Comparative Pharmacodynamics Study of 3 Different Botulinum Toxin Type A Preparations in Mice

Kwak, Seong-Sung; Kang, Won Hyoung; Rhee, Chang-Hoon; Yang, Gi-Hyeok; Cruz, Deu John M.

doi:10.1097/dss.0000000000002402

Cited by 10 publications

(15 citation statements)

References 44 publications

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“…Eight-week-old (221.2 ± 8.2 g) female Sprague-Dawley rats (Charles River, Hollister, CA, USA) were used in this study. Female rats are routinely used in our CMAP assay to provide standardization and published CMAP data are generally derived from females (e.g., [ 34 , 50 , 51 ]). Rats were socially housed in groups of four in shoebox cages, with woodchip shavings, and cardboard tunnels.…”

Section: Methodsmentioning

confidence: 99%

“…In summary, female CD-1 mice (Charles River), with a weight range of 20−28 g, and the weight of each mouse within an experimental replicate standardized to be within ± 2 g of the group mean, were used in this study. Similar to the reasons provided for the CMAP assay, female mice are routinely used in our DAS assay to provide standardization and published mouse DAS data are generally derived from females (e.g., [ 35 , 51 , 52 ]). Mice were housed in groups of six in polycarbonate cages with Alpha-dri ® bedding, shredded paper nesting material, and a plastic dome.…”

Section: Methodsmentioning

confidence: 99%

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OnabotulinumtoxinA Displays Greater Biological Activity Compared to IncobotulinumtoxinA, Demonstrating Non-Interchangeability in Both In Vitro and In Vivo Assays

Rupp

Nicholson

Canty

et al. 2020

Toxins

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Differences in botulinum neurotoxin manufacturing, formulation, and potency evaluation can impact dose and biological activity, which ultimately affect duration of action. The potency of different labeled vials of incobotulinumtoxinA (Xeomin®; 50 U, 100 U, or 200 U vials; incobotA) versus onabotulinumtoxinA (BOTOX®; 100 U vial; onabotA) were compared on a unit-to-unit basis to assess biological activity using in vitro (light-chain activity high-performance liquid chromatography (LCA-HPLC) and cell-based potency assay (CBPA)) and in vivo (rat compound muscle action potential (CMAP) and mouse digit abduction score (DAS)) assays. Using LCA-HPLC, incobotA units displayed approximately 54% of the protease activity of label-stated equivalent onabotA units. Lower potency, reflected by higher EC50, ID50, and ED50 values (pooled mean ± SEM), was displayed by incobotA compared to onabotA in the CBPA (EC50: incobotA 7.6 ± 0.7 U/mL; onabotA 5.9 ± 0.5 U/mL), CMAP (ID50: incobotA 0.078 ± 0.005 U/rat; onabotA 0.053 ± 0.004 U/rat), and DAS (ED50: incobotA 14.2 ± 0.5 U/kg; onabotA 8.7 ± 0.3 U/kg) assays. Lastly, in the DAS assay, onabotA had a longer duration of action compared to incobotA when dosed at label-stated equivalent units. In summary, onabotA consistently displayed greater biological activity than incobotA in two in vitro and two in vivo assays. Differences in the assay results do not support dose interchangeability between the two products.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

OnabotulinumtoxinA Displays Greater Biological Activity Compared to IncobotulinumtoxinA, Demonstrating Non-Interchangeability in Both In Vitro and In Vivo Assays

Rupp

Nicholson

Canty

et al. 2020

Toxins

View full text Add to dashboard Cite

show abstract

“…As a result, 0.06 and 0.12 mg/kg were selected as the dose of HSA. The dose of polysorbate 20 was selected based on the content of polysorbate 20 in COR-ETOX 1 (1.0 mg/vial, 60 kg human) and the human dosage of CORETOX 1 (0.2~3.6 vial) [12,13]. The dose of polysorbate 20 was also calculated in the same manner and 0.02, 0.1, and 0.4 mg/kg were selected as the dose of polysorbate 20.…”

Section: Animals and Facilitymentioning

confidence: 99%

“…For those reasons, Medytox, Inc. (Republic of Korea) has recently developed a complexing protein-free BoNT/A product (CORETOX 1 ) that uses polysorbate 20, a non-human-derived excipient, to replace the HSA [12,13]. Polysorbates, a series of polyoxyethylenated sorbitan esters, are hydrophilic and nonionic surfactants that have been widely used as a food additive and stabilizer in pharmaceuticals [14,15].…”

Section: Introductionmentioning

confidence: 99%

Safety verification for polysorbate 20, pharmaceutical excipient for intramuscular administration, in Sprague-Dawley rats and New Zealand White rabbits

Kim¹,

Kwak

Park³

et al. 2021

PLoS ONE

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Human serum albumin (HSA) has been widely used as a pharmaceutical excipient in Botulinum toxin serotype A (BoNT/A) products that are indicated for use in therapeutics and cosmetics. However, HSA as a human-derived material has some concerns, such as the potential risk of transmission of infectious agents, an insufficient supply, and difficulty in maintaining a certain quality. For those reasons, newly developed BoNT/A products (CORETOX®, Medytox, Inc., Republic of Korea) contained polysorbate 20, a non-human-derived excipient, to replace the HSA. However, most safety studies of polysorbate 20 have been conducted with non-invasive routes of administration, and thus there are a few studies on the safety of polysorbate 20 when administered intramuscularly. To secure the in vivo safety profile of polysorbate 20, a four-week repeated intramuscular dose toxicity study (0.02, 0.1, and 0.4 mg/kg, one injection every two weeks for a total of three injections) was conducted in 66 Sprague-Dawley (SD) rats. An intradermal irritation study was further conducted with 18 New Zealand White (NZW) rabbits. The toxicological evaluation of HSA (0.06 and 0.12 mg/kg) was also carried out as a comparative substance. Systemic and local toxicities were not observed in any of the SD rats or NZW rabbits based on clinical signs, body weight, hematology, clinical biochemistry, macroscopic findings on necropsy, histopathology of the injection site, and allergic reactions. The current study suggested that intramuscular administration of polysorbate 20 was considered to be safe at a level similar to that of HSA, which has an in vivo safety profile accumulated over the years. This provided the basis for the in vivo safety profile of polysorbate 20 administered intramuscularly and the scientific reliability of the use of polysorbate 20 as an alternative to HSA, which is used as an excipient for various pharmaceuticals in terms of its safety.

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“…Botulinum neurotoxins (BoNTs) are generated by the anaerobic bacterium Clostridium botulinum . There are seven antigenically distinct botulinum toxin serotypes (A to G), of which BoNT type A1 (BoNT/A1) has traditionally been indicated for use in cosmetics and various diseases such as axillary hyperhidrosis, chronic migraine, and neurogenic detrusor overactivity ( Nigam and Nigam, 2010 ; Chen, 2012 ; Walker and Dayan, 2014 ; Pirazzini et al, 2017 ; Kwak et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Model-Based Anticancer Effect of Botulinum Neurotoxin Type A1 on Syngeneic Melanoma Mice

Kang

Ryu

Kwak³

et al. 2022

Front. Pharmacol.

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In recent, Botulinum Neurotoxin A1 (BoNT/A1) has been suggested as a potential anticancer agent due to neuronal innervation in tumor cells. Although potential BoNT/A1’s mechanism of action for the tumor suppression has been gradually revealed so far, there were no reports to figure out the exposure-response relationships because of the difficulty of its quantitation in the biological matrix. The main objectives of this study were to measure the anticancer effect of BoNT/A1 using a syngeneic mouse model transplanted with melanoma cells (B16-F10) and developed a kinetic-pharmacodynamic (K-PD) model for quantitative exposure-response evaluation. To overcome the lack of exposure information, the K-PD model was implemented by the virtual pharmacokinetic compartment link to the pharmacodynamic compartment of Simeoni’s tumor growth inhibition model and evaluated using curve-fitting for the tumor growth-time profile after intratumoral injection of BoNT/A1. The final K-PD model was adequately explained for a pattern of tumor growth depending on represented exposure parameters and simulation studies were conducted to determine the optimal dose under various scenarios considering dose strength and frequency. The optimal dose range and regimen of ≥13.8 units kg−1 once a week or once every 3 days was predicted using the final model in B16-F10 syngeneic model and it was demonstrated with an extra in-vivo experiment. In conclusion, the K-PD model of BoNT/A1 was well developed to optimize the dosing regimen for evaluation of anticancer effect and this approach could be expandable to figure out quantitative interpretation of BoNT/A1’s efficacy in various xenograft and/or syngeneic models.

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Comparative Pharmacodynamics Study of 3 Different Botulinum Toxin Type A Preparations in Mice

Cited by 10 publications

References 44 publications

OnabotulinumtoxinA Displays Greater Biological Activity Compared to IncobotulinumtoxinA, Demonstrating Non-Interchangeability in Both In Vitro and In Vivo Assays

OnabotulinumtoxinA Displays Greater Biological Activity Compared to IncobotulinumtoxinA, Demonstrating Non-Interchangeability in Both In Vitro and In Vivo Assays

Safety verification for polysorbate 20, pharmaceutical excipient for intramuscular administration, in Sprague-Dawley rats and New Zealand White rabbits

Model-Based Anticancer Effect of Botulinum Neurotoxin Type A1 on Syngeneic Melanoma Mice

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