Biosimilarity. Do not confuse biosimilar and biocopy. Example of tenecteplase.

Non-innovator biological products (NIBPs) or 'biocopies' are available in several countries at lower prices than biosimilars. These drugs, sometimes so-called 'biosimilars', may not meet all of the quality criteria expected of clinically equivalent products. NIBPs can exhibit major differences in physicochemical and pharmacological properties compared with their reference biological but may be presented to prescribers based on clinical trial data and claimed clinical equivalence. Tenecteplase (TNK-tpA) is a recombinant derivative of tissue plasminogen activator, used as a third-generation thrombolytic agent for treatment of acute myocardial infarction. A TNK-tPA presented as biosimilar to the originator (Metalyse®, Boehringer Ingelheim; TNKase®, Roche/Genentech) is now available for use in India (Elaxim®, Gennova Pharmaceuticals). Elaxim® is not approved in Europe or the USA but has been proposed in several countries as a replacement for the originator. Based on available literature, we discuss why this biocopy cannot be considered biosimilar to the originator tenecteplase. We describe clear differences in physicochemical and pharmacological properties. For example, the biocopy demonstrates clot lysis activity that is substantially lower than the originator and contains high concentrations of foreign proteins that confer potential for immunological reactions. Clinical data on the biocopy are limited; randomized trials to demonstrate the absence of difference in efficacy and safety between the biocopy and originator have not been conducted. This example demonstrates that confirmation of similarity, by close examination of pharmaceutical quality attributes, and preclinical and clinical data, is mandatory before presenting to prescribers a biological product as clinically equivalent.

[Interchangeability and substitution of biosimilars]. / Interchangeabilité et substitution des biosimilaires.

The rationality of the interchangeability of biosimilars is based on broad scientific evidence and numerous clinical experiences in real life which show no sign of reduced efficacy or different tolerance compared to the original molecule. The substitution of biosimilars (pharmaceutical act) remains widely contested in many countries, notably in France. However, it would make it possible to make very significant savings in a context of major acceleration in health spending. This reluctance is unfounded in light of the quality of biosimilars authorized in Europe and their rigorous evaluation. It is therefore essential to improve the information of health professionals and patients on these biosimilars.

_{36}

Prompt γ-ray spectroscopy of the neutron-rich ^{96}Kr, produced in transfer- and fusion-induced fission reactions, has been performed using the combination of the Advanced Gamma Tracking Array and the VAMOS++ spectrometer. A second excited state, assigned to J^{π}=4^{+}, is observed for the first time, and a previously reported level energy of the first 2^{+} excited state is confirmed. The measured energy ratio R_{4/2}=E(4^{+})/E(2^{+})=2.12(1) indicates that this nucleus does not show a well-developed collectivity contrary to that seen in heavier N=60 isotones. This new measurement highlights an abrupt transition of the degree of collectivity as a function of the proton number at Z=36, of similar amplitude to that observed at N=60 at higher Z values. A possible reason for this abrupt transition could be related to the insufficient proton excitations in the g_{9/2}, d_{5/2}, and s_{1/2} orbitals to generate strong quadrupole correlations or to the coexistence of competing different shapes. An unexpected continuous decrease of R_{4/2} as a function of the neutron number up to N=60 is also evidenced. This measurement establishes the Kr isotopic chain as the low-Z boundary of the island of deformation for N=60 isotones. A comparison with available theoretical predictions using different beyond mean-field approaches shows that these models fail to reproduce the abrupt transitions at N=60 and Z=36.

Extended stability of the rituximab biosimilar CT-P10 in its opened vials and after dilution and storage in polyolefin bags.

The stability of the rituximab biosimilar CT-P10, in 50mL vials at a concentration of 10mg/mL, and after dilution to final concentrations of 1 and 4mg/mL and storage in polyolefin bags at 4°C and 25°C was studied by several orthogonal and complementary methods. No significant change (as defined by a magnitude greater than the inter-batch variability) was observed, for each of the parameters characterizing physical and chemical stability studied, for the two concentrations and temperatures tested, or for any of the three batches tested. This implies that cold-chain rupture and exposure to room temperature up to 15 days both for vials and diluted bags have no deleterious consequence on the quality of the product. Moreover, this extended stability permits safe in-advance preparation, dose-banding or flat-dose, that to avoid unnecessary delays in the management of the patient, improvement of the pharmacy and nurse workload and money saving by avoiding non justified losses of this expensive drug.

One-month stability study of a biosimilar of infliximab (Remsima®) after dilution and storage at 4°C and 25°C.

There is currently only one monoclonal antibody for which there is a biosimilar: infliximab, which was released onto the French market in 2015. The SPC for the biosimilar (Remsima®) are superimposable on those of the original, including 24-hour stability at both 4 and 25°C. The aim of our study was to determine the stability of this biosimilar during one month at 4 and 25°C. Three different batches at two concentrations (0.7mg/mL or 1.6mg/mL) were used. Physicochemical stability was evaluated by the following methods: turbidity, UV spectrometry, DLS, ion chromatography (CEX), gel exclusion chromatography (SEC), and light microscopy. The analyses were performed in triplicate. All methods used have been demonstrated to be valid for measuring antibody stability. There were no signs of physicochemical instability after seven days (on D7) of storage at 4 or 25°C. From D15, we observed slight changes by ion (percentage distribution of the different isoforms) and gel exclusion chromatography (percentage distribution of different polymers, i.e. dimers, oligomers). However, the areas under the curves were unchanged, and the proportions of polymers remained lower than 0.5%. Tertiary structure analysis also showed a change from D15. All observed changes are consistent with progressive oligomerization by hydrophobic interactions. In conclusion, the reconstituted biosimilar is stable for seven days at 4 and 25°C. Gradual oligomerization is observed from D15 but appears to be less than 0.5%, suggesting instability, albeit very limited, in the longer term; the practical consequences of this remain to be evaluated.

[Evaluation of professional practices: Implication of hospital pharmacist in improving care for vulnerable patients]. / Évaluation des pratiques professionnelles : implication du pharmacien hospitalier dans l'amélioration de la prise en charge des patients en précarité.

As drug delivery activity to outpatients in precarious situation is rising continuously, the goal of this work was to perform an assessment of the professional practices of the care pathway of these patients, called PASS in France (permanence d'accès aux soins de santé). At first, two pharmacists did an audit of this care pathway. Then, options for improvement were suggested and established after a multidisciplinary work with pharmacists, physicians and social workers of the relevant services. Finally, after six months, those actions and their impact were evaluated. Over a three-year period, the audit showed an increase by a factor of 1.77 of the average number of prescriptions provided per year. Over the same period, the number of dispensed lines was increased by 2.2 and the annual costs were multiplied per 1.82. The pharmacy department suggested several corrective actions: at first, initiating new schedules suited to the activity; then, making adjustments in the reception zone; but also, establishing two new specific prescriptions and 89 helps cards about the most frequently delivered medications. As a result, the time dedicated to drug delivery has been cut in half while the number of pharmaceutical actions remained constant. This assessment of the professional practices showed how hard it is to formalize a transversal circuit as the PASS in hospital. The actions established had improved the organization and the drug delivery activity in the pharmacy department.

[Study impacto: Descriptive analyzis of pharmacist's clinical practice in onco-hematology]. / Étude impacto : analyse descriptive des pratiques de pharmacie clinique en cancérologie.

Pharmaceutical analyses of chemotherapy prescriptions by hospital pharmacists are activities codified by regulation and rules (bon usage). The involvement of the pharmacists in clinical pharmacy activities in the oncology setting is not clearly identified, justifying the development of a mapping of these activities from a questionnaire addressed to the professionals. One hundred and seven centers have participated to this study at the national level (overall participation rate of 32.4%). More than 95% of them used a computerized ordering system and three quarter of them submit the introduction of new compounds to an analysis by the drug therapeutic committee. Prescription analysis allowed detecting around 2% of errors from the current prescription. Clinical pharmacist participates to tumor boards of onco-hematology (RCP) at a level of 46% for senior pharmacist and 42% for junior pharmacist. This involvement in the RCP allowed anticipating protocol's modification and temporary used authorization. Ninety-two percent of the senior pharmacists estimate that they highlight the risk of no reimbursement for prescription out of the guideline during RCP, resulting to a modification of the prescription for 40% of them. This level of intervention is lower with respectively 64% and 10% for the juniors. This study underlines the expert value of the clinical pharmacist dedicated to oncology setting in pre and post analysis prescriptions. It could be targeted by a prospective analysis of both clinical and pharmacoeconomics impact of these interventions.

Implementation of real-time identification analysis and quantification of chemotherapies preparations with a Multispec(®) analyser.

Post-production analytic control of chemotherapies preparations remains a challenge for hospital pharmacists. Indeed, to be feasible, this control needs to be reliable, fast and easy to implement and to use on real life. This is particularly true for teams not familiar with analytic methods. The Multispec(®) analyser has been specially manufactured for that purpose. After several years of daily use, we wanted to focus on its implementation, abilities and defects that should be corrected on the next analyser. Upon 24 months, 23,350 samples have been analysed. Four percent have been rejected on the first analysis, and finally only 0.37% with another sample after homogenization. Eighty-six preparations have been done another time for non-conformity purpose. Difficulties of implementation were in particular on anthracyclins, oxazophosphorins and monoclonal antibodies. However, compared to liquid chromatography for example, the ultraviolet and infrared combination allows a large number of drugs to be recognized and quantified fastly. As a conclusion this analyser is quite helpful and gives a serious alternative to post-production analytic control for chemotherapies preparations. Some points should however be improved, probably on the next analyser, for instance the sample volume necessary for analysis.

Characterization of mitotane (o,p'-DDD)--cyclodextrin inclusion complexes: phase-solubility method and NMR.

Mitotane (o,p'-dichlorodimethyl dichloroethane [o,p'-DDD]) is used for the treatment of adrenocortical cancer and occasionally Cushing's syndrome. This drug is very poorly soluble in water, and following oral administration, approximately 60% of the dose is recovered in the feces unaltered. The preparation of a soluble formulation (i.e. by complexation with cyclodextrins) with improved bioavailability is the aim of this work. The inclusion of mitotane in methyl-ß-cyclodextrins was studied using both phase-solubility methods and NMR experiments. To elucidate the inclusion mechanism, o,p'-DDD was compared to its regioisomer (i.e. p,p'-DDD). It was demonstrated that two dimethyl-ß-cyclodextrins (DMßCD) can complex with the aromatic rings. From the phase-solubility diagrams, we observe that both cases are very different: K(1:1) is between 37 000 and 85 000 mol.l(-1), whereas K(1:2) is between 5.3 and 32 mol.l(-1). The NMR experiments confirmed the inclusion but it also gave an insight into the kinetics of the dissociation: the ortho-chloro moiety is in slow exchange on the NMR time scale, whereas the para-chloro moiety is in fast exchange rate.

Physicochemical stability study of a new Trimix formulation for treatment of erectile dysfunction.

Currently, severe erectile dysfunction can be treated by intracavernous injections of solutions containing three active ingredients: prostaglandin E1 (PGE1), papaverine and urapidil. Very few data exist on this mixture where phentolamine has been replaced by Urapidil because Phentolamine is not used for this indication in France. The aim of our study was to assess the stability of this formulation and to extend its expiration to permit preparation of batches. Three batches of the preparation containing 15µg/mL PGE1, 15mg/mL of papaverine and 2mg/mL urapidil were made aseptically and then packed in polypropylene syringes stored at 4°C. The physico-chemical stability has been tested as follows: HPLC stability-indicating method, visual observation, measurement of pH and osmolarity. We found that the limiting factor was PGE1 and we exceeded the threshold of 10% loss after 55 days. Replacement of Urapidil by Phentolamine seems to have a slight detrimental effect on stability. Nevertheless, these results allow us to consider the advance preparation of this formulation and provide quality treatment to these patients by avoiding too frequent visits to the hospital.

[Evaluation of ownership of an implantable medical device by patients]. / Évaluation de l'appropriation d'un dispositif médical implantable par les patients.

INTRODUCTION: In order to improve the care of patients with pacemakers or defibrillators, a survey was realized to assess the adherence of the cardiac implant of patients PATIENTS AND METHOD: A survey was proposed to assess the level of information assimilation of patients' implant (indication of installation, precautions and conduct...) by patients presenting within the Cardiology Department concerning a first implantation or a change in the device. RESULTS: Early results show that 84% of patients have an indication of implant placement. Only 55% know that they must notify to the medical team they have a cardiac implant, especially when needing MRI. In case of a shock, only 35% of patients with defibrillator know how to behave. The majority of patients say they consult when signs of infection occur or when symptoms reappear. DISCUSSION: The results show that patients are generally well informed about the main precautions and have a good knowledge of their implant. Nevertheless, messages about "what to do if" are not well known. Patients with defibrillators have better assimilated the information than patient with pacemakers. CONCLUSION: Our approach has to account for the level of information and the degree of assimilation of information by patients. It is part of the development of patient's therapeutic education.

SFPO and ESOP recommendations for the practical stability of anticancer drugs: an update.

The recommendations for the practical stability of anticancer drugs published in 2010 by the French Society of Hospital Pharmacists (SFPO) and the European Society of Oncology Pharmacists (ESOP) have been updated. Ten new molecules have been included (asparaginase, azacitidine, bevacizumab, clofarabine, eribuline mesylate, folinate sodium, levofolinate calcium, nelarabine, rituximab, temsirolimus).

Long-term stability of bevacizumab repackaged in 1mL polypropylene syringes for intravitreal administration.

INTRODUCTION: The anti-angiogenic monoclonal antibody, bevacizumab, is currently used by intravitreal administration as off-label drug to treat age-related macular degeneration or other ophthalmologic diseases. For this purpose, commercial bevacizumab is repackaged in 1mL polypropylene syringes under sterile conditions. However, no complete study on the stability of this hospital-based preparation is available. METHODS: Commercial bevacizumab (25mg/mL; Avastin(®)) was aseptically repackaged in 1mL polypropylene syringes, stored at 4°C, and analyzed within the preparation day (D0), after 30 days (D30) and 90 days (D90). Some syringes were kept for up to 8 months to observe possible instability. Several complementary and stability-indicating analytical methods were used to assess in details the primary, secondary and tertiary structure of the antibody during its conservation: ionic chromatography, size-exclusion chromatography, peptide mapping, 2nd derivative UV and IR spectroscopy, turbidimetry, diffraction laser spectroscopy, thermal denaturation curves, microscopic examination and image analysis. RESULTS: We clearly demonstrate that the commercial solution of bevacizumab can be safely repackaged in polypropylene syringes and stored up to 3 months at 4°C without alteration of its primary, secondary and tertiary structure. The only difference observed is the contamination of the syringe content by silicone oil microdroplets, which is quite immediate and does not change significantly during the storage in terms of number and size. CONCLUSION: Our results support the off-label use of repackaged bevacizumab by intravitreal administration, at least from a pharmaceutical point of view, with a validated stability of 3 months. This stability period is largely enough to practical situations and support current practices, such as in advance or batch preparations, which present major advantages in terms of GMP respect, workload optimization and financial savings.

Guidelines for the practical stability studies of anticancer drugs: a European consensus conference.

Stability studies performed by the pharmaceutical industry are only designed to fulfill licensing requirements. Thus, post-dilution or -reconstitution stability data are frequently limited to 24h only for bacteriological reasons regardless of the true chemical stability which could, in many cases, be longer. In practice, the pharmacy-based centralized preparation may require infusions to be made several days in advance to provide, for example, the filling of ambulatory devices for continuous infusions or batch preparations for dose banding. Furthermore, a non-justified limited stability for expensive products is obviously very costly. Thus, there is a compelling need for additional stability data covering practical uses of anticancer drugs. A European conference consensus was held in France, May 2010, under the auspices of the French Society of Oncology Pharmacy (SFPO) to propose adapted rules on stability in practical situations and guidelines to perform corresponding stability studies. For each anticancer drug, considering their therapeutic index, the pharmacokinetics/pharmacodynamics (PK/PD) variability, specific clinical use and risks related to degradation products, the classical limit of 10% of degradation can be inappropriate. Therefore, acceptance limits must be clinically relevant and should be defined for each drug individually. Design of stability studies has to reflect the different needs of the clinical practice (preparation for the week-ends, outpatient transportations, implantable devices, dose banding…). It is essential to use validated stability-indicating methods, separating degradation products being formed in the practical use of the drug. Sequential temperature designs should be encouraged to replicate problems seen in daily practice such as rupture of the cold-chain or temperature-cycling between refrigerated storage and ambient in-use conditions. Stressed conditions are recommended to evaluate not only the role of classical variables (pH, temperature, light) but also the mechanical stress. Physical stability such as particles' formation should be systematically evaluated. The consensus conference focused on the need to perform more studies on the stability of biotherapies, including a minimum of three complementary separating methods and a careful evaluation of submicron aggregates. The determination of the biological activity of proteins could be also useful. A guideline on the practical stability of anticancer drugs is proposed to cover current clinical and pharmaceutical practice. It should contribute to improved security of use, optimization of centralized handling and reduced costs. Finally, we have attempted to establish a new drug stability paradigm based on practical clinical needs, to complement regulatory guidelines which are essentially orientated to the stability of manufactured drugs.

Novel manifestation of alpha-clustering structures: new "alpha+208Pb" states in 212Po revealed by their enhanced E1 decays.

Excited states in 212Po were populated by alpha transfer using the 208Pb(18O,14C) reaction, and their deexcitation gamma rays were studied with the Euroball array. Several levels were found to decay by a unique E1 transition (Egamma<1 MeV) populating the yrast state with the same spin value. Their lifetimes were measured by the Doppler-shift attenuation method. The values, found in the range 0.1-1.4 ps, lead to very enhanced transitions, B(E1)=2x10(-2)-1x10(-3) W.u. These results are discussed in terms of an alpha-cluster structure which gives rise to states with non-natural-parity values, provided that the composite system cannot rotate collectively, as expected in the "alpha+208Pb" case. Such states due to the oscillatory motion of the alpha-core distance are observed for the first time.

Two-particle separation energy trends in the superdeformed well.

A measurement of the energy and spin of superdeformed states in 190Hg, obtained through the observation of transitions directly linking superdeformed and normal states, expands the number of isotopes in which binding energies at superdeformation are known. Comparison with neighboring nuclei shows that two-proton separation energies are higher in the superdeformed state than in the normal state, despite the lower Coulomb barrier and lower total binding energy. This unexpected result provides a critical test for nuclear models.