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The Pharmacodynamic Effects of Rituximab at Very Low Doses
Clinical Therapeutics The Pharmacodynamic Effects of Rituximab at Very Low Doses C. Schoergenhofer1; C. Firbas1; U. Derhaschnig1; R.M. Mader1; R. Sunder-Plaßmann1; P. Jilma-Stohlawetz1; K. Desai2; P. Misra2; U. Jäger1; and B. Jilma1 1 Medical University of Vienna, Austria; and 2Apotex Inc, Toronto, Canada Background: No dose-finding trials are available for rituximab that could guide dosing in non-malignant diseases. We hypothesized that currently used doses (≥ 375mg/m2) exceed several hundred-fold the half-maximal effective dose, which is most sensitive for detecting putative differences between biosimilars and important for dosefinding. Methods: In an exploratory, dose-finding, trial healthy volunteers received single infusions of 0.1 (n= 4), 0.3 (n= 4) and 1 mg/m2 (n= 8) rituximab. Subsequently, in a randomized, double-blind trial, healthy volunteers received single infusions of 0.1 (n= 24) or 0.3 mg/ m2 (n= 12) of two rituximab products. CD19/20+ cell counts were measured, pharmacokinetics and, immunogenicity were assessed. Results: Single infusions of 0.1, 0.3 and 1 mg/m2 rituximab transiently depleted CD20+ cells by a mean 68% (95%CI: 24-100%), 74% (95%CI: 59-84%) and 97% (95%CI: 95-99%), respectively. In the randomized trial infusion of 0.1mg/m2 or 0.3mg/m2 proposed biosimilar or reference rituximab decreased CD20+cells by 45% (95%CI: 32-58%) - 55% (95%CI: 45-66%) and 81 (95%CI: 73-87%) – 87% (95%CI: 74-100%), respectively. In the randomized trial, 26 of 36 patients developed human anti-chimeric antibodies and 9 of 36 patients developed neutralizing anti-drug antibodies. Pharmacokinetic analyses were limited by the assay sensitivity and the very low rituximab doses. However, there was a clear pharmacokinetic signal during the first 24 hours in the 1mg/m2 group. Conclusions: It is important to understand that < 1% of the authorized rituximab doses depletes all circulating B lymphocytes in healthy volunteers. This will help particularly countries struggling to meet the financial burden of therapy with biologics.
On Demand Sildenafil as a Treatment of Raynaud’s Phenomenon: A Series of N-of-1 Trials M. Roustit1,2,3; J. Giai4,5,6; O. Gaget3; M. Mouhib3; A. Lotito3; C. Khouri3; S. Blaise2,3; C. Seinturier3; F. Subtil4,5,6; B. Imbert3; P.H. Carpentier1,3; S. Vohra7; and J.L. Cracowski1,2,3 1 Univ. Grenoble-Alpes, F-38000 Grenoble, France; 2Inserm, HP2 UMR 1042, F-38000 Grenoble, France; 3CHU Grenoble-Alpes, F-38000 Grenoble, France; 4Université de Lyon, F-69000, Lyon, France; 5CNRS, UMR5558, F-69622, Villeurbanne, France; 6 Hospices Civils de Lyon, F-69003, Lyon, France; and 7University of Alberta, Edmonton, Alberta, Canada Background: Continuous treatment of Raynaud’s phenomenon (RP) with phosphodiesterase-5 inhibitors has shown moderate efficacy (1). Moreover, patients with RP may not be willing to take a long-term treatment; as RP attacks are usually triggered by exposure to cold, “as required” single doses before/during exposure may be a good alternative. The objective of the present study is to assess the efficacy and safety of an on demand sildenafil treatment in RP. Methods: A series of randomized, double-blind, N-of-1 trials was conducted in patients with primary or secondary RP. Each trial consisted in repeated cycles of 1-week treatment periods with placebo, sildenafil 40 mg or sildenafil 80 mg taken as required, with a maximum of two doses daily. Mixed models were used and parameters were estimated in a Bayesian framework to determine individual and aggregated probabilities of efficacy on the Raynaud’s Condition Score (RCS) and the frequency of RP attacks. Skin blood flow in response to cooling was assessed with laser speckle contrast imaging.
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Results: Thirty-eight patients completed two to five treatment cycles (secondary RP, n= 12). Aggregated data demonstrates that the probability that the efficacy of sildenafil 40 mg is superior to that of the placebo on the frequency of RP is 93%, and 90.6% for the RCS; and 91.5% and 62.6%, respectively, for sildenafil 80 mg. Sildenafil was associated with significantly more adverse events than placebo. We observed a dose-dependent effect of sildenafil on skin blood flow during cooling. Conclusions: On demand sildenafil has a greater probability of efficacy than placebo in patients with RP. Individual data show highly heterogeneous response, highlighting the need for personalized treatment for these patients. ClinicalTrials.gov Identifier: NCT02050360
Reference 1. Roustit M, Blaise S, Allanore Y, Carpentier PH, Caglayan E, Cracowski J-L. Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud’s phenomenon: systematic review and meta-analysis of randomised trials. Ann. Rheum. Dis. 2013;72:1696–1699.
Do Electronic Prescribing Systems in English Hospitals Support Antimicrobial Stewardship? an Analysis of ‘Start Smart– Then Focus’ Functionality I.K. Madar1; J.J. Coleman1; A. Slee2; and S.K. Pontefract1 University of Birmingham, Birmingham, United Kingdom; and 2 NHS England, London, United Kingdom Background: Antimicrobial resistance is one of the greatest threats to global public health. The excessive and inappropriate use of antibiotics are significant contributors to the progression of resistance. This can be tackled through antimicrobial stewardship (AMS) initiatives. Electronic prescribing (ePrescribing) systems have been shown to encourage appropriate antibiotic use. Despite a brief investigation into AMS capabilities by a self-assessment of digital maturity disseminated by NHS England in 2015, the features of systems within English hospitals to support AMS remains poorly understood. The main aim of this research was to further investigate how ePrescribing systems in English hospitals support AMS. Methods: An online self-reported questionnaire was developed to assess the capability of hospital ePrescribing systems to prompt adherence to UK ‘Start Smart – Then Focus’ AMS. The questionnaire was emailed to ePrescribing pharmacists from 34 acute English NHS Trusts, purposefully sampled based on their self-reported digital maturity. The data were analysed according to the percentage of Trusts demonstrating each element of ‘Start Smart–Then Focus’. Results: Responses were received from 76.5% (n= 26/34) of hospitals surveyed. No systems could demonstrate all elements of ‘Start Smart–Then Focus’. Systems had more capability to promote documentation of initial antibiotic therapy as part of ‘Start Smart’, with the nature of allergy being the most common capability exhibited (96.2%, n= 25/26). One system prompted prescribers to change to a narrower spectrum antibiotic as part of ‘Then Focus’, but no system encouraged discontinuation of treatment if there was no evidence of a bacterial infection based on cultures and sensitivities. Conclusions: The ePrescribing systems investigated did not support AMS fully according to ‘Start Smart –Then Focus’. However, systems were more capable of promoting appropriate prescribing at initiation compared to rationalising antibiotic therapy upon review.
1
Five-Year Antimicrobial Susceptibility Trends Among Bacterial Isolates from King Faisal Hospital Tertiary Health-Care Facility in Kigali, Rwanda M. Carroll1; A. Rangaiahagari2,3; E. Musabeyezu3; D.R.J. Singer4; and O. Ogbuagu5
Volume 39 Number 8S
On Demand Sildenafil as a Treatment of Raynaud’s Phenomenon: A Series of N-of-1 Trials M. Roustit1,2,3; J. Giai4,5,6; O. Gaget3; M. Mouhib3; A. Lotito3; C. Khouri3; S. Blaise2,3; C. Seinturier3; F. Subtil4,5,6; B. Imbert3; P.H. Carpentier1,3; S. Vohra7; and J.L. Cracowski1,2,3 1 Univ. Grenoble-Alpes, F-38000 Grenoble, France; 2Inserm, HP2 UMR 1042, F-38000 Grenoble, France; 3CHU Grenoble-Alpes, F-38000 Grenoble, France; 4Université de Lyon, F-69000, Lyon, France; 5CNRS, UMR5558, F-69622, Villeurbanne, France; 6 Hospices Civils de Lyon, F-69003, Lyon, France; and 7University of Alberta, Edmonton, Alberta, Canada Background: Continuous treatment of Raynaud’s phenomenon (RP) with phosphodiesterase-5 inhibitors has shown moderate efficacy (1). Moreover, patients with RP may not be willing to take a long-term treatment; as RP attacks are usually triggered by exposure to cold, “as required” single doses before/during exposure may be a good alternative. The objective of the present study is to assess the efficacy and safety of an on demand sildenafil treatment in RP. Methods: A series of randomized, double-blind, N-of-1 trials was conducted in patients with primary or secondary RP. Each trial consisted in repeated cycles of 1-week treatment periods with placebo, sildenafil 40 mg or sildenafil 80 mg taken as required, with a maximum of two doses daily. Mixed models were used and parameters were estimated in a Bayesian framework to determine individual and aggregated probabilities of efficacy on the Raynaud’s Condition Score (RCS) and the frequency of RP attacks. Skin blood flow in response to cooling was assessed with laser speckle contrast imaging.
e4
Results: Thirty-eight patients completed two to five treatment cycles (secondary RP, n= 12). Aggregated data demonstrates that the probability that the efficacy of sildenafil 40 mg is superior to that of the placebo on the frequency of RP is 93%, and 90.6% for the RCS; and 91.5% and 62.6%, respectively, for sildenafil 80 mg. Sildenafil was associated with significantly more adverse events than placebo. We observed a dose-dependent effect of sildenafil on skin blood flow during cooling. Conclusions: On demand sildenafil has a greater probability of efficacy than placebo in patients with RP. Individual data show highly heterogeneous response, highlighting the need for personalized treatment for these patients. ClinicalTrials.gov Identifier: NCT02050360
Reference 1. Roustit M, Blaise S, Allanore Y, Carpentier PH, Caglayan E, Cracowski J-L. Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud’s phenomenon: systematic review and meta-analysis of randomised trials. Ann. Rheum. Dis. 2013;72:1696–1699.
Do Electronic Prescribing Systems in English Hospitals Support Antimicrobial Stewardship? an Analysis of ‘Start Smart– Then Focus’ Functionality I.K. Madar1; J.J. Coleman1; A. Slee2; and S.K. Pontefract1 University of Birmingham, Birmingham, United Kingdom; and 2 NHS England, London, United Kingdom Background: Antimicrobial resistance is one of the greatest threats to global public health. The excessive and inappropriate use of antibiotics are significant contributors to the progression of resistance. This can be tackled through antimicrobial stewardship (AMS) initiatives. Electronic prescribing (ePrescribing) systems have been shown to encourage appropriate antibiotic use. Despite a brief investigation into AMS capabilities by a self-assessment of digital maturity disseminated by NHS England in 2015, the features of systems within English hospitals to support AMS remains poorly understood. The main aim of this research was to further investigate how ePrescribing systems in English hospitals support AMS. Methods: An online self-reported questionnaire was developed to assess the capability of hospital ePrescribing systems to prompt adherence to UK ‘Start Smart – Then Focus’ AMS. The questionnaire was emailed to ePrescribing pharmacists from 34 acute English NHS Trusts, purposefully sampled based on their self-reported digital maturity. The data were analysed according to the percentage of Trusts demonstrating each element of ‘Start Smart–Then Focus’. Results: Responses were received from 76.5% (n= 26/34) of hospitals surveyed. No systems could demonstrate all elements of ‘Start Smart–Then Focus’. Systems had more capability to promote documentation of initial antibiotic therapy as part of ‘Start Smart’, with the nature of allergy being the most common capability exhibited (96.2%, n= 25/26). One system prompted prescribers to change to a narrower spectrum antibiotic as part of ‘Then Focus’, but no system encouraged discontinuation of treatment if there was no evidence of a bacterial infection based on cultures and sensitivities. Conclusions: The ePrescribing systems investigated did not support AMS fully according to ‘Start Smart –Then Focus’. However, systems were more capable of promoting appropriate prescribing at initiation compared to rationalising antibiotic therapy upon review.
1
Five-Year Antimicrobial Susceptibility Trends Among Bacterial Isolates from King Faisal Hospital Tertiary Health-Care Facility in Kigali, Rwanda M. Carroll1; A. Rangaiahagari2,3; E. Musabeyezu3; D.R.J. Singer4; and O. Ogbuagu5
Volume 39 Number 8S