic is disrupting our health environment. As expected, studies highlighted the great susceptibility of cancer patients to COVID-19 and more severe complications, leading oncologists to deeply rethink patient cancer care. This review is dedicated to the optimization of care pathways and therapeutics in cancer patients during the pandemic and aims to discuss successive issues. First we focused on the international guidelines proposing adjustments and alternative options to cancer care in order to limit hospital admission and cytopenic treatment in cancer patients, most of whom are immunocompromised. In addition cancer patients are prone to polypharmacy, enhancing the risk of drug-related problems as adverse events and drug-drug interactions. Due to increased risk in case of COVID-19, we reported a comprehensive review of all the drug-related problems between COVID-19 and antineoplastics. Moreover, in the absence of approved drug against COVID-19, infected patients may be included in clinical trials evaluating new drugs with a lack of knowledge, particularly in cancer patients. Focusing on the several experimental drugs currently being evaluated, we set up an original data board helping oncologists and pharmacists to identify promptly drug-related problems between antineoplastics and experimental drugs. Finally additional and concrete recommendations are provided, supporting oncologists and pharmacists in their efforts to manage cancer patients and to optimize their treatments in this new era related to COVID-19.

Impact of 3-week citrulline supplementation on postprandial protein metabolism in malnourished older patients: The Ciproage randomized controlled trial.

BACKGROUND: Citrulline (CIT), is not extracted by the splanchnic area, can stimulate muscle protein synthesis and could potentially find clinical applications in conditions involving low amino acid (AA) intake, such as in malnourished older subjects. OBJECTIVE: Our purpose was to research the effects of CIT supplementation on protein metabolism in particular on non-oxidative leucine disposal (NOLD, primary endpoint), and splanchnic extraction of amino acids in malnourished older patients. DESIGN: This prospective randomized multicenter study determined whole-body and liver protein synthesis, splanchnic protein metabolism and appendicular skeletal muscle mass (ASMM) in 24 malnourished older patients [80-92 years; 18 women and 6 men] in inpatient rehabilitation units. All received an oral dose of 10 g of CIT or an equimolar mixture of six non-essential amino acids (NEAAs), as isonitrogenous placebo, for 3 weeks. RESULTS: NOLD and albumin fractional synthesis rates were not different between the NEAA and CIT groups. Splanchnic extraction of dietary amino acid tended to decrease (p = 0.09) in the CIT group (45.2%) compared with the NEAA group (60.3%). Total differences in AA and NEAA area under the curves between fed-state and postabsorptive-state were significantly higher in the CIT than in the NEAA group. There were no significant differences for body mass index, fat mass (FM), lean mass (LM) or ASMM in the whole population except for a tendential decrease in FM for the citrulline group (p = 0.089). Compared with Day 1, lean mass and ASMM significantly increased (respectively p = 0.016 and p = 0.018) at Day 20 in CIT-treated women (mean respective increase of 1.7 kg and 1.1 kg), and fat mass significantly decreased (p = 0.001) at Day 20 in CIT-group women (mean decrease of 1.3 kg). CONCLUSIONS: Our results demonstrate that CIT supplementation has no effect on whole-body protein synthesis or liver protein synthesis in malnourished older subjects. However, CIT supplementation was associated with a higher systemic AA availability. In the subgroup of women, CIT supplementation increased LM and ASMM, and decreased FM.

Comparison of nanosuspensions and hydroxypropyl-beta-cyclodextrin complex of melarsoprol: pharmacokinetics and tissue distribution in mice.

The aim of this work was to develop and compare two formulations of melarsoprol (nanosuspension and hydroxypropyl-beta-cyclodextrin inclusion complex). The arsenic concentrations in the organs have been assessed on a mouse model. Since this organoarsenical drug has been proposed for the treatment of cerebral trypanosomiasis and refractory leukaemias, special emphasis has been put on the bone marrow and on the brain. The organic solution of melarsoprol (Mel B, 0.039mmol/kg), injected intravenously as control formulation, was found to concentrate significantly in the bone marrow (C(max)=1.64mmol/g), though, not surprisingly, the brain concentration was quite high (C(max)=0. 093mmol/g) and the LD(50) was 0.12mmol/kg. The hydroxypropyl-beta-cyclodextrin inclusion complex was found to concentrate much more in the brain (C(max)=0.25mmol/g) leading to a higher acute toxicity (i.e., lower LD(50); 0.056mmol/kg). Nevertheless, even if the encephalopathy risk has to be taken in to account, this could be considered as a positive point for the treatment of the cerebral trypanosomiasis, which is the main indication for this drug. On the contrary, the use of nanosuspensions allowed us to reduce the cerebral concentration (C(max)=0.02micromol/g) and the acute toxicity (LD(50)=0.25mmol/kg). Moreover, nanosuspensions, especially those prepared with polxamer 407, preserved a good in vitro antileukemic activity (IC(50)=3.34+/-0.33 after 48h on K562) with high bone marrow concentrations (C(max)=1.85micromol/g). As a consequence this formulation could be proposed for the treatment of refractory leukaemias.

Anti-colchicine Fab fragments prevent lethal colchicine toxicity in a porcine model: a pharmacokinetic and clinical study.

BACKGROUND: Colchicine poisoning is commonly lethal. Colchicine-specific Fab fragments increase rat urinary colchicine clearance and have been associated with a good outcome in one patient. We aimed to develop a porcine model of colchicine toxicity to study the pharmacokinetics and efficacy of ovine Fab. METHODS: A Göttingen minipig critical care model was established and serial blood samples taken for colchicine and Fab pharmacokinetics, clinical chemistry, and haematology. Animals were euthanised when the mean arterial pressure fell below 45 mmHg without response to vasopressor, or at study completion. RESULTS: Initial studies indicated that oral dosing produced variable pharmacokinetics and time-to-euthanasia. By contrast, intravenous infusion of 0.25 mg/kg colchicine over 1 h produced reproducible pharmacokinetics (AUC0-20 343 [SD = 21] µg/L/h), acute multi-organ injury, and cardiotoxicity requiring euthanasia a mean of 22.5 (SD = 3.2) h after dosing. A full-neutralising equimolar Fab dose given 6 h after the infusion (50% first hour, 50% next 6 h [to reduce renal-loss of unbound Fab]) produced a 7.35-fold increase in plasma colchicine (AUC0-20 2,522 [SD = 14] µg/L/h), and removed all free plasma colchicine, but did not prevent toxicity (euthanasia at 29.1 [SD = 3.4] h). Earlier administration over 1 h of the full-neutralising dose, 1 or 3 h after the colchicine, produced a 12.9-fold (AUC0-20 4,433 [SD = 607] µg/L/h) and 6.0-fold (AUC0-20 2,047 [SD = 51] µg/L/h) increase in plasma colchicine, respectively, absence of free plasma colchicine until 20 h, and survival to study end without marked cardiotoxicity. CONCLUSIONS: Colchicine-specific Fab given early, in equimolar dose, bound colchicine, eliciting its movement into the blood, and preventing severe toxicity. Clinical studies are now needed to determine how soon this antidote must be given to work in human poisoning.

A case of mixed intoxication with isopropyl alcohol and propanol-1 after ingestion of a topical antiseptic solution.

We report a mixed intoxication with isopropyl alcohol and propanol-1 in a hospitalized patient who ingested, on two separate days, two 100 ml bottles of a topical antiseptic solution containing isopropyl alcohol and propanol-1. Eight hours after the second ingestion, plasma concentrations of isopropanol, propanol-1 and acetone were 37 mg/dL, <10 mg/dL, and 227 mg/dl, respectively. Despite a lack of severe toxicity, 4-methylpyrazole (fomepizole) was initiated. This case points out the need to limit access to alcohol-containing antiseptic solutions on wards where alcoholic and psychotic patients are hospitalized.

How to select a nanosimilar.

Nanomedicines in the class of nonbiological complex drugs (NBCDs) are becoming increasingly available. Up to 23 nanomedicines have been approved, and approximately 50 are in clinical development. Meanwhile, the first nanosimilars have entered the market through the generic approval pathway, but clinical differences have been observed. Many healthcare professionals may be unaware of this issue and must be informed of these clinically relevant variances. This article provides a tool for rational decision making for the inclusion of nanomedicines into the hospital formulary, including defined criteria for evaluation of substitutability or interchangeability. The tool was generated by conducting a roundtable with an international panel of experts and follows the same thought process that was developed and published earlier for the selection of biologicals/biosimilars. In addition to the existing criteria for biosimilars, a set of seven criteria was identified that specifically apply to nanosimilars. These include (1) particle size and size distribution, (2) particle surface characteristics, (3) fraction of uncaptured bioactive moiety, (4) stability on storage, (5) bioactive moiety uptake and (6) distribution, and (7) stability for ready-to-use preparation. Pharmacists should utilize their pharmaceutical expertise to use the appropriate criteria to evaluate the comparability of the drug to decide on interchangeability or substitutability.

Identifying critical steps towards improved access to innovation in cancer care: a European CanCer Organisation position paper.

In recent decades cancer care has seen improvements in the speed and accuracy of diagnostic procedures; the effectiveness of surgery, radiation therapy and medical treatments; the power of information technology; and the development of multidisciplinary, specialist-led approaches to care. Such innovations are essential if we are to continue improving the lives of cancer patients across Europe despite financial pressures on our healthcare systems. Investment in innovation must be balanced with the need to ensure the sustainability of healthcare budgets, and all health professionals have a responsibility to help achieve this balance. It requires scrutiny of the way care is delivered; we must be ready to discontinue practices or interventions that are inefficient, and prioritise innovations that may deliver the best outcomes possible for patients within the limits of available resources. Decisions on innovations should take into account their long-term impact on patient outcomes and costs, not just their immediate costs. Adopting a culture of innovation requires a multidisciplinary team approach, with the patient at the centre and an integral part of the team. It must take a whole-system and whole-patient perspective on cancer care and be guided by high-quality real-world data, including outcomes relevant to the patient and actual costs of care; this accurately reflects the impact of any innovation in clinical practice. The European CanCer Organisation is committed to working with its member societies, patient organisations and the cancer community at large to find sustainable ways to identify and integrate the most meaningful innovations into all aspects of cancer care.

Pharmacokinetics of hydroxyurea 1,000 mg coated breakable tablets and 500 mg capsules in pediatric and adult patients with sickle cell disease.

Little is known about the pharmacokinetics of hydroxyurea in patients with sickle cell disease (SCD). Our aims were to evaluate bioequivalence between standard hydroxyurea capsules and a new formulation of 1,000 mg coated breakable tablets in adults and to compare pharmacokinetic parameters in adults and children with SCD. Fifteen adults received hydroxyurea capsules and tablets in a randomized cross-over study. Eleven children received hydroxyurea tablets. The results showed bioequivalence between capsules and tablets in adults. Pharmacokinetic parameters were not significantly different between adults and children. Considerable inter-individual variability was noted.

Distribution of calcineurin activity in blood cell fractions and impact of tacrolimus inhibition.

The aim of this study was to investigate calcineurin (PP2B) activity in different blood cell fractions and its inhibition by tacrolimus. Basal PP2B activity was measured in each blood cellular fraction collected from healthy volunteers. The inhibition profile of PP2B activity was explored in isolated peripheral blood mononuclear cells (PBMC) and platelets exposed directly to tacrolimus and in PBMC and platelets isolated from whole blood previously exposed to tacrolimus. Contrasting with red blood cells (30%) and platelets (25%), PBMC represented only 8.7% of PP2B activity of unfractionated whole blood. After tacrolimus exposure of isolated PBMC and platelets, the concentration of tacrolimus required to inhibit 50% of PP2B activity (EC(50)) in PBMC was significantly lower than in platelets (0.26 ng/mL vs. 0.83 ng/mL, P < 0.001). EC(50) values were similar in PBMC and platelets isolated from whole blood previously exposed to tacrolimus (7.69 ng/mL vs. 7.42 ng/mL, respectively). These results suggest PBMC is a very suitable matrix for PP2B measurement in monitoring transplant recipients but clinical studies are necessary to solve clearly this issue.

Implementation of automated dispensing cabinets for management of medical devices in an intensive care unit: organisational and financial impact.

BACKGROUND: Automated dispensing cabinets (ADCs) have been tested and approved for medication management in hospitals. OBJECTIVES: First, to evaluate the logistics and organisational effect of a similar system for management of sterile medical devices in a medical intensive care unit (ICU). Second, to assess the cost savings of this new organisation for the sterile medical devices budget of this department. METHODS: The organisational effect was evaluated by comparing (1) the workload of head nurse, nursing auxiliary and pharmacy technician and (2) sterile medical devices emergency orders, 1 year before and after implementation of three ADCs and 100 wireless open-access devices. The hospital's costs (ADC, wireless devices and software) and benefits (stock value and resupplying value before and after implementation) were evaluated. RESULTS: Employment of ADCs led to organisational improvement: the total time saved by the pharmacy and ICU together was 34% of the time spent before introduction. The number of emergency orders decreased from 6% to 1% of total orders after 1 year. €55 000 were saved (stock value + resupplying value) 1 year after introduction of ADCs. These benefits were almost equal to the cost of introducing the system. CONCLUSIONS: ADCs could provide an innovative and efficient solution for the management of sterile medical devices in hospitals. Further investigations are needed to complete the financial evaluation, and to develop this system to provide a secure a medical devices circuit.