Dose equivalence of two commercial preparations of botulinum neurotoxin type A: time for a reassessment?

ABSTRACT

Background: The units of different preparations of botulinum neurotoxin type A (BoNT-A) have different potencies, and dosing recommendations for each product are not interchangeable. Historically, there has been debate concerning the dose-equivalence ratio that should be used in clinical practice.

Methods: Published evidence was considered to establish an appropriate dose-conversion ratio for the two main commercially available preparations of BoNT-A – Dysport (Dp) and Botox (Bx).

Results: Four key areas of evidence were identified: nonclinical and preclinical studies; studies exploring the diffusion characteristics and effects of complexing proteins; comparative experimental data from human studies; and clinical studies. Nonclinical data indicate that the principal reasons for differences in unit potency between the two products are dilution artefacts in the mouse assay. Use of saline as a diluent, at high dilutions, results in significant loss of potency in the Bx assay, whereas use of gelatin phosphate buffer in the Dp assay procedure protects the toxin during dilution. The published data on mouse assays show a Dp : Bx unit ratio range of 2.3–2.5 : 1 in saline and 1.8–3.2 : 1 in gelatin phosphate buffer. Data indicate that complexing proteins or size of the complex, which is highly pH sensitive, play no role in toxin diffusion and that Dp and Bx have similar diffusion characteristics when used at comparable doses. Randomized, controlled clinical studies indicate that 3 : 1 is more appropriate than 4 : 1, but the two products are not equivalent at this ratio. Comparative human experimental studies using the extensor digitorum brevis test, facial lines and anhidrotic action halo tests support dose-conversion ratios less than 3 : 1.

Limitations: Data comparing dose equivalence ratios from the non-clinical setting should be extrapolated into the clinical setting with some caution.

Conclusions: Dose-conversion ratios between Dp and Bx of 4 : 1 and greater are not supported by the recent literature.

Transparency

Declaration of funding

This article was supported by Ipsen Limited, Slough, UK. Ipsen Limited is the manufacturer of botulinum neurotoxin type A (Dysport).

Declaration of financial/other relationships

D.C. has disclosed that he an employee of Ipsen Pharma GmbH. K.W. has disclosed that he has previously received unrestricted grants from Ipsen, Allergan and Merz. H.N. has disclosed that he has previously received unrestricted grants from Ipsen and Allergan, and that he has been a member of advisory boards for both companies. D.R. has disclosed that she has received educational grants from Ipsen and Allergan. T.S. has disclosed that he has received educational grants from Ipsen, Allergan and Merz.

All peer reviewers receive honoraria from CMRO for their review work. Peer Reviewer 1 has disclosed that he/she has received research grants from Bial, Teva, Solvay, Ipsen, Merz, GSK, Novartis, Allergan and Lundbeck and that he/she is a consultant for Gruenthal. Peer Reviewer 2 has disclosed that he/she has no relevant financial relationships.

Acknowledgments

Particular thanks are due to Andy Pickett, Senior Director of Biological Science and Technology, Ipsen Limited, for helpful comments on the manuscript. Editorial support for the preparation of this article was provided by Suzanne Patel, PhD and Christine Elsner at Ogilvy Healthworld Medical Education; funding for this support was provided by Ipsen Limited.

Notes

* Dysport is a registered trade name of Ipsen Limited; Botox is a registered trade name of Allergan Incorporated; Xeomin is a registered trade name of Merz Pharmaceuticals GmBH, Germany