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– Highlights from the latest news and research in clinical pharmacology

Methotrexate increases incidence of melanoma in rheumatoid arthritis patients A recent study, which was published in the June issue of Arthritis Care & Research suggests an increased risk of melanoma, as well as other malignancies, for rheumatoid arthritis (RA) patients receiving methotrexate. A chronic, inflammatory disease of unknown origin, RA affects approximately 1% of adults worldwide. Marked by joint destruction, RA often leads to disability and diminished quality of life, and can also lead to various cancers. The study focused on 459 RA patients in Melbourne, Australia, all of whom had started treatment with methotrexate prior to June 1986. Researchers set out to determine the cancer incidence in these patients compared with the general population and with the results of published studies on the incidence of malignancy in methotrexate-treated RA populations in other countries. Rheumatoid arthritis patients exposed to methotrexate have an estimated 50% excess risk of developing cancer in any form. The risk of non-Hodgkin’s lymphoma was more than five-times higher in RA patients than in the general population. RA patients also had a threefold increased risk of melanoma and almost a threefold increased risk of lung cancer. While the increased risk levels for nonHodgkin’s lymphoma and lung cancer were in line with the findings of related studies in Europe and the USA, the high risk for melanoma stood out as novel. “This study is, to our knowledge, the first to report an increased risk of melanoma in patients with RA treated with methotrexate compared with the general population”, notes its lead author Rachelle Buchbinder, from Monash University, Victoria, Australia. Interestingly, the researchers observed a 2.5-fold increased cancer risk for methotrexate-treated RA patients

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exposed to cyclophosphamide; however, contrary to expectation, no increased risk with exposure to azathioprine. “Further investigation is needed to determine whether this risk is unique to Australia and what role methotrexate, immunosuppression per se, and/or environmental factors, such as exposure to UV radiation, play in its development”, Buchbinder stresses. “Our findings, taken together with other studies

investigating the risk of skin cancer in patients with RA, may support a role for regular skin cancer screening for all patients with RA, particularly those receiving immunosuppressive therapy.” Source: Buchbinder R, Barber M, Heuzenroeder L et al. Incidence of melanoma and other malignancies among rheumatoid arthritis patients treated with methotrexate. Arthritis Care Res. 59(6), 794–799 (2008).

Combination treatment of nab-paclitaxel, carboplatin and trastuzumab for breast cancer found to increase progression-free survival Patients fighting metastatic breast cancer achieved a 16-month progressionfree survival when taking a combination treatment of nanoparticle albumin bound (nab)-paclitaxel, carboplatin and trastuzumab, according to research reported at the American Society of Clinical Oncology (ASCO) 44th Annual Meeting. In the study, a total of 32 women with metastatic breast cancer with normal left ventricular function, whose tumors overexpressed the HER2 gene, were treated with nab-paclitaxel 100 mg/m2 weekly for 3 weeks in a 4-week cycle, carboplatin at the same dosing schedule, and trastuzumab 2 mg/kg once weekly following a 4 mg/m2 loading dose. Overall, progression-free survival was 15.9 months and median response duration was 28 months. A total of two of the patients achieved a complete response to the treatment regimen and 14 patients achieved a documented partial response. An additional ten patients were able to stabilize their conditions.

10.1586/17512433.1.4.475

“Treatment continued in the absence of disease progression or unacceptable toxicity”, said lead author Andrew Seidman of the Memorial Sloan-Kettering Cancer Center, NY, USA. “In the absence of progression at six cycles, chemotherapy could be discontinued and trastuzumab maintenance therapy continued at the discretion of the treating oncologist.”

“…activity and the favorable toxicity profile support continued exploration of this regimen” “Both the activity and the favorable toxicity profile support continued exploration of this regimen in a larger population for first-line treatment of HER2positive metastatic breast cancer”, Seidman concluded. Source: Seidman AD. Phase II study of weekly nanoparticle albumin bound (nab)paclitaxel with carboplatin and trastuzumab as 1st-line therapy for HER2-positive metastatic breast cancer (MBC). Presented at: 2008 ASCO Annual Meeting. McCormick Place, Chicago, IL, USA. 30 May–3 June 2008.

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News in Brief

Study suggests anti-CD20 therapy effective against B-cell depletion in rheumatoid arthritis The critical role of memory B cells in the compromised immune reaction of rheumatoid arthritis has been revealed. A recent analysis, featured in the June 2008 issue of Arthritis & Rheumatism, reveals the critical role of memory B cells in the compromised immune reaction of rheumatoid arthritis (RA) and the short-term gains of rituximab therapy. With the goal of identifying reliable predictors of response or relapse to rituximab, researchers from the University of Wurzburg (Wurzburg, Germany), focused on the critical role of memory B cells in the compromised immune reaction of RA and the short-term gains of rituximab therapy. The investigation began with an openlabel trial constisting of one cycle of rituximab on 17 RA patients. The participants, 14 women and three men, had a median age of 51 years, a median disease duration of 14 years and a history of failure to respond to disease-modifying antirheumatic drugs (DMARDs) and/or antiTNF-α therapy. Blood samples from all participants were obtained at baseline, on day 15 and at a 3-month follow-up, and analyzed for B-cell repopulation.

“…the extent of memory B-cell repletion seems to be a key factor influencing the pathophysiology of RA.” After receiving one cycle of rituximab, 12 out of the 17 patients showed a good clinical response with significant improvement. Within the group of 12 responders, six patients experienced an early relapse of RA activity. A total of 11 patients were retreated and, again, achieved a good clinical response. After the second cycle of rituximab, the pattern of B-cell reconstitution was repeated. The number of B cells was still reduced at the time of second depletion but recovered to levels similar to those following the first cycle of therapy, indicating an unimpaired capacity of B-cell regeneration after repeated B-cell depletion. 476

Based on statistical analysis, the researchers found a significant correlation between the size of the IgD+, CD27 + memory B-cell subset during the early phase of B-cell repletion and the response to anti-CD20 treatment. “Patients with lower numbers of IgD memory cells at the beginning of peripheral B-cell repopulation had a much more favourable clinical response”, noted researcher Hans-Peter Tony. ‘Therefore, the extent of memory B-cell repletion seems to be a key factor influencing the pathophysiology of RA.”

While revealing a potentially important target for rituximab therapy in RA patients, this study calls for further research into whether patients with a high level of particular memory B cells may benefit from early retreatment or may even require higher doses of this anti-CD20 antibody. Source: Roll P, Dörner T, Tony H-P et al. AntiCD20 therapy in patients with rheumatoid arthritis: Predictors of response and B cell subset regeneration after repeated treatment. Arthritis Rheum. 58(6), 1566–1575 (2008).

Restless legs syndrome relieved by rotigotine skin patches A recent paper that was published online demonstrates that patients with restless leg syndrome (RLS) may get some relief during both the day and night by using skin patches that contain the drug rotigotine. The findings come from a randomized, placebo-controlled, doubleblind study published in the July edition of The Lancet Neurology. The trial analysed 458 patients with moderate-to-severe RLS, with an average baseline score on the International Restless Leg Syndrome Study Group Severity Rating Scale (IRLS) of 28.1 and a score of 4 or more on the Clinical Global Impressions (CGI) item 1 score, which measures severity of symptoms. Rotigotine was delivered via skin patches that were applied once a day over a period of 6 months. A total of 75% of patients indicated that their rotigotine patches were ‘good’ or ‘very good’ in a follow-up survey, although 43% of patients (145 out of 341) had (mostly mild or moderate) skin reactions to rotigotine. Only 2% of participants who received placebo reported skin reactions.

“The results of this 6-month trial indicate that transdermal delivery of low doses of rotigotine for 24 h per day is more effective than placebo in relieving the symptoms of RLS in patients who are moderately to severely affected. This trial … suggest(s) that, despite differences in treatment duration and other design features, there exists a clear therapeutic window in terms of dose of rotigotine to treat restless legs syndrome between 1 mg over 24 h to 3 mg over 24 h”, conclude the authors. In an accompanying commentart, Kapil Sethi (Medical College of Georgia, Augusta, GA, USA) noted, “The introduction of a patch with a constant delivery of a dopamine agonist is a welcome addition to the armamentarium. Unfortunately, the rotigotine patch has been temporarily withdrawn from the US market because of problems with manufacturing and the unreliable delivery of the drug.” Source: Trenkwalder C, Beneš H, Poewe W et al. Efficacy of rotigotine for treatment of moderate-tosevere restless legs syndrome: a randomised, doubleblind, placebo-controlled trial. Lancet Neurol. (Epub ahead of print).

Expert Rev. Clin. Pharmacol. 1(4), (2008)

News in Brief

BioPhausia acquires drug portfolio from AstraZeneca AstraZeneca has sold a portfolio of 16 prescription drugs to the Swedish pharmaceutical firm BioPhausia AB, a transaction part of BioPhausia’s strategy to strengthen its position as a leading speciality pharmaceutical company, and to increase its potential for future expansion. BioPhausia, based in Stockholm, Sweden, is paying 535 million Swedish kroner, or approximately US$91 million, for 16 drugs that have combined sales of 200 million kroner, 84% of which are generated in Sweden. The firm said that the acquisition is expected to be earnings positive in the current year and is predicted to boost pretax earnings by approximately 100 million kroner, almost double the 52 million kroner that was reported in 2007.

“Sales of the drug portfolio ‘have been stable despite the lack of marketing activities during the past couple of years’, according to BioPhausia.” The portfolio includes the pain treatment Citodon® (paracetamol/dihydrocodeine), Mollipect® (bromhexine/ephedrine) for coughs and Mucomyst® (acetylcysteine) for chronic bronchitis. Together, these drugs represent approximately 45% of sales. Regarding sales of the drug portfolio, they “have been stable despite the lack of marketing activities during the past couple of years”, according to BioPhausia. BioPhausia added that it had “good experiences from this acquisition and see interesting opportunities to, in a similar way, integrate the new portfolio into current operations.”

Single-dose rituximab as effective at desensitizing highly HLA-sensitized patients as double dose Study:

Comparison of two desensitization strategies using intravenous immunoglobulin (IVIG) and rituximab to improve transplantation rates

Participants:

16 highly HLAsensitized patients awaiting transplantation

Conclusion:

Administration of IVIG plus a single dose of rituximab is more effective than a double dose in desensitisation of highly HLAsensitized patients

A recent study presented at the 2008 American Transplant Congress (ATC) suggests that when added to intravenous immunoglobulin (IVIG) and given in a single dose, rituximab is as effective as two doses in desensitizing patients who are highly sensitized to HLA and who are awaiting living- or deceased-donor kidney transplants. Lead author Ashley Vo, of the PharmD Transplant Immunotherapy Program, University of California at Los Angeles School of Medicine (Los Angeles, CA, USA) and

colleagues compared two desensitisation strategies: IVIG 2 g/kg on days 1 and 30 plus two doses of rituximab 1 g on days 7 and 22 (group 1); or IVIG 2 g/kg on days 1 and 30 plus one dose of rituximab 1 g administered on day 15 (group 2). All 16 patients in group 1 received induction therapy with alemtuzumab, while patients in group 2 received alemtuzumab, daclizumab or antithymocyte globulin. All patients were maintained on tacrolimus, mycophenolate and steroids. An analysis of the results found no significant differences in graft survival, mean serum creatinine values or infection rates between the two groups; the rate of acute rejections was significantly lower among subjects in group 2. These data indicate that the administration of IVIG plus a single dose of rituximab allows for more rapid and effective desensitization of highly HLAsensitized patients awaiting transplantation compared with IVIG plus two doses of rituximab, the researchers concluded. Source: Vo A. Comparison of two desensitisation strategies using IVIG and rituximab to improve transplantation rates in highly-HLA sensitized patients (HS) awaiting living (LD) and deceased donor (DD) Transplantation. Presented at: 2008 American Transplant Congress. Toronto, ON, Canada, 31 May–4 June 2008.

About the News in Brief The News in Brief highlights some of the most important events and launches in the clinical pharmacology field. The editorial team welcomes suggestions for timely, relevant items. If you have newsworthy information, please contact: Sara Guy, Commissioning Editor, Expert Review of Clinical Pharmacology, Expert Reviews Ltd, Unitec House, 2 Albert Place, London N3 1QB, UK Tel.: +44 (0)20 8371 6090 Fax: +44 (0)20 8343 2313

Source: www.biophausia.se

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Methotrexate increases incidence of melanoma in rheumatoid arthritis patients.

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