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Single, very low rituximab doses in healthy volunteers - a pilot and a randomized trial: implications for dosing and biosimilarity testing.

ABSTRACT: There are no dose-finding trials available for rituximab that could guide dosing in non-malignant diseases. We hypothesized that currently used doses (?375?mg/m2) exceed several hundred-fold the half-maximal effective dose, which is most sensitive for detecting putative differences between biosimilars and important for dose finding. In an open label, exploratory trial healthy volunteers received single infusions of rituximab at doses of 0.1, 0.3 or 1.0?mg/m2. Subsequently, in a double-blind, randomized trial healthy volunteers received single infusions of two rituximab products at doses of 0.1 and 0.3?mg/m2. In the exploratory trial rituximab transiently depleted CD20+ cells by a mean 68% (range: 57-95%), 74% (55-82%) and 97% (94-100%) immediately after the infusion of 0.1 (n?=?4), 0.3 (n?=?4) and 1?mg/m2 (n?=?8), respectively. In the randomized trial CD20+ cells decreased by a mean 48% (25-84%) - 55% (26-85%) and 81 (67-89%) - 87% (77-96%) after infusion of 0.1?mg/m2 (n?=?12) or 0.3?mg/m2 (n?=?8 proposed biosimilar, n?=?4 reference product) of the proposed biosimilar or the reference product, respectively. It is important to understand that in healthy volunteers <1% of the authorized rituximab doses depletes almost all circulating B lymphocytes. Thus, for non-malignant diseases alternative, more cost-effective dosing regimens seem plausible, but require clinical testing. (EudraCT-No. 2010-023781-45; EudraCT-No. 2013-001077-24).

SUBMITTER: Schoergenhofer C

PROVIDER: S-EPMC5760686 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Single, very low rituximab doses in healthy volunteers - a pilot and a randomized trial: implications for dosing and biosimilarity testing.

Schoergenhofer Christian C Schwameis Michael M Firbas Christa C Bartko Johann J Derhaschnig Ulla U Mader Robert M RM Plaßmann Raute Sunder RS Jilma-Stohlawetz Petra P Desai Kalpna K Misra Priya P Jäger Ulrich U Jilma Bernd B

Scientific reports 20180109 1

There are no dose-finding trials available for rituximab that could guide dosing in non-malignant diseases. We hypothesized that currently used doses (≥375 mg/m<sup>2</sup>) exceed several hundred-fold the half-maximal effective dose, which is most sensitive for detecting putative differences between biosimilars and important for dose finding. In an open label, exploratory trial healthy volunteers received single infusions of rituximab at doses of 0.1, 0.3 or 1.0 mg/m<sup>2</sup>. Subsequently, ...[more]

PMID: 29317666

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Project description:(1) Background: Studies have reported the effectiveness of light therapy in various medical conditions. Our pilot study aimed to assess the effect of Maharishi light therapy (MLT) on physiological parameters, such as the heart rate (HR), HR variability (HRV), blood pressure (BP), BP variability (BPV), and the retinal microvasculature of healthy participants; (2) Methodology: Thirty (14 males and 16 females) healthy, non-smoking participants between 23 and 71 years old (46 ± 18 years) were included in this randomized crossover study. Each participant was tested with a placebo (using LED light) and gem lights, 24 h apart. Hemodynamic parameters were recorded during the session, and 24 h heart rate and BP levels were assessed via mobile devices. Retinal vascular responses were captured with fundus images and the subsequent analysis of retinal vessel widths. A linear model, using repeated measures ANOVA, was used to compare the responses across the sexes and to assess the effect of the MLT; (3) Results: Changes in the central retinal artery equivalent (CRAE) (p < 0.001) and central retinal vein equivalent (CRVE) (p = 0.002) parameters were observed. CRAE and CRVE decreased under MLT and increased under the placebo condition from before to after. However, the baseline values of the participants already differed significantly before the application of any therapy, and the variation in the retinal vessel diameters was already large in the baseline measurements. This suggests that the observed effect results may only reflect naturally occurring fluctuations in the microcirculation and not the effect of MLT. Furthermore, no significant effects were observed in any other investigated parameters; (4) Conclusion: Our study with healthy participants finds significant changes in retinal parameters, but the biological variation in the baseline measurements was large to begin with. This suggests that the observed effect results only reflect naturally occurring fluctuations in the microcirculation and not the effect of MLT. However, in the future, larger studies in which MLT is applied for longer periods and/or in patients with different diseases could discover the physiological impacts of this type of therapy.

Dataset Information

Single, very low rituximab doses in healthy volunteers - a pilot and a randomized trial: implications for dosing and biosimilarity testing.

Publications

Single, very low rituximab doses in healthy volunteers - a pilot and a randomized trial: implications for dosing and biosimilarity testing.

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