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INTRODUCTION: This study aimed to determine the stability of cetuximab: (1) under "in-use" conditions after dilution to 1â mg/mL in 0.9% sodium chloride in polyolefin bags and (2) as an undiluted solution (5â mg/mL) repackaged in polypropylene bags or kept in the vial after opening. METHODS: Ready-to-use 500â mg/100â mL vials of cetuximab solution were diluted to 1â mg/mL in 100â mL bags of 0.9% sodium chloride or repackaged as a 5â mg/mL solution into empty 100â mL bags. Bags and vials were stored at 4°C for 90 days and 25°C for 3 days. A syringe sample of 7â 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.
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Embalagem de Medicamentos , Cloreto de Sódio , Humanos , Cetuximab , Cloreto de Sódio/química , Infusões Parenterais , Temperatura , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Cromatografia Líquida de Alta PressãoRESUMO
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.
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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.
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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.
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Adalimumab , Medicamentos Biossimilares , República da CoreiaRESUMO
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.
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Anticorpos Monoclonais/farmacologia , Produtos Biológicos/farmacologia , Indústria Farmacêutica/normas , Preparações Farmacêuticas/normas , Composição de Medicamentos , Estabilidade de Medicamentos , Monitoramento Ambiental , Humanos , Proteólise , Controle de Qualidade , Medição de Risco , Gestão de RiscosRESUMO
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.
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Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Oncologia/normas , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Farmácia/normas , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Betacoronavirus/isolamento & purificação , COVID-19 , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Infecções por Coronavirus/virologia , Humanos , Oncologia/métodos , Neoplasias/virologia , Pandemias , Farmácia/métodos , Pneumonia Viral/virologia , Guias de Prática Clínica como Assunto , SARS-CoV-2RESUMO
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.
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Anticorpos Monoclonais/química , Produtos Biológicos/química , Fenômenos Químicos , Química Farmacêutica/métodos , Animais , Anticorpos Monoclonais/metabolismo , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/metabolismo , Produtos Biológicos/metabolismo , Estabilidade de Medicamentos , Humanos , Estabilidade Proteica , Estresse MecânicoRESUMO
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.
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Citrulina/uso terapêutico , Proteínas Alimentares/metabolismo , Avaliação Geriátrica/métodos , Desnutrição/tratamento farmacológico , Proteínas Musculares/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Citrulina/administração & dosagem , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Humanos , Masculino , Período Pós-Prandial , Estudos ProspectivosRESUMO
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.
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Antídotos/farmacologia , Antídotos/uso terapêutico , Colchicina/sangue , Colchicina/intoxicação , Fragmentos Fab das Imunoglobulinas/farmacologia , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Administração Intravenosa , Administração Oral , Animais , Fragmentos Fab das Imunoglobulinas/sangue , Modelos Animais , Suínos , Porco MiniaturaRESUMO
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.
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Medicamentos Biossimilares/normas , Aprovação de Drogas/métodos , Medicamentos Genéricos/normas , Nanomedicina/métodos , Algoritmos , Medicamentos Biossimilares/farmacocinética , Medicamentos Biossimilares/uso terapêutico , Medicamentos Genéricos/farmacocinética , Medicamentos Genéricos/uso terapêutico , Guias como Assunto , Humanos , Cooperação Internacional , Farmacovigilância , Equivalência TerapêuticaRESUMO
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.
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Atenção à Saúde/organização & administração , Acessibilidade aos Serviços de Saúde/organização & administração , Neoplasias/terapia , Terapias em Estudo , Europa (Continente) , Disparidades em Assistência à Saúde , HumanosRESUMO
PURPOSE: Well-documented stability data of monoclonal antibodies are generally missing. That is why we studied the physicochemical and biological stability of undiluted ipilimumab (IPI) in glass vial (5 mg/ml) over 28 d after opening, stored at 4 °C and 25 °C. METHOD: A stressed study (60 °C) was performed to validate our analytical methods as 'stability indicating'. The different methods used were turbidimetry, dynamic light scattering (DLS), second-derivative ultraviolet and chromatographic methods as size-exclusion chromatography (SEC) and cation-exchange (CEX). Biological characterisation was performed by an in vitro functional binding inhibition bioassay. RESULTS: We demonstrated that ipilimumab in opened vials stored at 4 °C and 25 °C remained stable for at least 28 d. No physical, chemical or structural instability was found. No aggregation was observed by turbidimetry, SEC and DLS. Hydrodynamic diameters remained unchanged, as chromatographic profiles in CEX and thermal aggregation curves. Functionally, the ability of IPI to antagonise CTLA-4/B7.2 binding remained stable over 1 month at 4 °C. CONCLUSION: These results indicate that unused residues of IPI in their original vials can be safely kept up to 28 d, following good manufacturing procedures, allowing re-use for another patient or in case of cold-chain rupture.
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Anticorpos Monoclonais/química , Antineoplásicos/química , Embalagem de Medicamentos , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antígeno B7-2/metabolismo , Ligação Competitiva , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/metabolismo , Química Farmacêutica , Cromatografia em Gel , Cromatografia por Troca Iônica , Estabilidade de Medicamentos , Vidro , Hibridomas/metabolismo , Ipilimumab , Luz , Nefelometria e Turbidimetria , Ligação Proteica , Desnaturação Proteica , Estabilidade Proteica , Espalhamento de Radiação , Espectrofotometria Ultravioleta , Tecnologia Farmacêutica/métodos , Temperatura , Fatores de TempoRESUMO
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, 1â 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 1â year. 55â 000 were saved (stock value + resupplying value) 1â 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.
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Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individualise treatment by adapting drug dose to improve efficacy and/or reduce toxicity. The cytotoxic drugs are characterised by steep dose-response relationships and narrow therapeutic windows. Inter-individual pharmacokinetic (PK) variability is often substantial. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies and the paucity of published data from pharmacological trials. The situation is different with targeted therapies. The large interindividual PK variability is influenced by the pharmacogenetic background of the patient (e.g. cytochrome P450 and ABC transporters polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure correlates with treatment response in various cancers. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and concerns over adherence treatment. There are still few data with monoclonal antibodies (mAbs) in favour of TDM approaches, even if data showed encouraging results with rituximab and cetuximab. TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.
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Antineoplásicos/farmacocinética , Monitoramento de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Antineoplásicos/toxicidade , Citotoxinas/farmacocinética , Relação Dose-Resposta a Droga , HumanosRESUMO
Most of oral targeted therapies are tyrosine kinase inhibitors (TKIs). Oral administration generates a complex step in the pharmacokinetics (PK) of these drugs. Inter-individual PK variability is often large and variability observed in response is influenced not only by the genetic heterogeneity of drug targets, but also by the pharmacogenetic background of the patient (e.g. cytochome P450 and ABC transporter polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure, reflected in the area under the plasma concentration-time curve (AUC) correlates with treatment response (efficacy/toxicity) in various cancers. Nevertheless levels of evidence for therapeutic drug monitoring (TDM) are however heterogeneous among these agents and TDM is still uncommon for the majority of them. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and/or concerns over adherence treatment. Interpatient PK variability observed with monoclonal antibodies (mAbs) is comparable or slightly lower to that observed with TKIs. There are still few data with these agents in favour of TDM approaches, even if data showed encouraging results with rituximab, cetuximab and bevacizumab. At this time, TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.
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Antineoplásicos/farmacocinética , Monitoramento de Medicamentos/métodos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Antineoplásicos/toxicidade , Antineoplásicos Hormonais/farmacocinética , Ensaios Clínicos como Assunto , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Inibidores de Proteínas Quinases/farmacocinéticaRESUMO
Most anticancer drugs are characterised by a steep dose-response relationship and narrow therapeutic window. Inter-individual pharmacokinetic (PK) variability is often substantial. The most relevant PK parameter for cytotoxic drugs is the area under the plasma concentration versus time curve (AUC). Thus it is somewhat surprising that therapeutic drug monitoring (TDM) is still uncommon for the majority of agents. Goals of the review were to assess the rationale for more widely used TDM of cytotoxics in oncology. There are several reasons why TDM has never been fully implemented into daily oncology practice. These include difficulties in establishing appropriate concentration target ranges, common use of combination chemotherapies for many tumour types, analytical challenges with prodrugs, intracellular compounds, the paucity of published data from pharmacological trials and 'Day1 = Day21' administration schedules. There are some specific situations for which these limitations are overcome, including high dose methotrexate, 5-fluorouracil infusion, mitotane and some high dose chemotherapy regimens. TDM in paediatric oncology represents an important challenge. Established TDM approaches includes the widely used anticancer agents carboplatin, busulfan and methotrexate, with 13-cis-retinoic acid also recently of interest. Considerable effort should be made to better define concentration-effect relationships and to utilise tools such as population PK/PD models and comparative randomised trials of classic dosing versus pharmacokinetically guided adaptive dosing. There is an important heterogeneity among clinical practices and a strong need to promote TDM guidelines among the oncological community.
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Antineoplásicos/farmacocinética , Citotoxinas/farmacocinética , Monitoramento de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Antineoplásicos/toxicidade , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , HumanosRESUMO
In this paper, we examined arsthinol-cyclodextrin complexes, which display an anticancer activity. The association constants were 17,502±522 M(-1) for hydroxypropyl-ß-cyclodextrin and 12,038±10,168 M(-1) for randomized methylated ß-cyclodextrin. (1)H NMR experiments in solution also confirmed the formation of these complexes and demonstrated an insertion of the arsthinol (STB) with its dithiarsolane extremity into the wide rim of the hydroxypropyl-ß-cyclodextrin cavity. Complexed arsthinol was more effective than arsenic trioxide (As2O3) and melarsoprol on the U87 MG cell line. Importantly, in the in vivo study, we observed significant antitumor activity against heterotopic xenografts after i.p. administration and did not see any signs of toxicity. This remains to be verified using an orthotopic model.
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Arsenicais/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Melarsoprol/administração & dosagem , Óxidos/administração & dosagem , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacologia , Trióxido de Arsênio , Arsenicais/química , Arsenicais/farmacologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Excipientes/química , Feminino , Glioma/patologia , Humanos , Injeções Intraperitoneais , Espectroscopia de Ressonância Magnética , Melarsoprol/química , Melarsoprol/farmacologia , Camundongos , Camundongos Nus , Óxidos/química , Óxidos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , beta-Ciclodextrinas/químicaRESUMO
Using several complementary analytical methods, we demonstrated that the monoclonal antibody Trastuzumab (Tz), diluted in 0.9% sodium chloride can be stored in polyolefin infusion bags at 4°C or room temperature up to 6 months with no evidence of chemical or physical instability. No aggregation of Tz was observed and its three dimensional structure remains unaltered. Thus, the practical use of diluted Tz can be safely extended to optimize the workload of centralized preparation units and to minimize costs.
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Anticorpos Monoclonais Humanizados/química , Antineoplásicos/química , Embalagem de Medicamentos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Polienos , Temperatura , TrastuzumabRESUMO
As it is an important challenge for pharmacists to access the stability of monoclonal antibodies because of the widespread of centralized preparation units, we conducted a study to evaluate the physicochemical and biological stability of diluted rituximab at 1mg/mL over six months at 4 °C. We also conducted the study at 40 °C to demonstrate that all methods employed were stability indicating. Various protein characterization methods were used to determine changes in physicochemical properties of rituximab, including size-exclusion chromatography, dynamic light scattering, turbidimetry, cation-exchange chromatography, second-derivative ultraviolet and infrared spectroscopy, and peptide mapping. Cell culture was used to assess biological stability. We demonstrated that diluted rituximab stored at 4 °C in polyolefine bags remained stable for at least six months. No physical or chemical instability was observed, and the biological activity was fully maintained. Size exclusion chromatography did not show polymerization or fragmentation. No difference was noticed in the hydrodynamic diameter of RTX. No additional peak or decrease in the areas under curve was found by cation exchange chromatography. The thermal aggregation curves and their derived thermodynamic parameters were unchanged. The primary, secondary and tertiary structures of the protein were not modified. Finally, the direct cytotoxic effect of rituximab was fully maintained.