Confusion about diffusion and the art of misinterpreting data when comparing different botulinum toxins used in aesthetic applications

Sirs, The recent review by Drs de Almeida and de Boulle (1), describing probable diffusion characteristics of the botulinum neurotoxin products when used in aesthetic and other indications, has sought to highlight potential differences between the Type A botulinum toxin products, based upon a range of data. Diffusion, or, more correctly, migration of Type A toxin products has become of concern recently as clinicians change from one product to another, based upon several reasons. A clear understanding of migration and the reasons for this are therefore essential if products are to be compared, particularly with respect to their activities in patients. There are, however, considerable difficulties with the data that currently exist on Type A toxin comparisons, both generated from preclinical models and as tested clinically. From a preclinical perspective, the doses given to animals are exceptionally high (up to 200 BOTOXH units per kilogram) (2–4) when compared to human maximum dosages (equivalent to 4 BOTOX units per kilogram in a patient with, for example, cerebral palsy (5)). Also, no account has been taken in many animal studies of the differences between the potency units of, for example, Dysport and BOTOX (6–8). The potency difference is a controversial issue that has been well recognized by clinicians, scientists and regulatory authorities worldwide for many years, yet has not been addressed in animal studies (2–4,9,10). Doses given in some animal studies have even been based upon the protein content of the product vial (9). No licensed clinical uses have ever been based upon vial protein content and, indeed, would have been erroneous based upon the incorrect information on protein load that has been referenced in the past, but now corrected (11). Finally, the response of different species to the botulinum toxins administered in clinically relevant doses has been well documented (12,13). No one species can provide absolute answers. Therefore, extrapolations from animal studies to clinical settings must only be made with significant caution. Assumptions have regrettably prevailed in several clinical studies which have tried to compare Type A toxin products. For example, assumptions about dose-ratio product conversions have been made, perhaps based upon other clinical publications, and applied directly to investigative patient treatments. Often, only a limited number of product dose ratios are examined in any study (see, for example, 1,14,15). These clinical comparisons generally produce results that show the absence of product equivalence at the dose-ratios tested. In such cases, the available data are then further extrapolated to statements such as ‘one product diffuses more than another’. This is incorrect. When the Type A toxins are tested in patients at different dose-ratios, the results obtained are simply for a given product at a given dose. In some cases, for example as presented by de Almeida and de Boulle (1), this might result in a different ‘action halo’ of anhidrosis for each product. In fact, what has been observed is the result of administering different doses of each toxin product and not different migration of the products. If more toxin is administered then more chemodenervation will occur and the action halo will be larger. If a comparison of products shows differences in action halo size, then the dose-ratio used in the study is inappropriate. Certainly, no