Publications by authors named "Michael Leach"

68 Publications

Functional outcomes following an in-hospital cardiac arrest: A retrospective cohort study.

Aust Crit Care 2021 Aug 25. Epub 2021 Aug 25.

School of Rural Health, Faculty of Medicine, Nursing and Health Sciences, Monash University, Bendigo, Victoria, Australia. Electronic address:

Background/purpose: Whilst much is known about the survival outcomes of patients that suffer an in-hospital cardiac arrest (IHCA) in Australia very little is known about the functional outcomes of survivors. This study aimed to describe the functional outcomes of a cohort of patients that suffered an in-hospital cardiac arrest (IHCA) and survived to hospital discharge in a regional Australian hospital.

Methods: This is a single-centre retrospective observational cohort study conducted in a regional Australian hospital. All adult patients that had an IHCA in the study hospital between 1 Jan 2017 and 31 Dec 2019 and survived to hospital discharge were included in the study. Functional outcomes were reported using the Modified Rankin Scale (mRS), a six-point scale for which increasing scores represent increasing disability. Scores were assigned through a retrospective review of medical notes.

Results: Overall, 102 adult patients had an IHCA during the study period, of whom 50 survived to hospital discharge. The median age of survivors was 68 years, and a third had a shockable initial arrest rhythm. Of survivors, 47 were able to be assigned both mRS scores. At discharge, 81% of patients achieved a favourable functional outcome (mRS 0-3 or equivalent function at discharge equal to admission).

Conclusions: Most survivors to hospital discharge following an IHCA have a favourable functional outcome and are discharged home. Although these results are promising, larger studies across multiple hospitals are required to further inform what is known about functional outcomes in Australian IHCA survivors.
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http://dx.doi.org/10.1016/j.aucc.2021.07.002DOI Listing
August 2021

Quantitative microcapillary electrophoresis immunoassay (mCE IA) for end-to-end analysis of pertactin within in-process samples and Quadracel® vaccine.

J Pharm Biomed Anal 2021 Sep 26;204:114284. Epub 2021 Jul 26.

Analytical Sciences Toronto, Sanofi Pasteur Ltd., Toronto, ON, M2R 3T4, Canada. Electronic address:

Protein concentration is an important attribute in the production of subunit or component-based vaccine antigens. Rigorous monitoring of protein concentration is required to identify potential areas for yield improvement. The current GMP method for quantitation is the plate-based ELISA which requires numerous hands-on steps and has low sensitivity in comparison to new microfluidic systems. To address this issue, a sensitive automated microCapillary Electrophoresis ImmunoAssay (mCE IA) method was developed to accurately separate and quantitate pertactin (PRN), an important antigen of the modern acellular Pertussis (aP) vaccine. PRN is reported to be a low-yielding antigen; thus, it is critical to observe its concentration throughout its manufacturing process. First, a primary antibody for PRN was identified to establish suitable immunoprobing conditions for detection of PRN over a wide linear dynamic range that spans 3 orders of magnitude. Next, the pre-adsorbed PRN Drug Substance (DS) was used as a reference standard to quantitate PRN samples against a calibration curve with adequate accuracy and precision. Four representative samples including three in-process steps and final adjuvanted drug product: Quadracel®, were examined to demonstrate the capability of mCE IA to quantitate PRN with high sensitivity and specificity. The matrices of the selected samples contain additional components (e.g. other proteins, growth factors, cell culture media, residual ammonium sulfate, and aluminum adjuvant) often making the quantitation of PRN challenging. The specificity and method linearity were demonstrated by spiking pre-adsorbed PRN DS into the four representative samples. In addition, it was shown that reportable concentrations of PRN for nine downstream process steps as analyzed by our method is comparable to concentrations obtained with ELISA. Most importantly, this study demonstrated that our method's quantitative accuracy is independent of matrix components, as each sample undergoes extensive dilution. This allows for seamless end-to-end analysis of PRN from fermenter harvest, through to complex downstream process samples to adjuvanted drug products. Finally, for the first time the developed and qualified mCE IA method was shown to quantify PRN throughout the entire manufacturing process to provide rapid feedback for process optimizations allowing for accurate yield and step-loss calculations.
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http://dx.doi.org/10.1016/j.jpba.2021.114284DOI Listing
September 2021

Block of TREK and TRESK K2P channels by lamotrigine and two derivatives sipatrigine and CEN-092.

Biochem Biophys Rep 2021 Jul 19;26:101021. Epub 2021 May 19.

Medway School of Pharmacy, University of Kent and University of Greenwich, Central Avenue, Chatham Maritime, ME4 4TB, UK.

TREK and TRESK K2P channels are widely expressed in the nervous system, particularly in sensory neurons, where they regulate neuronal excitability. In this study, using whole-cell patch-clamp electrophysiology, we characterise the inhibitory effect of the anticonvulsant lamotrigine and two derivatives, sipatrigine and 3,5-diamino-6-(3,5-bistrifluoromethylphenyl)-1,2,4-triazine (CEN-092) on these channels. Sipatrigine was found to be a more effective inhibitor than lamotrigine of TREK-1, TREK-2 and TRESK channels. Sipatrigine was slightly more potent on TREK-1 channels (EC = 16 μM) than TRESK (EC = 34 μM) whereas lamotrigine was equally effective on TREK-1 and TRESK. Sipatrigine was less effective on a short isoform of TREK-2, suggesting the N terminus of the channel is important for both inhibition and subsequent over-recovery. Inhibition of TREK-1 and TREK-2 channels by sipatrigine was reduced by mutation of a leucine residue associated with the norfluoxetine binding site on these channels (L289A and L320A on TREK-1 and TREK-2, respectively) but these did not affect inhibition by lamotrigine. Inhibition of TRESK by sipatrigine and lamotrigine was attenuated by mutation of bulky phenylalanine residues (F145A and F352A) in the inner pore helix. However, phosphorylation mutations did not alter the effect of sipatrigine. CEN-092 was a more effective inhibitor of TRESK channels than TREK-1 channels. It is concluded that lamotrigine, sipatrigine and CEN-092 are all inhibitors of TREK and TRESK channels but do not greatly discriminate between them. The actions of these compounds may contribute to their current and potential use in the treatment of pain and depression.
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http://dx.doi.org/10.1016/j.bbrep.2021.101021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144350PMC
July 2021

Factors Associated With Quality of Life Among People Living With a Stoma in Nonmetropolitan Areas.

Nurs Res 2021 Jul-Aug 01;70(4):281-288

Background: Interruption of gastrointestinal continuity through surgical formation of a stoma can be lifesaving. However, it is also typically associated with reduced quality of life (QoL). Although past research has investigated QoL among people living with a stoma, no known studies have investigated stoma-related QoL, specifically among nonmetropolitan residents who may experience distinct health issues compared with their metropolitan counterparts.

Objectives: The aim of the study was to investigate the level of and factors associated with QoL among people living with a stoma in nonmetropolitan Australia.

Methods: In a cross-sectional survey, 678 adults with colostomy, ileostomy, and/or urostomy and with membership in a regional Victorian stoma association were given the City of Hope Quality of Life Questionnaire for a Patient With an Ostomy (QOL-O). Total QoL score was calculated and described before categorization into quintiles. Patient factors associated with quintiles of QoL were assessed using univariable and multivariable proportional odds ordinal logistic regression, with a 95% confidence interval excluding 1.00 denoting statistical significance.

Results: Overall, 311 regional ostomy association members (46%) responded to any QOL-O questions; 285 members responded to >80% of QOL-O questions and contributed data to the study. Their median age was 73 years, and 60% were male. The median total QoL score was 6.9 on a scale of 0-10, where a higher number indicates better QoL. Factors independently associated with better QoL in the multivariable model were working full/part time, no poststoma clothing change, poststoma sexual activity, and older age. Factors independently associated with worse QoL were poststoma depression and a stoma location issue.

Discussion: People living with a stoma in nonmetropolitan Australia reported moderate-to-high QoL. Better QoL was identified in those who worked, had no poststoma clothing change, were sexually active poststoma, and were older. Worse QoL was seen in those who had poststoma depression and stoma location issues. Healthcare providers could influence stoma-related QoL by identifying risk factors and tailoring interventions toward individuals in nonmetropolitan settings.
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http://dx.doi.org/10.1097/NNR.0000000000000511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231669PMC
August 2021

A data visualisation method for assessing exposure misclassification in case-crossover studies: the example of tricyclic antidepressants and the risk of hip fracture in older people.

BMC Med Res Methodol 2021 02 27;21(1):43. Epub 2021 Feb 27.

Quality Use of Medicines and Pharmacy Research Centre (QUMPRC), UniSA Clinical and Health Sciences, CEA-19, University of South Australia, Adelaide, SA, 5001, Australia.

Background: The case-crossover design is suited to medication safety studies but is vulnerable to exposure misclassification. Using the example of tricyclic antidepressants and the risk of hip fracture, we present a data visualisation tool for observing exposure misclassification in case-crossover studies.

Methods: A case-crossover study was conducted using Australian Government Department of Veterans' Affairs claims data. Beneficiaries aged over 65 years who were hospitalised for hip fracture between 2009 and 2012 were included. The case window was defined as 1-50 days pre fracture. Control window one and control window two were defined as 101-150 and 151-200 days pre fracture, respectively. Patients were stratified by whether exposure status changed when control window two was specified instead of control window one. To visualise potential misclassification, each subject's tricyclic antidepressant dispensings were plotted over the 200 days pre fracture.

Results: The study population comprised 8828 patients with a median age of 88 years. Of these subjects, 348 contributed data to the analyses with either control window. The data visualisation suggested that 14% of subjects were potentially misclassified with control window one while 45% were misclassified with control window two. The odds ratio for the association between tricyclic antidepressants and hip fracture was 1.18 (95% confidence interval = 0.91-1.52) using control window one, whereas risk was significantly increased (odds ratio = 1.43, 95% confidence interval = 1.11-1.83) using control window two.

Conclusions: Exposure misclassification was less likely to be present with control window one than with an earlier control window, control window two. When specifying different control windows in a case-crossover study, data visualisation can help to assess the extent to which exposure misclassification may contribute to variable results.
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http://dx.doi.org/10.1186/s12874-021-01230-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913256PMC
February 2021

Oesophageal cancer treatment patterns, timeliness of care and outcomes in the Loddon Mallee region of Victoria: A retrospective cohort study.

J Med Imaging Radiat Oncol 2021 Apr 26;65(2):242-250. Epub 2021 Feb 26.

Loddon Mallee Integrated Cancer Service, Bendigo, Victoria, Australia.

Introduction: Few studies have investigated oesophageal cancer care in regional areas. This study aimed to describe treatment patterns for oesophageal cancer in a regional area, and to identify factors associated with radiotherapy utilisation, timeliness of care, and death.

Methods: In a retrospective cohort study, medical records were reviewed to source data on all patients diagnosed with and/or treated for oesophageal cancer at two regional Victorian hospitals over July 2015-June 2018. Cox proportional hazards regression was employed to identify factors associated with time from diagnosis to death while binary logistic regression was used to identify factors associated with radiotherapy utilisation and treatment within 28 days of diagnosis - a time frame derived from the relevant optimal care pathway.

Results: Of 95 patients, 72% had radiotherapy, 32% received any treatment within 28 days, and 78% died over a median time of nine months. Odds of not receiving radiotherapy were decreased (odds ratio [OR] = 0.26, 95% confidence interval [CI] = 0.08-0.87) for histology other than adenocarcinoma. Odds of timely care were increased for any palliative radiotherapy (OR = 3.47, 95% CI = 1.15-10.5) and decreased for older age (OR = 0.95, 95% CI = 0.91.0.999). Hazard of death was elevated for stage IV disease (hazard ratio [HR] = 2.73, 95% CI = 1.64-4.54) and reduced for radical intent (HR = 0.27, 95% CI = 0.15-0.48).

Conclusion: Nearly three-quarters of regional oesophageal cancer patients had radiotherapy while approximately one-third received any treatment within the recommended 28 days. Any palliative radiotherapy and younger age were associated with timely treatment. Future studies could further investigate factors related to timely oesophageal cancer care.
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http://dx.doi.org/10.1111/1754-9485.13167DOI Listing
April 2021

Classic and evolving approaches to evaluating cross reactivity of mAb and mAb-like molecules - A survey of industry 2008-2019.

Regul Toxicol Pharmacol 2021 Apr 22;121:104872. Epub 2021 Jan 22.

Drug Safety Research and Development, Pfizer, Inc, 300 Technology Square, Cambridge, MA, 02139, USA.

Monoclonal antibodies (mAbs) and mAb derivatives have become mainstay pharmaceutical modalites. A critical assessment is to ascertain the specificity of these molecules prior to human clinical trials. The primary technique for determining specificity has been the immunohistochemistry (IHC)-based "Tissue Cross-Reactivity" (TCR) assay, where the candidate molecule is applied to > 30 tissues to look for unexpected staining. In the last few years, however, non-IHC array-based platforms have emerged that allow for screening 75-80% of the human membrane proteome, indicating a viable alternative and/or addition to the IHC methods. The preclinical sciences subcommittee of the Biotechnology Innovation Organization (BIO), "BioSafe", conducted a survey of 26 BIO member companies to understand current sponsor experience with the IHC and array techniques. In the last ten years, respondents noted they have conducted more than 650 IHC TCR assays, largely on full length mAbs, with varying impacts on programs. Protein/cell arrays have been utilized by almost half of the companies and sponsors are gaining familiarity and comfort with the platform. Initial experience with recent versions of these arrays has been largely positive. While most sponsors are not prepared to eliminate the IHC TCR assay, growing experience with these alternatives allows them to confidently choose other approaches with or without TCR assays.
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http://dx.doi.org/10.1016/j.yrtph.2021.104872DOI Listing
April 2021

A national survey of COVID-19 challenges, responses and effects in Australian general practice.

Aust J Gen Pract 2020 11;49(11):745-751

MBA, GradCertMgmt, MAICD, Chief Executive Officer, General Practice Supervisors Australia, Vic.

Method: A national cross-sectional online survey of Australian general practitioners was conducted in April and May 2020, with 572 respondents.

Results: The COVID-19 pandemic in Australia has resulted in major changes to general practice business models. Most practices have experienced increased workload and reduced income.

Discussion: Australian general practices have undertaken major innovation and realignment to respond to staff safety and patient care challenges during the COVID-19 pandemic. Increased administration, reduced billable time, managing staffing and pivoting to telehealth service provision have negatively affected practice viability. Major sources of information for general practice are primary care-specific, but many practices turn to colleagues for support and resources.
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http://dx.doi.org/10.31128/AJGP-06-20-5465DOI Listing
November 2020

Timeliness of cancer care in a regional Victorian health service: A comparison of high-volume (Lung) and low-volume (oesophagogastric) tumour streams.

Cancer Rep (Hoboken) 2021 02 7;4(1):e1301. Epub 2020 Oct 7.

Loddon Mallee Integrated Cancer Service, Bendigo Health, Bendigo, Victoria, Australia.

Background: Timeliness of cancer care is vital for improved survival and quality of life of patients. Service and care centralisation at larger-volume centres has been associated with improved outcomes. However, there is a lack of systematic data on the impact of tumour stream volume on timeliness of care.

Aims: To investigate and compare timeliness of care for lung cancer, a high-volume (more commonly diagnosed) tumour stream, and oesophagogastric (OG) cancer, a low-volume (less commonly diagnosed) tumour stream, at a regional health service in Victoria, Australia.

Methods: A retrospective cohort study comprising random samples of 75 people newly diagnosed with lung cancer (International Classification of Diseases and Related Health Problems-10 [ICD-10] diagnosis codes C34 in the Victorian Cancer Registry [VCR]) and 50 people newly diagnosed with OG cancer (ICD-10 diagnosis codes C15 or C16 in VCR) at one regional Victorian health service between 2016 and 2017. Binary logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between patient factors and suboptimal timeliness of care.

Results: In comparison to OG cancer patients, lung cancer patients had reduced odds of suboptimal timeliness of care in reference to times outside OCP for referral to diagnosis (OR [95% CI] = 0.34 [0.14 to 0.83]) but increased odds of suboptimal timeliness for diagnosis to treatment (OR [95% CI] = 2.48 [1.01 to 6.09]).

Conclusion: In the low-volume OG cancer stream, patients had longer wait times from referral to an MDM, where treatment decisions occur, but shorter time to commencement of first treatment. Conversely in the high-volume lung cancer group, there was delayed initiation of first treatment following presentation at MDM. There is need to explore ways to fast-track MDM presentation and commencement of therapy among people diagnosed with low-volume and high-volume cancers, respectively.
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http://dx.doi.org/10.1002/cnr2.1301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941434PMC
February 2021

Strategies and Recommendations for Using a Data-Driven and Risk-Based Approach in the Selection of First-in-Human Starting Dose: An International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Assessment.

Clin Pharmacol Ther 2021 06 3;109(6):1395-1415. Epub 2020 Nov 3.

Pharmacokinetic Sciences, Novartis Institute of BioMedical Research, Inc., Cambridge, Massachusetts, USA.

Various approaches to first-in-human (FIH) starting dose selection for new molecular entities (NMEs) are designed to minimize risk to trial subjects. One approach uses the minimum anticipated biological effect level (MABEL), which is a conservative method intended to maximize subject safety and designed primarily for NMEs having high perceived safety risks. However, there is concern that the MABEL approach is being inappropriately used for lower risk molecules with negative impacts on drug development and time to patient access. In addition, ambiguity exists in how MABEL is defined and the methods used to determine it. The International Consortium for Innovation and Quality in Pharmaceutical Development convened a working group to understand current use of MABEL and its impact on FIH starting dose selection, and to make recommendations for FIH dose selection going forward. An industry-wide survey suggested the achieved or estimated maximum tolerated dose, efficacious dose, or recommended phase II dose was > 100-fold higher than the MABEL-based starting dose for approximately one third of NMEs, including trials in patients. A decision tree and key risk factor table were developed to provide a consistent, data driven-based, and risk-based approach for selecting FIH starting doses.
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http://dx.doi.org/10.1002/cpt.2009DOI Listing
June 2021

Novel Bacteriophages Capable of Disrupting Biofilms From Clinical Strains of .

Front Microbiol 2020 14;11:194. Epub 2020 Feb 14.

Department of Pharmacy and Biomedical Science, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia.

The increase in global warming has favored growth of a range of opportunistic environmental bacteria and allowed some of these to become more pathogenic to humans. is one such organism. Surviving in moist conditions in temperate climates, these bacteria have been associated with a range of diseases in humans, and in systemic infections can cause mortality in up to 46% of cases. Their capacity to form biofilms, carry antibiotic resistance mechanisms, and survive disinfection, has meant that they are not easily treated with traditional methods. Bacteriophage offer a possible alternative approach for controlling their growth. This study is the first to report the isolation and characterization of bacteriophages lytic against clinical strains of which carry intrinsic antibiotic resistance genes. Functionally, these novel bacteriophages were shown to be capable of disrupting biofilms caused by clinical isolates of The potential exists for these to be tested in clinical and environmental settings.
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http://dx.doi.org/10.3389/fmicb.2020.00194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033617PMC
February 2020

Comparative nonclinical assessments of the biosimilar PF-06410293 and originator adalimumab.

Regul Toxicol Pharmacol 2020 Apr 30;112:104587. Epub 2020 Jan 30.

Drug Safety Research and Development, Pfizer Inc., 300 Technology Square Drive, Cambridge, MA, USA. Electronic address:

Adalimumab, a recombinant fully human monoclonal antibody targeting tumor necrosis factor (TNF), is approved in the United States and Europe to treat various inflammatory and autoimmune indications. Biosimilars are approved biologics highly similar, but not identical, to approved biotherapeutics. To support clinical development of PF-06410293, an adalimumab biosimilar, nonclinical studies evaluated the structural, functional, toxicologic, and toxicokinetic similarity to originator adalimumab sourced from the United States (adalimumab-US) and European Union (adalimumab-EU). Structural similarity was assessed by peptide mapping. Biologic activity was measured via inhibition of TNF-induced apoptosis and Fc-based functionality assessments. In vivo nonclinical similarity was evaluated in a toxicity study in cynomolgus monkeys administered subcutaneous PF-06410293 or adalimumab-EU (0 or 157 mg/kg/week). Peptide mapping demonstrated PF-06410293, adalimumab-US, and adalimumab-EU had identical amino acid sequences. Comparative functional and binding assessments were similar. Effects of PF-06410293 and adalimumab-EU were similar and limited to pharmacologically mediated decreased cellularity of lymphoid follicles and germinal centers in spleen. Toxicokinetics were similar; maximum plasma concentration and area-under-the-concentration-time curve ratio of PF-06410293:adalimumab-EU ranged from 1.0 to 1.2. These studies supported PF-06410293 entry into clinical development. Many regulatory agencies now only request nonclinical in vivo testing if there is residual uncertainty regarding biosimilarity after in vitro analytical studies.
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http://dx.doi.org/10.1016/j.yrtph.2020.104587DOI Listing
April 2020

AKT/mTORC2 Inhibition Activates FOXO1 Function in CLL Cells Reducing B-Cell Receptor-Mediated Survival.

Clin Cancer Res 2019 03 17;25(5):1574-1587. Epub 2018 Dec 17.

Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.

Purpose: To determine whether inhibition of mTOR kinase-mediated signaling represents a valid therapeutic approach for chronic lymphocytic leukemia (CLL).

Experimental Design: Stratification of mTOR activity was carried out in patients with primary CLL samples and an aggressive CLL-like mouse model. The potency of dual mTOR inhibitor AZD8055 to induce apoptosis in primary CLL cells was assessed in the presence/absence of B-cell receptor (BCR) ligation. Furthermore, we addressed the molecular and functional impact of dual mTOR inhibition in combination with BTK inhibitor ibrutinib.

Results: Differential regulation of basal mTORC1 activity was observed in poor prognostic CLL samples, with elevated p4EBP1 and decreased p70S6 kinase activity, suggesting that dual mTORC1/2 inhibitors may exhibit improved response in poor prognostic CLL compared with rapalogs. AZD8055 treatment of primary CLL cells significantly reduced CLL survival compared with rapamycin, preferentially targeting poor prognostic subsets and overcoming BCR-mediated survival advantages. Furthermore, AZD8055, and clinical analog AZD2014, significantly reduced CLL tumor load in mice. AKT substrate FOXO1, while overexpressed in CLL cells of poor prognostic patients in LN biopsies, peripheral CLL cells, and mouse-derived CLL-like cells, appeared to be inactive. AZD8055 treatment partially reversed FOXO1 inactivation downstream of BCR crosslinking, significantly inhibiting FOXO1 phosphorylation in an mTORC2-AKT-dependent manner, to promote FOXO1 nuclear localization, activity, and FOXO1-mediated gene regulation. FOXO1 activity was further significantly enhanced on combining AZD8055 with ibrutinib.

Conclusions: Our studies demonstrate that dual mTOR inhibitors show promise as future CLL therapies, particularly in combination with ibrutinib.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398589PMC
March 2019

Nonclinical assessments of the potential biosimilar PF-06439535 and bevacizumab.

Regul Toxicol Pharmacol 2018 Jun 21;95:236-243. Epub 2018 Mar 21.

Drug Safety Research and Development, Pfizer Inc, 610 Main St, Cambridge, MA 02139, USA. Electronic address:

Bevacizumab, a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF), is approved for treatment of metastatic colorectal cancer, nonsquamous non-small-cell lung cancer, metastatic kidney cancer, and glioblastoma. To support clinical development of the potential bevacizumab biosimilar PF-06439535, nonclinical studies evaluated structural, functional, toxicological, and toxicokinetic similarity to bevacizumab sourced from the European Union (bevacizumab-EU) and United States (bevacizumab-US). Peptide mapping demonstrated the amino acid sequence of PF-06439535 was identical to bevacizumab-EU and bevacizumab-US. Biologic activity, measured via inhibition of VEGF-induced cell proliferation in human umbilical vein endothelial cells and binding to VEGF isoforms, was similar across the three drugs. In vivo similarity was demonstrated in cynomolgus monkeys administered intravenous PF-06439535 or bevacizumab-EU (0 or 10 mg/kg/dose twice weekly for 1 month; total of nine doses). Systemic exposure appeared similar and test article-related effects were limited to physeal dysplasia of the distal femur. The potential for non-target-mediated toxicity of PF-06439535 was evaluated in rats administered intravenous PF-06439535 (15 or 150 mg/kg/dose twice weekly for 15 days; total of five doses). Nonadverse higher liver weights and minimal sinusoidal cell hyperplasia were observed. Collectively, these studies demonstrated similarity of PF-06439535 to bevacizumab, supporting entry into clinical development.
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http://dx.doi.org/10.1016/j.yrtph.2018.03.020DOI Listing
June 2018

The Risk of Hip Fracture Due to Mirtazapine Exposure When Switching Antidepressants or Using Other Antidepressants as Add-On Therapy.

Drugs Real World Outcomes 2017 Dec;4(4):247-255

Quality Use of Medicines and Pharmacy Research Centre (QUMPRC), Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, GPO Box 2471, Adelaide, SA, 5001, Australia.

Background: Antidepressants are associated with adverse effects such as sedation and hypotension, which can result in falls and fractures. Few studies have assessed the risk of hip fracture due to mirtazapine, and no known studies have assessed whether the risk of hip fracture is higher in patients taking other antidepressant medicines in combination with mirtazapine.

Objectives: This study aimed to examine the risk of hip fracture in older people due to mirtazapine use as well as switching between or concurrently using mirtazapine and other antidepressants.

Method: A matched case-control study was conducted. Cases were people aged over 65 years who were eligible for Australian Government Department of Veterans' Affairs (DVA) benefits and who sustained a hip fracture between 2009 and 2012. Each case was matched with up to four randomly selected controls of the same gender and age (± 2 years). Multivariable conditional logistic regression was used to estimate associations between antidepressant use and hip fracture. In order to assess whether combined antidepressant effects differed from the sum of individual effects, the relative excess risk due to interaction (RERI) was calculated.

Results: The study population comprised 8828 cases and 35,310 controls. The median age of these participants was 88 years and 63% were women. The risk of hip fracture was increased for mirtazapine (continuous use: odds ratio [OR] 1.27, 95% confidence interval [CI] 1.12-1.44). The combinations associated with increased odds of hip fracture were addition of selective serotonin reuptake inhibitors (SSRIs) to mirtazapine (OR 11, 95% CI 2.2-51; RERI 7.7, 95% CI -9.0 to 24), addition of tricyclic antidepressants (TCAs) to mirtazapine (OR 14, 95% CI 1.4-132; RERI 12, 95% CI -19 to 43) and continuous use of both SSRIs and mirtazapine (OR 2.4, 95% CI 1.4-4.2; RERI 0.4, 95% CI -0.9 to 1.7). RERIs indicated that the effect of each antidepressant pair equalled the sum of the effects of individual antidepressant use. There was no evidence of dispensing of lower strength mirtazapine upon introducing TCAs and SSRIs.

Conclusions: Our results show elevated risk of hip fracture following use of mirtazapine alone and in combination with other antidepressants. The overlapping use of antidepressants may reflect the treatment of comorbidities (e.g. anxiety), switching from mirtazapine to other antidepressants, or add-on therapy. Our results highlight the risks of employing add-on therapy or switching antidepressants in older people, providing further evidence to support cautious cross-tapering where switching between antidepressants is required.
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http://dx.doi.org/10.1007/s40801-017-0120-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684049PMC
December 2017

High-precision quantitation of a tuberculosis vaccine antigen with capillary-gel electrophoresis using an injection standard.

Talanta 2017 Dec 15;175:273-279. Epub 2017 Jul 15.

Department of Chemistry and Centre for Research on Biomolecular Interactions, York University, Toronto, Ontario, Canada M3J 1P3. Electronic address:

Analysis of proteinogenic vaccine antigens in a quality control environment requires an accurate, precise, and reliable method for protein separation and quantitation. While having multiple advantages over the classical SDS-PAGE, capillary gel electrophoresis (CGE) has not yet become a standard tool in vaccine antigen analysis. Here we report on development of a CGE-based method for quantitative analysis of a tuberculosis vaccine fusion antigen protein, H4, currently in clinical trials. We demonstrate that our method can monitor antigen purity and relative quantity with greater precision and accuracy versus SDS-PAGE. In addition, due to use of direct light-absorbance detection, the CGE method is suitable for absolute quantitation, an application for which SDS-PAGE is limited due to the need for staining and limited dynamic range of detection. To further improve the performance of our quantitation method, we introduced Bovine Serum Albumin (BSA) as an injection standard to correct for signal variance associated with the injected sample volume. We found that, for our specific application, BSA was more appropriate as an injection standard versus one provided in a commercial kit, in terms of precision and accuracy for quantitation of H4. In addition to providing better method performance versus SDS-PAGE, CGE is also faster and less resource-intensive. We conclude that CGE should be considered as a replacement for traditional SDS-PAGE methods for vaccine antigen quantitation in a quality-control environment.
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http://dx.doi.org/10.1016/j.talanta.2017.07.047DOI Listing
December 2017

Clouds.

Med Humanit 2017 12 8;43(4):e37-e38. Epub 2017 Jul 8.

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http://dx.doi.org/10.1136/medhum-2017-011299DOI Listing
December 2017

Risk of Hip Fracture in Older People Using Selective Serotonin Reuptake Inhibitors and Other Psychoactive Medicines Concurrently: A Matched Case-Control Study in Australia.

Drugs Real World Outcomes 2017 Jun;4(2):87-96

Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, GPO Box 2471, Adelaide, SA, 5001, Australia.

Background: Few studies have assessed the risk of hip fracture following concurrent use of psychoactive medicines, and none has investigated combinations with selective serotonin reuptake inhibitors.

Objectives: To assess the risk of hip fracture in older people as a result of concurrent use of selective serotonin reuptake inhibitors and other psychoactive medicines.

Methods: A matched case-control design was employed. Cases were Australian Government Department of Veterans' Affairs beneficiaries aged over 65 years who experienced a hip fracture between 2009 and 2012. Each case was matched with up to four randomly selected controls of the same age (±2 years) and sex. Medicine-hip fracture associations were estimated via conditional logistic regression. The relative excess risk due to interaction (RERI) was calculated to determine whether combined effects differed from the sum of individual effects.

Results: There were 8828 cases and 35,310 controls. The median age of subjects was 88 years and 63% were women. The risk of hip fracture was elevated for all medicines assessed individually, most notably selective serotonin reuptake inhibitors (initiation: odds ratio [OR] = 2.7, 95% confidence interval [CI] 2.1, 3.6) and opioids (initiation: OR = 2.3, 95% CI 1.9, 2.9). Combinations associated with an increased odds of hip fracture included addition of benzodiazepines to selective serotonin reuptake inhibitor therapy (OR = 3.0, 95% CI 1.9, 4.8; RERI = 0.9, 95% CI -0.5, 2.3), concurrent use of both opioids and selective serotonin reuptake inhibitors (OR = 2.2, 95% CI 1.9, 2.6; RERI = 0.1, 95% CI -0.3, 0.5), addition of opioids to selective serotonin reuptake inhibitor therapy (OR = 3.2, 95% CI 1.8, 5.5; RERI = -0.1, 95% CI -2.0, 1.7), and initiation of both benzodiazepines and selective serotonin reuptake inhibitors (OR = 4.7, 95% CI 1.7, 13; RERI = 1.3, 95% CI -3.8, 6.3). The RERI results suggested that the effect of each of these medicine combinations equalled the sum of the effects of individual medicine use.

Conclusions: In older people, the concurrent use of selective serotonin reuptake inhibitors and other psychoactive medicines increased the risk of hip fracture as much as the sum of the risks owing to individual medicine use. Our results highlight the need for prescribers to consider the sedative burden of medicines in each older patient as well as the potential for an additive risk of hip fracture when initiating additional psychoactive therapy.
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http://dx.doi.org/10.1007/s40801-017-0107-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457310PMC
June 2017

Nonclinical Evaluation of PF-06438179: A Potential Biosimilar to Remicade (Infliximab).

Adv Ther 2016 11 1;33(11):1964-1982. Epub 2016 Sep 1.

Pfizer Inc., Drug Safety Research and Development, Andover, MA, USA.

Introduction: PF-06438179, a potential biosimilar to Remicade (infliximab, Janssen Biotech, Inc.), is a chimeric mouse-human monoclonal antibody targeting human tumor necrosis factor alpha (TNF).

Methods: Analytical (small subset reported here) and nonclinical studies compared the structural, functional, and in vivo nonclinical similarity of PF-06438179 with Remicade sourced from the United States (infliximab-US) and/or European Union (infliximab-EU).

Results: The peptide map profiles were superimposable, and peptide masses were the same, indicating identical amino acid sequences. Data on post-translational modifications, biochemical properties, and biological function provided strong support for analytical similarity. Administration of a single intravenous (IV) dose (10 or 50 mg/kg) of PF-06438179 or infliximab-EU to male rats was well tolerated. There were no test article-related clinical signs or effects on body weight or food consumption. Systemic exposures [maximum drug concentration (C ) and area under the concentration-time curve (AUC)] in rats administered PF-06438179 or infliximab-EU were similar, with mean exposure ratio of PF-06438179 relative to infliximab-EU ranging from 0.88 to 1.16. No rats developed anti-drug antibodies. A 2-week IV toxicity study was conducted with once-weekly administration of 10 or 50 mg/kg of PF-06438179 to male and female rats. PF-06438179-related hyperplasia of sinusoidal cells occurred in the liver in rats administered 50 mg/kg, but was not adverse based on its minimal to mild severity. The no-observed adverse-effect level for PF-06438179 was 50 mg/kg. At this dose, C was 1360 µg/mL and AUC at 168 h was 115,000 µg h/mL on day 8.

Conclusions: The analytical and nonclinical studies have supported advancement of PF-06438179 into global comparative clinical trials.

Funding: Pfizer Inc.
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http://dx.doi.org/10.1007/s12325-016-0403-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5083783PMC
November 2016

A Synopsis of the "Influence of Epigenetics, Genetics, and Immunology" Session Part A at the 35th Annual Society of Toxicologic Pathology Symposium.

Toxicol Pathol 2017 01 5;45(1):114-118. Epub 2016 Oct 5.

6 Drug Safety Research and Development, Pfizer, Andover, Massachusetts, USA.

The overarching theme of the 2016 Society of Toxicology Pathology's Annual Symposium was "The Basis and Relevance of Variation in Toxicologic Responses." Session 4 focused on genetic variation as a potential source for variability in toxicologic responses within nonclinical toxicity studies and further explored how knowledge of genetic traits might enable targeted prospective and retrospective studies in drug development and human health risk assessment. In this session, the influence of both genetic sequence variation and epigenetic modifications on toxicologic responses and their implications for understanding risk were explored. In this overview, the presentations in this session will be summarized, with a goal of exploring the ramifications of genetic and epigenetic variability within and across species for toxicity studies and disseminating information regarding novel tools to harness this variability to advance understanding of toxicologic responses across populations.
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http://dx.doi.org/10.1177/0192623316670781DOI Listing
January 2017

Nonproliferative and Proliferative Lesions of the Gastrointestinal Tract, Pancreas and Salivary Glands of the Rat and Mouse.

J Toxicol Pathol 2016 13;29(1 Suppl):1S-125S. Epub 2016 Feb 13.

Global VetPathology, Montgomery Village, MD, USA.

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) project is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature and diagnostic criteria for nonproliferative and proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature and diagnostic criteria for classifying lesions in the digestive system including the salivary glands and the exocrine pancreas of laboratory rats and mice. Most lesions are illustrated by color photomicrographs. The standardized nomenclature, the diagnostic criteria, and the photomicrographs are also available electronically on the Internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and age related lesions as well as lesions induced by exposure to test items. Relevant infectious and parasitic lesions are included as well. A widely accepted and utilized international harmonization of nomenclature and diagnostic criteria for the digestive system will decrease misunderstandings among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.
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http://dx.doi.org/10.1293/tox.29.1SDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4765498PMC
March 2016

Blue Thought.

Med Humanit 2016 Jun 17;42(2):e3. Epub 2016 Feb 17.

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http://dx.doi.org/10.1136/medhum-2015-010861DOI Listing
June 2016

Waiving in vivo studies for monoclonal antibody biosimilar development: National and global challenges.

MAbs 2016 ;8(3):427-35

m Integrated Biologix , Switzerland.

Biosimilars are biological medicinal products that contain a version of the active substance of an already authorised original biological medicinal product (the innovator or reference product). The first approved biosimilar medicines were small proteins, and more recently biosimilar versions of innovator monoclonal antibody (mAb) drugs have entered development as patents on these more complex proteins expire. In September 2013, the first biosimilar mAb, infliximab, was authorised in Europe. In March 2015, the first biosimilar (Zarxio™, filgrastim-sndz, Sandoz) was approved by the US Food and Drug Administration; however, to date no mAb biosimilars have been approved in the US. There are currently major differences between how biosimilars are regulated in different parts of the world, leading to substantial variability in the amount of in vivo nonclinical toxicity testing required to support clinical development and marketing of biosimilars. There are approximately 30 national and international guidelines on biosimilar development and this number is growing. The European Union's guidance describes an approach that enables biosimilars to enter clinical trials based on robust in vitro data alone; in contrast, the World Health Organization's guidance is interpreted globally to mean in vivo toxicity studies are mandatory. We reviewed our own experience working in the global regulatory environment, surveyed current practice, determined drivers for nonclinical in vivo studies with biosimilar mAbs and shared data on practice and study design for 25 marketed and as yet unmarketed biosimilar mAbs that have been in development in the past 5y. These data showed a variety of nonclinical in vivo approaches, and also demonstrated the practical challenges faced in obtaining regulatory approval for clinical trials based on in vitro data alone. The majority of reasons for carrying out nonclinical in vivo studies were not based on scientific rationale, and therefore the authors have made recommendations for a data-driven approach to the toxicological assessment of mAb biosimilars that minimises unnecessary use of animals and can be used across all regions of the world.
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http://dx.doi.org/10.1080/19420862.2016.1145331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966840PMC
December 2016

Psychoactive medicine use and the risk of hip fracture in older people: a case-crossover study.

Pharmacoepidemiol Drug Saf 2015 Jun 16;24(6):576-82. Epub 2015 Apr 16.

Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.

Purpose: Many factors can increase the risk of hip fracture, including medicines. Traditional observational studies have assessed the risk, but results may be confounded by unmeasured factors. The case-crossover design is an alternative approach that controls for patient-specific, time-invariant confounding factors. This study aimed to assess associations between psychoactive medicines and hip fracture in the elderly using the case-crossover method.

Methods: Data were sourced from the Australian Government Department of Veterans' Affairs healthcare claims database. The study population comprised beneficiaries aged over 65 years who were hospitalised for hip fracture between 2009 and 2012. The case-crossover method was used to compare individuals' medicine exposure immediately before hip fracture (case window) with their exposure at an earlier time (control window). Conditional logistic regression was employed to quantify associations between medicine use and hip fracture. Alternative exposure windows were assessed in sensitivity analyses.

Results: Eight thousand eight hundred twenty-eight patients were hospitalised for hip fracture. Their median age was 88 years, and 63% were female. Odds of hip fracture were increased for opioids (odds ratio [OR] = 1.62, 95% confidence interval [CI] = 1.42-1.84), selective serotonin reuptake inhibitors (OR = 1.54, 95% CI = 1.28-1.86) and antipsychotics (OR = 1.47, 95% CI = 1.21-1.80). There was no significant association for tricyclic antidepressants in the primary analysis (OR = 1.18, 95% CI = 0.91-1.52), but there was a significant association in the sensitivity analysis using an alternative, earlier control window (OR = 1.43, 95% CI = 1.11-1.83).

Conclusions: Increased risk of hip fracture in older people was found for opioids, selective serotonin reuptake inhibitors and antipsychotics. The choice of control window influenced the result for tricyclic antidepressants.
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http://dx.doi.org/10.1002/pds.3785DOI Listing
June 2015

Scientific and Regulatory Policy Committee Points-to-consider Paper*: Drug-induced Vascular Injury Associated with Nonsmall Molecule Therapeutics in Preclinical Development: Part I. Biotherapeutics.

Toxicol Pathol 2015 Oct 26;43(7):915-34. Epub 2015 Feb 26.

FDA, CDER, Silver Spring, Maryland, USA.

Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. Although DIVI in laboratory animal species has been well characterized for vasoactive small molecules, there is little available information regarding DIVI associated with biotherapeutics such as peptides/proteins or antibodies. Because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans and the lack of robust biomarkers of DIVI, preclinical DIVI findings can cause considerable delays in or even halt development of promising new drugs. This review discusses standard terminology, characteristics, and mechanisms of DIVI associated with biotherapeutics. Guidance and points to consider for the toxicologist and pathologist facing preclinical cases of biotherapeutic-related DIVI are outlined, and examples of regulatory feedback for each of the mechanistic types of DIVI are included to provide insight into risk assessment.
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http://dx.doi.org/10.1177/0192623315570340DOI Listing
October 2015

Scientific and Regulatory Policy Committee Points-to-consider Paper*: Drug-induced Vascular Injury Associated with Nonsmall Molecule Therapeutics in Preclinical Development: Part 2. Antisense Oligonucleotides.

Toxicol Pathol 2015 Oct 24;43(7):935-44. Epub 2015 Feb 24.

Genentech, South San Francisco, California, USA.

Drug-induced vascular injury (DIVI) is a recurrent challenge in the development of novel pharmaceutical agents. In recent years, DIVI has been occasionally observed in nonhuman primates given RNA-targeting therapeutics such as antisense oligonucleotide therapies (ASOs) during chronic toxicity studies. While DIVI in laboratory animal species has been well characterized for vasoactive small molecules, and immune-mediated responses against large molecule biotherapeutics have been well described, there is little published information regarding DIVI induced by ASOs to date. Preclinical DIVI findings in monkeys have caused considerable delays in development of promising new ASO therapies, because of the uncertainty about whether DIVI in preclinical studies is predictive of effects in humans, and the lack of robust biomarkers of DIVI. This review of DIVI discusses clinical and microscopic features of vasculitis in monkeys, their pathogenic mechanisms, and points to consider for the toxicologist and pathologist when confronted with ASO-related DIVI. Relevant examples of regulatory feedback are included to provide insight into risk assessment of ASO therapies.
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http://dx.doi.org/10.1177/0192623315570341DOI Listing
October 2015

Comparative nonclinical assessments of the proposed biosimilar PF-05280014 and trastuzumab (Herceptin(®)).

BioDrugs 2014 Oct;28(5):451-9

Pharmacodynamics and Metabolism, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT, 06340, USA,

Background And Objectives: Trastuzumab (Herceptin(®)) is a humanized monoclonal antibody (mAb) that binds to the HER2 protein. PF-05280014 is being developed as a potential biosimilar to trastuzumab products marketed in the United States (trastuzumab-US) and European Union (trastuzumab-EU). Nonclinical studies were designed to evaluate the similarity of PF-05280014 to trastuzumab-US and trastuzumab-EU using in vitro structural and functional analyses, and in vivo pharmacokinetic and immunogenicity assessments.

Methods: Peptide mapping was utilized to determine structural similarity. Functional similarity was assessed via an in vitro tumor cell growth inhibition assay. CD-1 male mice were administered a single-dose (0, 1, 10, or 100 mg/kg) of PF-05280014, trastuzumab-US, or trastuzumab-EU. Mice were monitored for clinical signs and body weight changes over a 4-month period. At approximately 720, 1,080, 1,440, 2,160, and 2,880 h post-dose, terminal blood samples were collected and assayed for PF-05280014, trastuzumab-US, or trastuzumab-EU concentrations and anti-drug antibodies (ADA). Values for C max, area under the concentration time curve (AUC), clearance (CL), volume of distribution (V ss), half-life (t ½), and the presence of ADA were determined.

Results: In this report, peptide mapping of PF-05280014, trastuzumab-US, and trastuzumab-EU showed similar chromatographic profiles in a side-by-side analysis. The tumor cell growth inhibition of PF-05280014 was similar to trastuzumab-US and trastuzumab-EU. C max and AUC0-∞ values in mice were similar and dose-dependent across the mAbs at all doses, and CL and V ss values were similar and dose-independent. The CL values across doses ranged from 0.193 to 0.350 mL/h/kg (PF-05280014), from 0.200 to 0.346 mL/h/kg (trastuzumab-US), and from 0.193 to 0.335 mL/h/kg (trastuzumab-EU). V ss values across doses ranged from 84.9 to 120 mL/kg (PF-05280014), 86.7 to 130 mL/kg (trastuzumab-US), and 85.4 to 116 mL/kg (trastuzumab-EU). The incidence of ADA was low (~10%) and also similar across all dose levels and the three mAbs. The lower exposure generally observed in ADA-positive animals did not impact the overall PK interpretation. All animals survived to their scheduled terminal blood collection with no mAb-related differences in body weight gain or clinical signs.

Conclusions: PF-05280014, trastuzumab-US, and trastuzumab-EU were well tolerated during the 4-month observation period following a single dose of up to 100 mg/kg. PF-05280014, trastuzumab-US, and trastuzumab-EU showed similar structural properties, tumor cell growth inhibition properties, and PK profiles. The incidence of ADA was low and similar across the three mAbs. The results of these studies support the development of PF-05280014 as a proposed biosimilar to Herceptin.
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http://dx.doi.org/10.1007/s40259-014-0103-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176567PMC
October 2014

Comparative nonclinical assessments of the proposed biosimilar PF-05280586 and rituximab (MabThera®).

Toxicol Pathol 2014 Oct 6;42(7):1069-81. Epub 2014 Mar 6.

Drug Safety Research and Development, Pfizer Inc., Andover, Massachusetts, USA.

Comparative nonclinical studies were conducted with the proposed biosimilar PF-05280586 and rituximab-EU (MabThera®). In side-by-side analyses, peptide maps and complement-dependent cytotoxicity assay results were similar. Sexually-mature cynomolgus monkeys were administered PF-05280586 or rituximab-EU as a single dose of 0, 2, 10, or 20 mg/kg on day 1 and observed for 92 days (single-dose study) or as 5 weekly injections of 0 or 20 mg/kg and necropsied on day 30, the day after the 5th dose, or on day 121 (repeat-dose study). The pharmacokinetic and pharmacodynamic profiles for both molecules were similar. Marked depletion of peripheral blood B cells 4 days after dosing was followed by near or complete repletion (single-dose study) or partial repletion (repeat-dose study). In the single-dose study, anti-drug antibodies (ADA) were detected by day 29 in all animals administered PF-05280586 or rituximab-EU and persisted through day 85, the last day tested. In the repeat-dose study, ADA were detected on day 121 in 50% of animals administered PF-05280586 or rituximab-EU. Both molecules were well tolerated at all doses. In all endpoints evaluated, PF-05280586 exhibited similarity to rituximab-EU.
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http://dx.doi.org/10.1177/0192623313520351DOI Listing
October 2014

Immunogenicity/hypersensitivity of biologics.

Toxicol Pathol 2014 Jan 14;42(1):293-300. Epub 2013 Nov 14.

1Pfizer Drug Safety Research and Development, Andover, Massachusetts, USA.

This continuing education course was designed to provide an overview of the immunologic mechanisms involved in immunogenicity and hypersensitivity reactions following administration of biologics in nonclinical toxicity studies, the methods used to determine whether such reactions are occurring, and the associated clinical and anatomic pathology findings. Hypersensitivity reactions have classically been divided into type I, II, III, and IV reactions; type I and III reactions are those most often observed following administration of biologics. A variety of methods can be used to detect these reactions. Antemortem methods include hematology; detection of antidrug antibodies, circulating immune complexes and complement fragments, and immunoglobulin E in serum; tests for serum complement activity; and evaluation of complement receptor 1 on erythrocytes. Postmortem methods include routine light microscopy and electron microscopy, which can demonstrate typical findings associated with hypersensitivity reactions, and immunohistochemistry, which can detect the presence of immune complexes in tissues, including the detection of the test article. A final determination of whether findings are related to a hypersensitivity reaction in individual animals or across the entire study should rely on the overall weight of evidence, as findings indicative of these reactions are not necessarily consistent across all affected animals.
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http://dx.doi.org/10.1177/0192623313510987DOI Listing
January 2014

Clostridium perfringens septicaemia.

Br J Haematol 2013 Dec 10;163(5):549. Epub 2013 Sep 10.

Department of Haematology, Gartnavel Hospital, Glasgow, UK.

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http://dx.doi.org/10.1111/bjh.12551DOI Listing
December 2013
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