Publications by authors named "Martin Barrett"

8 Publications

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Quantitative Clinical Pharmacology Supports the Bridging from i.v. Dosing and Approval of s.c. Rituximab in B-Cell Hematological Malignancies.

Clin Pharmacol Ther 2021 May 26. Epub 2021 May 26.

Clinical Pharmacology, Pharmaceutical Sciences, Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.

A fixed-dose subcutaneous (s.c.) formulation of the anti-CD20 antibody, rituximab, has been developed to address safety, infusion time, and patient comfort concerns relating to intravenous (i.v.) dosing, and has been approved based upon a pharmacokinetic (PK)-clinical bridging strategy, which demonstrated noninferiority of s.c. vs. i.v. dosing in malignancies, including follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). A clinical development plan was undertaken to identify rituximab s.c. doses achieving noninferior exposure to rituximab i.v., and to confirm PK-clinical bridging, with the same efficacy and similar safety. This drew upon data from 1,579 patients with FL, CLL, or diffuse large B-cell lymphoma in 5 clinical studies, and showed minimum steady-state serum concentration (C ) as the most appropriate exposure bridging measure. Population PK models were developed, simulations were run using covariates and PK parameters from clinical studies, and exposure-efficacy and -safety analyses performed. Population PKs showed a two-compartment model with time-dependent and -independent clearances. Clearance and volume were predominantly influenced by body surface area; disposition and elimination were similar for the s.c. and i.v. formulations. After s.c. administration, patients with FL and CLL achieved noninferior exposures to i.v. dosing. Overall, rituximab exposure and route of administration did not influence clinical responses in patients with FL or CLL, and there was no association between exposure and safety events. C was shown to be an effective pharmacologic-clinical bridging parameter for rituximab in patients with FL or CLL. Clinically effective exposures are achieved with either s.c. or i.v. dosing.
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http://dx.doi.org/10.1002/cpt.2308DOI Listing
May 2021

Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience.

Adv Ther 2017 10 5;34(10):2232-2273. Epub 2017 Oct 5.

Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Rituximab is a human/murine, chimeric anti-CD20 monoclonal antibody with established efficacy, and a favorable and well-defined safety profile in patients with various CD20-expressing lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin lymphoma. Since its first approval 20 years ago, intravenously administered rituximab has revolutionized the treatment of B-cell malignancies and has become a standard component of care for follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma. For all of these diseases, clinical trials have demonstrated that rituximab not only prolongs the time to disease progression but also extends overall survival. Efficacy benefits have also been shown in patients with marginal zone lymphoma and in more aggressive diseases such as Burkitt lymphoma. Although the proven clinical efficacy and success of rituximab has led to the development of other anti-CD20 monoclonal antibodies in recent years (e.g., obinutuzumab, ofatumumab, veltuzumab, and ocrelizumab), rituximab is likely to maintain a position within the therapeutic armamentarium because it is well established with a long history of successful clinical use. Furthermore, a subcutaneous formulation of the drug has been approved both in the EU and in the USA for the treatment of B-cell malignancies. Using the wealth of data published on rituximab during the last two decades, we review the preclinical development of rituximab and the clinical experience gained in the treatment of hematologic B-cell malignancies, with a focus on the well-established intravenous route of administration. This article is a companion paper to A. Davies, et al., which is also published in this issue.

Funding: F. Hoffmann-La Roche Ltd., Basel, Switzerland.
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http://dx.doi.org/10.1007/s12325-017-0612-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656728PMC
October 2017

Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial.

Lancet Haematol 2017 Jun 2;4(6):e272-e282. Epub 2017 May 2.

QEII Health Sciences Centre, Halifax, NS, Canada.

Background: Intravenous rituximab is the standard of care in B-cell non-Hodgkin lymphoma, and is administered over 1·5-6 h. A subcutaneous formulation could reduce patients' treatment burden and improve resource utilisation in health care. We aimed to show the pharmacokinetic non-inferiority of subcutaneous rituximab to intravenous rituximab in follicular lymphoma and to provide efficacy and safety data.

Methods: SABRINA is a two-stage, randomised, open-label phase 3 study at 113 centres in 30 countries. Eligible patients were aged 18 years or older and had histologically confirmed, previously untreated, CD20-positive grade 1, 2, or 3a follicular lymphoma; Eastern Co-operative Oncology Group performance statuses of 0-2; bidimensionally measurable disease (by CT or MRI); life expectancy of 6 months or more; adequate haematological function for 28 days or more; and one or more symptoms requiring treatment according to the Groupe d'Etudes des Lymphomes Folliculaires criteria. Patients were randomly assigned (1:1) by investigators or members of the research team via a dynamic randomisation algorithm to 375 mg/m intravenous rituximab or 1400 mg subcutaneous rituximab, plus chemotherapy (six-to-eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] or eight cycles of cyclophosphamide, vincristine, and prednisone [CVP]), every 3 weeks during induction, then rituximab maintenance every 8 weeks. Randomisation was stratified by selected chemotherapy, Follicular Lymphoma International Prognostic Index, and region. The primary endpoint for stage 2 was overall response (ie, confirmed complete response, unconfirmed complete response, and partial response) at the end of induction. Efficacy analyses were done in the intention-to-treat population. Pooled data from stages 1 and 2 are reported on the basis of the clinical cutoff date of the last patient completing the maintenance phase of the study. This trial is registered with ClinicalTrials.gov, number NCT01200758; new patients are no longer being recruited, but some patients are still being followed up.

Findings: Between Feb 15, 2011, and May 15, 2013, 410 patients were randomly assigned, 205 to intravenous rituximab and 205 to subcutaneous rituximab. Investigator-assessed overall response at the end of induction was 84·9% (95% CI 79·2-89·5) in the intravenous group and 84·4% (78·7-89·1) in the subcutaneous group. The frequency of adverse events was similar in both groups (199 [95%] of 210 in the intravenous group vs 189 [96%] of 197 in the subcutaneous group); the frequency of adverse events of grade 3 or higher was also similar (116 [55%] vs 111 [56%]). The most common grade 3 or higher adverse event was neutropenia, which occurred in 44 patients (21%) in the intravenous group and 52 (26%) in the subcutaneous group. Serious adverse events occurred in 72 patients (34%) in the intravenous group and 73 (37%) in the subcutaneous group. Administration-related reactions occurred in 73 patients (35%) in the intravenous group and 95 (48%) patients in the subcutaneous group (mainly grade 1 or 2 local injection-site reactions).

Interpretation: Intravenous and subcutaneous rituximab had similar efficacy and safety profiles, and no new safety concerns were noted. Subcutaneous administration does not compromise the anti-lymphoma activity of rituximab when given with chemotherapy.

Funding: F Hoffmann-La Roche.
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http://dx.doi.org/10.1016/S2352-3026(17)30078-9DOI Listing
June 2017

Remembering Joan (Jan) Mary Anderson (1932-2015).

Photosynth Res 2016 Aug;129(2):129-46

Division of Plant Sciences, Research School of Biology, The Australian National University, 46 Sullivan's Creek Road, Acton, ACT, 2601, Australia.

Joan Mary Anderson, known to most people as Jan, was born on May 12, 1932 in Dunedin, New Zealand. She died on August 28, 2015 in Canberra, Australia. To celebrate her life, we present here a brief biography, some comments on her discoveries in photosynthesis during a career spanning more than half a century, and reminiscences from family and friends. We remember this wonderful person who had an unflagging curiosity, creative ability to think laterally, enthusiasm, passion, generosity and love of color and culture.
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http://dx.doi.org/10.1007/s11120-016-0287-1DOI Listing
August 2016

Response to "a rose by any other name" published in the 2014 July edition of the Journal of Forensic and Legal Medicine.

J Forensic Leg Med 2014 Aug 21;26:14. Epub 2014 May 21.

University of Central Lancashire, Preston, UK. Electronic address:

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http://dx.doi.org/10.1016/j.jflm.2014.05.002DOI Listing
August 2014

Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study.

Lancet Oncol 2014 Mar 10;15(3):343-52. Epub 2014 Feb 10.

Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada.

Background: Intravenous rituximab is a mainstay of treatment for follicular lymphoma. A subcutaneous formulation that achieves equivalent rituximab serum concentrations might improve convenience and save health-care resources without sacrificing clinical activity. We aimed to assess pharmacokinetic non-inferiority of 3 week cycles of fixed-dose subcutaneous rituximab versus standard intravenous rituximab.

Methods: In our two-stage, randomised, open-label, phase 3 trial, we enrolled patients with previously untreated grade 1-3a, CD20-positive follicular lymphoma at 67 centres in 23 countries. In stage 1, we randomly allocated patients 1:1 with the Pocock and Simon algorithm to intravenous rituximab (375 mg/m(2)) or fixed-dose subcutaneous rituximab (1400 mg), stratified by induction chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine, prednisone or cyclophosphamide, vincristine, prednisone), Follicular Lymphoma International Prognostic Index score, and region. After randomisation, patients received one induction dose of intravenous rituximab in cycle 1 and then allocated treatment for cycles 2-8. Patients with a complete or partial response following induction therapy continued intravenous or subcutaneous rituximab as maintenance every 8 weeks. The primary endpoint was the ratio of observed rituximab serum trough concentrations (Ctrough) between groups at cycle 7 (before cycle 8 dosing) of induction treatment in a per-protocol population. Patients were analysed as treated for safety endpoints. Stage 2 follow-up is ongoing and is fully accrued. This study is registered with ClinicalTrials.gov, number NCT01200758.

Findings: Between Feb 4, 2010, and Oct 21, 2011, we enrolled 127 patients. Pharmacokinetic data were available for 48 (75%) of 64 patients randomly allocated intravenous rituximab and 54 (86%) of 63 patients randomly allocated subcutaneous rituximab. Geometric mean Ctrough was 83·13 μg/mL in the intravenous group and 134·58 μg/mL in the subcutaneous group (ratio 1·62, 90% CI 1·36-1·94), showing non-inferiority of subcutaneous rituximab. 57 (88%) of 65 patients in the intravenous rituximab safety population had adverse events (30 [46%] grade ≥3), as did 57 (92%) of 62 patients in the subcutaneous rituximab safety population (29 [47%] grade ≥3). The most common grade 3 or worse adverse event in both groups was neutropenia (14 [22%] patients in the intravenous group and 16 [26%] patients in the subcutaneous group). Adverse events related to administration were mostly grade 1-2 and occurred in 21 (32%) patients in the intravenous group and 31 (50%) patients in the subcutaneous group.

Interpretation: Stage 1 data show that the pharmacokinetic profile of subcutaneous rituximab was non-inferior to intravenous rituximab and was not associated with new safety concerns. Stage 2 will provide data for efficacy and safety of the subcutaneous administration.

Funding: F Hoffmann-La Roche.
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http://dx.doi.org/10.1016/S1470-2045(14)70005-1DOI Listing
March 2014

Forensic physicians and written evidence: witness statements v. expert reports.

J Forensic Leg Med 2014 Feb 18;22:93-8. Epub 2013 Dec 18.

St Peter's Surgery, La Rue De L'Eglise, St Peter, Jersey JE3 7AG, United Kingdom. Electronic address:

When assisting the courts in criminal proceedings, the work of forensic physicians are leaning more towards the preparation of written evidence rather than the giving of oral evidence in person. For this, they may be asked to serve either as professional witnesses or expert witnesses. These 2 roles have nevertheless been a constant source of confusion among forensic physicians. In view of this, the article aims to highlight the similarities and differences between these 2 roles particularly in relation to the preparation of written evidence. It will take a close look at the forms of written evidence which forensic physicians are expected to produce in those distinct capacities and the attending duties, evidentiary rules and legal liabilities. Through this, the work aspires to assist forensic physicians undertake those responsibilities on a more informed footing.
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http://dx.doi.org/10.1016/j.jflm.2013.12.014DOI Listing
February 2014

Factors influencing early failure of central venous catheters in children with cancer.

J Pediatr Surg 2004 Oct;39(10):1520-3

Department of Paediatric Surgery, Royal Victoria Infirmary, Newcastle upon Tyne, UK.

Background: The authors report the results of a prospective, multicenter, multidisciplinary study of central venous catheters (CVCs) in pediatric oncology patients analyzing factors involved in early failure.

Methods: Information was collected from parent-held records on the fate of 824 devices inserted over a 20-month period, 415 of which were no longer in situ.

Results: Within the first 7 weeks after insertion, there were 66 failures, all occurring in external lines. Accidental dislodgement was the principal reason for CVC failure (44 of 66, 67%). Detailed analysis of the reason for failure of this large subgroup showed 11 factors individually associated with early dislodgement, of which, 4 were independently associated with failure by multivariate analysis. These 4 variables were the use of multilumen catheters, the absence of a skin exit site suture, platelet transfusion at the time of insertion, and patient age less than 2 years.

Conclusions: This study confirms the multiple influences on successful CVC usage. Our analysis supports the principle of only using multilumen lines when clinically essential. The findings also support the inception of randomized studies of fixation, particularly in infants.
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http://dx.doi.org/10.1016/j.jpedsurg.2004.06.020DOI Listing
October 2004
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