Reports Of Hypersensitivity Reactions Research Articles

Safety and tolerability of intravenous aprepitant and fosaprepitant in children with cancer: A retrospective, single-center review.

NK-1 receptor antagonists (NK1-RA) are key agents for chemotherapy-induced nausea and vomiting (CINV) prevention in patients receiving highly emetogenic chemotherapy. Current pediatric practice guidelines recommend the use of intravenous fosaprepitant or oral aprepitant. However, there are reports of hypersensitivity reactions with fosaprepitant due to polysorbate 80. Intravenous aprepitant does not contain polysorbate 80, but its use in pediatric patients has not been described. In this retrospective, single-center study, 106 pediatric patients received either fosaprepitant or intravenous aprepitant as part of their antiemetic regimen. Intravenous aprepitant was well tolerated and did not lead to any instances of hypersensitivity reactions requiring discontinuation.

Hypersensitivity reactions amongst Hungarian Patients with Hereditary Angioedema due to C1-Inhibitor Deficiency

BackgroundIn hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE), bradykinin-mediated submucosal and/or subcutaneous angioedema dominates the clinical picture. The deficiency of C1-inhibitor can lead to the over-activation of the complement system. Complement plays an important role in all types of hypersensitivity reactions. On the other hand, during the degranulation of mast cells, heparin is also released amongst other substances. Heparin can activate the plasma kinin-kallikrein system, leading to bradykinin generation. These observations suggest a possible connection between C1-INH-HAE and mast cell-mediated hypersensitivity reactions. ObjectiveTo assess the occurrence of hypersensitivity reactions in the Hungarian C1-INH-HAE population. MethodsPatients filled out a questionnaire of 112 questions, either online or on paper. The questions were about hypersensitivity and C1-INH-HAE symptoms, the relation between these 2, general health, and demographic data. The study protocol was approved by the institutional review board of Semmelweis University, Budapest, and informed consent was obtained from the participants. ResultsOne hundred and six patients (64 female, 42 male, median age 46 years) responded, with 63.2% having hypersensitivity. Hypersensitivity was provoked by pollen in 25.5% of patients, by contact sensitivity in 22.6%, by food in 21.7%, by insect sting in 19.8%, by pet in 15.1%, by drug in 14.2%, by dust mite in 5.7%, and by mold in 1.9%. In 11 patients, hypersensitivity symptoms appeared after the diagnosis of C1-INH-HAE. Six hypersensitive patients experienced improvement in their symptoms; 42 remained the same, but none experienced worsening after the diagnosis of C1-INH-HAE. In 7.8% of the hypersensitive patients, a C1-INH-HAE attack worsened the hypersensitivity symptoms, while 15.7% of the hypersensitive patients experienced a C1-INH-HAE attack provoked by contact with the provoking factor. ConclusionWhile 63.2% of our C1-INH-HAE patients have reported hypersensitivity symptoms, Eurostat's latest data puts the prevalence of self-reported allergies in Hungary at 19.3%. Since in our experience most Hungarian patients report hypersensitivity reactions as allergies, this may support a possible connection between the 2 diseases, but further molecular studies are needed.

Processionary caterpillar reactions in Southern Italy forestry workers: description of three cases

BackgroundProcessionary caterpillar (PC), also named Thaumatopea pityocampa, has been reported to cause hypersensitivity reactions after contact with a toxin contained in hair-like bristles which cover this insect. Occupational exposure to PC is underestimated in outdoor workers and especially in forestry workers (FW) and is globally diffusing because of rising temperatures.Cases presentationWe present the first three cases of FW from Sicily, a Southern Italy (SI) region, which reported hypersensitivity reactions due to exposure to PC infested trees. These cases were identified by the occupational health physician during the annual screening of FW working in the Mountains of north-eastern Sicily. Interviewing a population of 630 FW, 1 male and 2 females reported direct contact skin reactions together with airborne contact reactions to PC hairs causing mild respiratory symptoms in two cases and ocular symptoms in one case, which needed treatment with systemic corticosteroids and antihistamines.ConclusionsThis is the first report of hypersensitivity reactions in SI FW due to occupational exposure to PC. Further screenings not only in FW but also in other populations of outdoor workers are needed in order to assess the real incidence of contact and airborne reactions due to occupational exposure to PC. Though so far no correlation has been found with atopy, it seems apparent that the reactions occur in susceptible subjects; further research is needed for a correct diagnosis and to identify possible desensitization procedures.

Hypersensitivity Reactions to Vaccines: Current Evidence and Standards for SARS-CoV-2 Vaccines.

The first reports of hypersensitivity reactions following the rollout of COVID-19 vaccination programs have raised public concern. Given the recent availability and novel mechanisms of COVID-19 vaccines, there is limited data on possible hypersensitivity reactions. Although it seems rare, the incidence of anaphylaxis for approved COVID-19 vaccines has been suggested as being higher when compared to previous vaccines. Adequate risk assessment, recognition, classification, and management of hypersensitivity reactions is crucial to ensure safe immunization and avoid misinformation and vaccine hesitancy. In this review, we present an overview of the types of hypersensitivity reactions that can potentially occur due to vaccination and the possible allergenic components of COVID-19 vaccines, as well as a suggestion for causality and risk assessment for the BNT162b2, mRNA-1273 and AZD1222 vaccines.

Hypersensitivity in patients receiving metal implants: a scoping review protocol.

The objective of this scoping review is to gather the available evidence on metal hypersensitivity to determine the extent of the problem and identify gaps in the evidence about screening practices. Hypersensitivity to metal was first reported in 1966. Since this time, the use of metal in prosthetic devices has increased with an associated rise in reported hypersensitivity reaction to other metals. Symptoms of metal hypersensitivity can be subtle, and it is unclear whether clinicians are aware of or routinely ask patients about metal hypersensitivity when documenting allergies. This can lead to a delay in diagnosis, which puts patients at risk of poor outcomes. Hence, there is a need to map the available evidence on hypersensitivity reaction in people who receive metallic device implantation. The review will consider studies that include patients who undergo procedures involving metal implantation. The concept to be explored is hypersensitivity following a procedure that involves the implementation of a device with metal components. Implementation is defined as permanent integration of a foreign (non-biological) object into the human body to restore function. The proposed scoping review will be conducted in accordance with JBI methodology for scoping reviews. Searches will be generated in multiple databases and updated as needed. Gray literature and organizational websites will also be searched. Titles, abstracts, and full articles will be screened according to the inclusion criteria. Studies published in English from 1960 to the present will be included. Data will be extracted and findings will be presented in tabular form with a narrative summary.

A quality improvement intervention to increase the use of first line antibiotic for prevention of surgical site infections in patients with penicillin allergy labels

BackgroundPerioperative use of cephalosporins is avoided in patients with penicillin (PCN) allergy labels due to concern for cross-reactivity and shared hypersensitivity. However, second line antibiotics are associated with higher risk of surgical site infections, higher cost, and higher incidence of antibiotic-related adverse events. PurposeQuality improvement interventions incorporating a novel screening tool were implemented to increase the proportion of PCN allergy labeled patients who received first line perioperative prophylaxis with cephalosporins. MethodsInterventions were aimed at the anesthesia team members (MD/CRNA) and included education about penicillin allergy labels and cross reactivity (handouts, lectures, emails), introduction and explanation of the screening tool, and team-based accountability and behavioral interventions during a three-month period. After implementation, data was collected for the ensuing six months to assess for change in practice. Demographic information and patient-reported PCN allergy reaction data were collected via the electronic medical record. Documentation of adverse reaction to penicillin intraoperatively was collected via review of the anesthesia records. ResultsA total of 4391 patient records were assessed from September 2018 through February 2020. The percentage of PCN allergic patients receiving first line cephalosporin increased from 35% at baseline to 72% 6 months post-intervention without any reported hypersensitivity reactions. ConclusionOur intervention resulted in a significant increase in the proportion of patients with PCN allergy labels who received first line cephalosporins at our institution.

Clinical Characterization and Diagnostic Approaches for Patients Reporting Hypersensitivity Reactions to Quinolones

Quinolones are the second most frequent cause of hypersensitivity reactions (HSRs) to antibiotics. A marked increase in the number of patients with HSRs to quinolones has been detected. To describe the clinical characteristics of patients with HSRs to quinolones and present methods for their diagnosis. Patients attending the allergy unit due to reactions suggestive of HSRs to quinolones were prospectively evaluated between 2005 and 2018. Diagnosis was achieved using clinical history, skin tests (STs), basophil activation tests (BATs), and drug provocation tests (DPTs) if ST and BAT results were negative. We included 128 subjects confirmed as having HSRs to quinolones and 42 found to be tolerant. Anaphylaxis was the most frequent entity in immediate HSRs and was most commonly induced by moxifloxacin. Patients were evaluated a median of 150 days (interquartile range, 60-365 days) after the reaction. Of patients who underwent ST and BAT, 40.7% and 70%, respectively, were positive. DPT with a quinolone was performed in 48 cases, giving results depending on the culprit drug: when moxifloxacin was involved, 62.5% of patients gave a positive DPT result to ciprofloxacin, whereas none reacted to levofloxacin. The risk of HSR was 96 times higher in subjects who reported moxifloxacin-induced anaphylaxis and 18 times higher in those reporting immediate reactions compared with clinical entities induced by quinolones other than moxifloxacin and nonimmediate reactions. The diagnosis of HSR to quinolones is complex. The use of clinical history is essential as a first step. BAT shows higher sensitivity than STs. DPTs can be useful for finding safe alternative quinolones.

Non-β-Lactam Antibiotic Hypersensitivity Reactions.

Antibiotics are among the most common prescriptions in children, and non-β-lactam antibiotics (NBLAs) account for almost half of those prescribed in Australian pediatric hospitals. Despite this, data on NBLA hypersensitivity in children are limited. This study describes reported hypersensitivity reactions to NBLAs in children and the results of allergy evaluation. Children with a suspected NBLA allergy who had skin testing and/or an intravenous or oral challenge test (OCT) between May 2011 and June 2018 were included. Patients were excluded if they were >18 years old or did not complete the allergy evaluation for any reason other than allergic reaction. Over the 7-year study period, 141 children had 150 allergy evaluations of 15 different NBLAs. The median time from the initial reported reaction to allergy evaluation was 1.9 (range 0.1-14.9) years. Overall, 27 of the 150 (18.0%) challenge tests to NBLAs had positive results, with the rate of positive OCT results being highest for trimethoprim-sulfamethoxazole (15 of 46; 32.6%) and macrolides (8 of 77; 10.4%). Although 4 children reported initial anaphylactic reactions, no patients had severe symptoms on rechallenge or required adrenaline. Of the challenges that had positive results, the majority of children (23 of 27; 85.2%) had symptoms on repeat challenge similar to those that were initially reported. Overall, 8 of 10 children with NBLA allergy could be delabeled. On average, patients waited 1.9 years to be rechallenged. Timely access to allergy evaluation to delabel these patients is needed to preserve first-line antibiotics.

The Allergic Bone Marrow? The Immuno-Capacity of the Human Bone Marrow in Context of Metal-Associated Hypersensitivity Reactions.

Arthroplasty ranks among the greatest achievements of surgical medicine, with total hip replacement termed “the operation of the century.” Despite its wide success, arthroplasty bears risks, such as local reactions to implant derived wear and corrosion products. Prevalence of allergies across Western society increases and along the number of reported hypersensitivity reactions to orthopedic implant materials. In this context the main focus is on delayed hypersensitivity (DTH). This mechanism is mainly attributed to T cells and an overreaction of the adaptive immune system. Arthroplasty implant materials are in direct contact with bone marrow (BM), which is discussed as a secondary lymphoid organ. However, the mechanisms of sensitization toward implant wear remain elusive. Nickel and cobalt ions can form haptens with native peptides to activate immune cell receptors and are therefore common T helper allergens in cutaneous DTH. The rising prevalence of metal-related allergy in the general population and evidence for the immune-modulating function of BM allow for the assumption hypersensitivity reactions could occur in peri-implant BM. There is evidence that pro-inflammatory factors released during DTH reactions enhance osteoclast activity and inhibit osteoblast function, an imbalance characteristic for osteolysis. Even though some mechanisms are understood, hypersensitivity has remained a diagnosis of exclusion. This review aims to summarize current views on the pathomechanism of DTH in arthroplasty with emphasis on BM and discusses recent advances and future directions for basic research and clinical diagnostics.

Hypersensitivity reactions to antiepileptic drugs in children.

Antiepileptic drugs (AEDs) can cause hypersensitivity reactions in children. These reactions are mainly cutaneous, self-limiting, and benign, but life-threatening severe cutaneous adverse reactions can occur. Infections can lead to skin eruptions and mimic drug hypersensitivity reactions, if a drug is taken at the same time. The aims of our study were to confirm or rule out the diagnosis of hypersensitivity reactions to AEDs in children and to detect an infection which mimics these reactions. A prospective survey was conducted in a group of 100 children with histories of hypersensitivity reactions to AEDs by performing patch tests, delayed-reading intradermal test, and, in case of negative results, challenge test. In all children, a study was performed to detect infections by viruses or Mycoplasma pneumoniae. Maculopapular exanthema and delayed-appearing urticaria were the most reported hypersensitivity reactions to AEDs. Sixty-six (66%) of 100 children had confirmed hypersensitivity reactions to AEDs. Fifty-nine children had positive patch test. No children had positive challenge tests. The most common AEDs causing hypersensitivity reactions were carbamazepine (45.4%) and lamotrigine (43.6%). Thirty-two children had positive tests for viruses or Mpneumoniae, and nine of them had also a positive allergy work-up. Considering that there are no specific tests to distinguish between a viral infection and hypersensitivity reactions to AEDs in the acute phase, a diagnostic work-up should be performed in all children with suspected hypersensitivity reactions to AEDs, as well as infectious agent study, to remove a false label of hypersensitivity.

Cyclo-oxygenase selectivity and chemical groups of nonsteroidal anti-inflammatory drugs and the frequency of reporting hypersensitivity reactions: a case/noncase study in VigiBase.

To date, no reports of hypersensitivity reactions (HSRs) among nonsteroidal anti‐inflammatory drugs (NSAIDs) according to cyclo‐oxygenase (COX) selectivity and chemical groups have been published in a single study. The present study assessed the reporting frequency of HSRs for NSAIDs based on their relative inhibitory potency toward COX enzymes and chemical groups, including the presence/absence of a functional sulfonamide group, in strata observed 5 years after market authorization. A case/noncase study was performed among individual case safety reports (ICSRs) with NSAIDs as suspected drugs in VigiBase, the WHO spontaneous reporting database. Cases were ICSRs mentioning angioedema and anaphylactic/anaphylactoid shock conditions, while noncases were ICSRs without HSRs. NSAIDs were categorized into (i) NSAIDs with high COX‐2 selectivity (coxibs), (ii) noncoxib NSAIDs with COX‐2 preference, (iii) NSAIDs with poor selectivity, or (iv) NSAIDs with unknown selectivity. Chemical groups were defined based on the Anatomical Therapeutic Chemical classification system and the presence/absence of a functional sulfonamide group. Reporting odds ratios (RORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression analysis. We identified 13 229 cases and 106 444 noncases. In the first 5 years after marketing, poor‐selectivity NSAIDs and acetic acid derivatives were associated with the highest ROR of HSRs (age‐ and sex‐adjusted ROR 2.12, 95% CI 1.98–2.28; and ROR 2.21, 95% CI 1.83–2.66, respectively) compared with coxibs, and sulfonamide NSAIDs were associated with the highest ROR of HSRs compared with nonsulfonamide NSAIDs (age‐ and sex‐adjusted ROR 1.38, 95% CI 1.29–1.47). After the first 5 years of marketing, most of the RORs returned to approximately 1.

Prevalence of Hypersensitivity Reactions in Children Associated with Acetaminophen: A Systematic Review and Meta-Analysis

Background: Acetaminophen is the most commonly used antipyretic in children. However, there are limited data assessing hypersensitivity reactions related to acetaminophen usage. Objectives: To conduct a systematic review to characterize reported reactions to acetaminophen in adults and children, and perform a meta-analysis to assess the prevalence of acetaminophen hypersensitivity in children with a suspected acetaminophen allergy. Methods: We performed a systematic review of studies reporting hypersensitivity reactions to acetaminophen by searching 2 electronic databases. From the selected studies, we included those assessing the prevalence of acetaminophen hypersensitivity by performing oral challenge in our meta-analysis. Results: Eighty-five studies were included in the systematic review, assessing a total of 1,030 participants. Immediate (within 1 h of exposure) hypersensitivity reactions were reported in > 25% of the articles, while cutaneous nonimmediate reactions were similarly reported in about 25% of the articles. The remaining articles reported Steven-Johnson syndrome/toxic epidermal necrolysis, fixed drug eruptions, and cross-intolerance reactions. Five pediatric studies were included in our meta-analysis. The prevalence of acetaminophen hypersensitivity reaction among children undergoing oral challenge was 10.1% (95% confidence interval 4.5–15.5). Conclusion: Future studies assessing the risk of immediate and nonimmediate hypersensitivity reactions to acetaminophen and elucidating the mechanism of acetaminophen hypersensitivity reactions are required.

Incidence of Hypersensitivity Reactions During Hemodialysis

Background/Aims: A recent alert from Spanish health authorities warned of a higher incidence of reported hypersensitivity reactions to hemodialysis membranes with polysulfone, in the 2017 review of acute reactions to dialyzers found only published reports in the 21^st century on polysulfone and its derivatives. The aim is to assess/evaluate the current incidence and characteristics of hypersensitivity reactions in hemodialysis patients. Methods: A retrospective multicentre study in 9 Spanish hospitals evaluated patients in whom a hypersensitivity reaction required a change in dialyzer membrane. Results: A total of 37 patients out of 1561 (2.37%) had hypersensitivity reactions and clinical, epidemiological and analytical data were available for 33 patients (2.11%). The membranes involved were polysulfone (n=23), polynephron (n=8), polyethersulfone (n=1) and polyacrylonitrile (n=1). This distribution reflected the frequency of use of membranes in the participating dialysis units. The reactions were described as type A in 18 cases and type B in 15 cases. There were no significant differences between the two types in clinical symptoms, the composition of the membrane involved, the method of sterilization, the season, or the time during the session in which they occurred. The most frequent symptom was dyspnea/breathlessness (64% of reactions). Eosinophilia was common (74%). 54% of the reactions occurred within the first 30 minutes of hemodialysis, 64% occurred during the first year of dialysis, and 54% required discontinuation of dialysis session. Cellulose triacetate was used as an alternative dialyzer in 78% of the cases. Conclusion: The incidence of hypersensitivity reactions was in the range found in reports from 20 years ago and is observed associated with synthetic membranes, not just polysulfones. Cellulose triacetate appears to be a good alternative for these patients.

Methotrexate hypersensitivity reactions in pediatrics: Evaluation and management

Reports of hypersensitivity reactions (HSRs) to MTX are limited to single case studies. We retrospectively reviewed HSRs to MTX during a 12-year period in our tertiary care pediatric center. Seven patients were evaluated for HSRs to MTX. Skin testing was positive in one of the four patients tested. One patient underwent successful graded challenge to MTX. Seventeen desensitizations to MTX were successfully performed in the other six patients. Skin testing, graded challenge, and desensitization were safe and effective procedures in the evaluation and management of patients with HSRs to MTX in our pediatric population.

Cross-reactivity between carbapenems: Two case reports

Carbapenems (imipenem, meropenem, and ertapenem) (Figure 1) are broad-spectrum b-lactam antibiotics. They are typically used as second-line treatment for severe polymicrobial and resistant bacterial infections in hospitals. The antimicrobial spectrum of imipenem and meropenem is similar, with coverage of most of the gram-positive cocci, gram-negative bacilli, and anaerobic microorganisms. Imipenem is inactivated in the kidneys and produces a nephrotoxic metabolite, so it is formulated (in 1:1 proportion) with cilastatin, an enzymatic inhibitor of human dehydropeptidase-I, that blocks its metabolism in the kidneys, which increases levels of drug in the urine and reduces its toxicity. Meropenem and ertapenem are compounds with a methyl group at C1 and are resistant to the kidney enzymes that inactivate imipenem. The frequency of reported hypersensitivity reactions to carbapenems is estimated to be approximately 2% to 3% per therapeutic exposure. It is unknown if there is significant T-cellemediated immunologic cross-reactivity between individual carbapenems. We present 2 cases of delayed onset, apparently T-cellemediated, serious cutaneous adverse reactions associated with imipenem and meropenem use.

Hypersensitivity associated with sugammadex administration: a systematic review.

Sugammadex is a drug used to reverse neuromuscular blockade induced by rocuronium or vecuronium. It has not yet been approved by the Food and Drug Administration in the USA due to concerns regarding hypersensitivity. The objective of this review was to identify similarities in the presentation of hypersensitivity reactions to sugammadex. A comprehensive search was performed in PubMed, Scopus and Web of Science for cases reporting hypersensitivity reactions to sugammadex. In addition, we contacted regulatory agencies and the company marketing the drug for unpublished reports. Reports were included if they were in English, primary investigations, lacked an alternative probable explanation for the reaction and included a comprehensive description of the hypersensitivity. We identified 15 cases of hypersensitivity following sugammadex administration. All cases that reported exact timing (14/15) occurred in 4min or less. Most of the patients (11/15; 73%) met World Anaphylaxis Organization criteria for anaphylaxis. Awareness must be raised for the possibility of drug-induced hypersensitivity during the critical 5-min period immediately following sugammadex administration.

Hypersensitivity Reactions Associated With Fidaxomicin Use

We report hypersensitivity reactions associated with fidaxomicin, an antibacterial drug approved for the treatment of Clostridium difficile-associated diarrhea. These reactions are viewed as significant because of severity and unexpected because fidaxomicin is minimally absorbed. The fidaxomicin labeling was revised to include information about the possibility of hypersensitivity reactions.

Immediate hypersensitivity reactions following monovalent 2009 pandemic influenza A (H1N1) vaccines: Reports to VAERS

BackgroundHypersensitivity disorders following vaccinations are a cause for concern. ObjectiveTo determine the type and rate by age, gender, and vaccine received for reported hypersensitivity reactions following monovalent 2009 pandemic influenza A (H1N1) vaccines. DesignA systematic review of reports to the Vaccine Adverse Event Reporting System (VAERS) following monovalent 2009 pandemic influenza A (H1N1) vaccines. Setting/patientsUS Civilian reports following vaccine received from October 1, 2009 through May 31, 2010. MeasurementsAge, gender, vaccines received, diagnoses, clinical signs, and treatment were reviewed by nurses and physicians with expertise in vaccine adverse events. A panel of experts, including seven allergists reviewed complex illnesses and those with conflicting evidence for classification of the event. ResultsOf 1984 reports, 1286 were consistent with immediate hypersensitivity disorders and 698 were attributed to anxiety reactions, syncope, or other illnesses. The female-to-male ratio was ≥4:1 for persons 20-to-59 years of age, but approximately equal for children under 10. One hundred eleven reports met Brighton Collaboration criteria for anaphylaxis; only one-half received epinephrine for initial therapy. The overall rate of reported hypersensitivity reactions was 10.7 per million vaccine doses distributed, with a 2-fold higher rate for live vaccine. LimitationsUnderreporting, especially of mild events, would result in an underestimate of the true rate of immediate hypersensitivity reactions. Selective reporting of events in adult females could have resulted in higher rates than reported for males. ConclusionsAdult females may be at higher risk of hypersensitivity reactions after influenza vaccination than men. Although the risk of hypersensitivity reactions following 2009 pandemic influenza A (H1N1) vaccines was low, all clinics administering vaccines should be familiar with treatment guidelines for these adverse events, including the use of intramuscular epinephrine early in the course of serious hypersensitivity reactions.

Is an Alternative Drug Delivery System Needed for Docetaxel? The Role of Controlling Epimerization in Formulations and Beyond

The presence of 7-epidocetaxel in docetaxel injection and in vivo epimerisation has been reported to be the cause for development of tumor resistance to chemotherapy including docetaxel by inducing tumor cell protein cytochrome P450 1B1. The objective of this study was to determine systemic toxicity of Taxotere® containing 10% 7-epidocetaxel and to develop PEGylated liposomal injection that could resist epimerization in vivo. Another need for PEGylated liposomal delivery of docetaxel is to avoid reported hypersensitivity reactions of marketed products like Taxotere® and Duopafei® containing high concentration of tween-80. The PEGylated liposomes loaded with docetaxel were prepared using thin film hydration method. The in vivo toxicity of Taxotere® containing 10% 7-epimer was studied in B16F10 experimental metastasis model. B16F10 experimental metastasis model using C57BL/6 mice injected with Taxotere® containing 10% 7-epimer showed higher weight loss as compared to Taxotere® containing no epimer at single dose of 40 mg/kg indicating higher systemic toxicity. Incubation of PEGylated liposomes with phosphate buffer saline (pH 7.4) containing 0.1% w/v Tween-80 for 48 h showed better resistance to docetaxel degradation when compared with Taxotere® injection indicating better in vivo stability of liposomal docetaxel. In addition, PEGylated liposomes showed enhanced in vitro cytotoxicity, against A549 and B16F10 cells, than Taxotere®. We can therefore expect less in vivo conversion of liposomal loaded docetaxel into 7-epimer, more passive targeting to tumor tissues, decreased 7-epimer induced systemic toxicity and tumor resistance to chemotherapy compared to Taxotere®. Further in vivo studies are needed to ascertain these facts.

Phase I study of weekly treatment with paclitaxel injection concentrate for nanodispersion (PICN), a novel solvent and protein-free formulation of paclitaxel.

3039 Background: PICN is a novel solvent and protein-free 100-110 nm particle formulation of paclitaxel stabilized with polymer and lipid using Nanotecton Technology. Paclitaxel has shown superior safety and efficacy profile when administered on a weekly schedule. We studied safety, tolerability, and pharmacokinetics (PK) of PICN using a weekly schedule in patients with advanced solid malignancies. Methods: Patients aged18-65 years with advanced solid malignancies, ECOG performance status ≤ 2, estimated survival ≥ 12 weeks, and adequate organ function were enrolled. A standard phase I, 3+3 dose escalation design to determine the maximum tolerated dose (MTD) of PICN administered on a weekly schedule (three consecutive weeks, one week recovery) was employed. PICN dose was escalated at pre-determined fixed dose levels of 80, 100, 125, 150, 175, and 200 mg/m2. PICN was administered as a 30 min infusion without any premedication for hypersensitivity. Results: Twenty-one patients treated with PICN had a mean age of 52.1 yrs (range 35-67); 20 were female and entered with metastatic breast cancer (MBC; n=15), cervical cancer (n=3), skin cancer (n=2). One male had oral cancer. Doses studied were 80 (n=3), 100 (n=3), 125 (n=3), 150 (n=3), 175 (n=6), and 200 (n=3) mg/m2. Despite the lack of dexamethasone premedication, no patient receiving PICN reported hypersensitivity reaction. Two DLTs (neutropenia and febrile neutropenia; both grade 3) were reported at PICN 200 mg/m2. PICN PK (AUC0-24, AUC0-∞, and Cmax) increased in a dose proportionate manner from 80 to 200 mg/m2. Grade 3 or worse related AEs were: neutropenia, leucopenia, peripheral neuropathy, febrile neutropenia, anemia, thrombocytopenia, fatigue, syncope, hypotension and maculopapular rash. Partial responses were observed in MBC (100, 125, 150, 175, and 200 mg/m2) and cervical cancer (80 mg/m2). Conclusions: PICN on thrice monthly schedule was tolerable in the dose range evaluated. Two DTLs were reported: neutropenia and febrile neutropenia (both grade 3). Anti-tumor activity was observed in MBC and cervical cancer. Final trial data for PICN PK, safety, and efficacy will be presented at the conference. Clinical trial information: CTRI/2011/11/002124.