Using translational medicine to understand clinical differences between botulinum toxin formulations

Abstract

When using botulinum toxin-based products, the physician must decide the optimal location and dose required to alleviate symptoms and improve the patient's quality of life. To deliver effective treatment, the physician needs to understand the importance of accurate target muscle selection and localization and the implications of each product's migration properties when diluted in different volumes. Pre-clinical mouse models of efficacy and safety have been utilized to compare local and distal muscle relaxation effects following defined intramuscular administration. Data from the model allow the products to be ranked based on their propensity for local efficacy versus their distal migration properties. Using standardized dilutions, the non-parallel dose-response curves for the various formulations demonstrate that they have different efficacy profiles. Distal effects were also noted at different treatment doses, which are reflected in the different safety and/or therapeutic margins. Based on these pre-clinical data, the safety and therapeutic margin rankings are ordered, largest to smallest, as BOTOX, Dysport and Myobloc. The results of subsequent clinical trials are variable and dose comparisons are inconclusive, thus supporting the regulatory position that the dose units of the individual preparations are unique and cannot be simply converted between products.

Clinical differences between botulinum neurotoxin type A and B

“…A rough estimate is that 1 A/Ona U corresponds 1 U A/Inco, 3e5 A/Abo U, and 50 B/Rima U, but the equivalence changes under different conditions. The reported equivalence ratio A/Abo: A/Ona in clinical studies ranges widely (1:1e1:11), although the most commonly quoted figures are 1:3 or 1:4 (Sampaio et al, 1997;Aoki et al, 2006;Bentivoglio et al, 2012). In two randomized, controlled studies, A/ Abo produced better results than A/Ona at 1:4 ratio, with higher occurrence of side effects (Sampaio et al, 1997;Nüssgens and Roggenk€ amper, 1997).…”

Assay of diffusion of different botulinum neurotoxin type a formulations injected in the mouse leg

“…It has been claimed that, because of the size of the complexes, the diffusion of neurotoxin into adjacent tissues is slower in the high molecular weight complex compared with the lower molecular weight complexes or with free neurotoxin. 2 This possibility has not been analyzed in vivo. Therefore, owing to its paramount importance, we undertook an ad hoc study to compare the diffusion of the above-mentioned BoNT/A formulations in vivo.…”

Retrospective evaluation of the dose equivalence of Botox® and Dysport® in the management of blepharospasm and hemifacial spasm: a novel paradigm for a never ending story

“…In our paradigm we did not include patients with other type of dystonia (e.g. torticollis) since size and number of cholinergic synapses, density and type of muscular fibers, as well as the number and precise site of the injections, may be variable across subjects further increasing the variability of outcome after BoNT treatment [8]. Therefore, in order to avoid the differences related to intra-and inter-individual variability, we focused our interest only in patients receiving BoNT into orbicularis oculi, given also its anatomical consistency across subjects.…”

“…To date, a large number of attempts (in vivo and in vitro animal models, clinical evaluations in humans) have been made to find a conversion factor that would allow a reliable conversion between Botox Ò and Dysport Ò (Table 4). Published conversion factors ranged from 1:1 [9] to 1:11 [10], although the most commonly quoted figures are 1:3 or 1:4 [8]. Two randomized and controlled studies using a conversion factor of 4 showed that Dysport Ò is more likely to produce better results (considering both efficacy and duration of improvement) than Botox Ò but it is associated with an increased occurrence of side effects [11,12].…”