Update on Botulinum Toxins in Oculofacial Plastic Surgery
Update on Botulinum Toxins in Oculofacial Plastic Surgery
Although 5 of the botulinum toxin serotypes are potentially active in human tissue, only types A and B are approved by the FDA for therapeutic injection. There are 4 commercially available preparations of these toxins in the United States, each with its own structure and approved therapeutic indications (Table 1). There are 3 type A formulations (Fig. 4): OnabotulinumtoxinA or Botox (Allergan, Inc., Irvine, CA), IncobotulinumtoxinA or Xeomin (Merz Pharmaceuticals, Frankfurt, Germany), and AbobotulinumtoxinA or Dysport (Ipsen, Paris, France). Only 1 formulation of botulinum toxin type B is available: RimabotulinumtoxinB or Myobloc (Solstice Neurosciences, South San Francisco, CA). Myobloc, mainly used to manage cervical dystonia, has a relatively shorter duration of action compared with the type A toxins and is less commonly used in oculofacial plastic surgery. Therefore, we will be primarily discussing the similarities, differences, and practical utility of the 3 botulinum toxin type A preparations.
(Enlarge Image)
Figure 4.
Front and side-view photographs of the 3 type A toxin preparations available for injection in the United States. A and B, OnabotulinumtoxinA (Botox); C and D, AbobotulinumtoxinA (Dysport); E and F, Incobotulinumtoxina (Xeomin).
The active neurotoxin derived from C. botulinum is a 150 kDa molecule which is invariably present in each type A formulation. The main structural variability among the available type A formulations is related to the presence and relative amount of complexing proteins associated with the neurotoxin. The function of these proteins has not been clearly delineated, but some studies indicate that they stabilize the structural integrity of the compound in an acidic environment such as the gastrointestinal tract, thereby protecting the toxin as it passes through the stomach until it reaches the small intestine where it can be absorbed. It has also been suggested that they facilitate binding activity in target tissues, although this is likely not true. In fact, it has been shown that there is no difference in diffusion rate among the toxin preparations once in target tissues. Once exposed to physiological pH in the tissues of the neuromuscular junction, the neurotoxin, which is identical in each product, dissociates from the proteins and acts on the presynaptic terminal. A definitive need for the presence of these accessory proteins has not been established. Both onabotulinumtoxinA and abobotulinumtoxinA are associated with complexing proteins in differing amounts, whereas incobotulinumtoxinA, the newest formulation on the market, is pure toxin with the proteins removed.
All of the botulinum toxin serotypes interfere with the activity of soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) proteins, which are involved in the release of acetylcholine at the neuromuscular junction. Type A toxin specifically targets and cleaves synapsomal-associated protein (SNAP-25). Although the pure toxin in each type A formulation acts in this way, there are some differences among the products with regard to certain pharmacologic parameters. Type B toxin acts on vesicle-associated membrane protein synaptobrevin, a membrane protein of small synaptic vesicles.
Because each type A preparation has a unique biochemical profile, they vary with regard to their potency. As such, they are not equivalent with regard to dosing. A unit of onabotulinumtoxinA has a potency similar to a unit of incobotulinumtoxinA. Therefore, the dosing units of these toxins are essentially interchangeable, practically speaking. However, onabotulinumtoxinA and incobotulinumtoxinA are about 3 times as potent as abobotulinumtoxinA. Taking into account safety issues and antigenic potential, a conversion factor of 2.5 to 3 has been suggested when calculating a treatment dosage of abobotulinumtoxinA to equate that of onabotulinumtoxinA/incobotulinumtoxinA. A simplifying factor in this situation is the absolute amount of toxin present in each vial. Vials of both onabotulinumtoxinA and incobotulinumtoxinA contain 100 U of toxin. A vial of abobotulinumtoxinA contains 300 U. Therefore, if the same volume of normal saline is used as diluent in all preparations, the resultant concentrations would allow for equal volumes of solution to be administered while maintaining the 3 to 1 dosing ratio.
The type A formulations also differ with regard to their storage requirements. The compounds containing complexing proteins (onabotulinumtoxinA and abobotulinumtoxinA) have shorter shelf lives (3 y for onabotulinumtoxinA and 2 y for abobotulinumtoxinA) and must be stored at 2 to 8°C. In contrast, incobotulinumtoxinA seems to remain stable with retained biological activity at room temperature (25°C) for up to 4 years. This suggests that the stability of the formulations is not enhanced by the presence of complexing proteins.
An often-discussed aspect of botulinum toxin is its potential antigenicity. Treatment with botulinum toxin can occasionally fail as it is possible for patients to develop neutralizing antibodies. Although incobotulinumtoxinA has been available for a much shorter time, recent studies have indicated that it results in the formation of fewer neutralizing antibodies and may have reduced antigenicity in comparison to onabotulinumtoxinA and abobotulinumtoxinA. It has been hypothesized that these results from short-term data may be due to the lack of complexing protein in incobotulinumtoxinA. IncobotulinumtoxinA also contains less inactivated botulinum toxin, which is another potential immunogenic factor. Long-term analyses of development of neutralizing antibodies are necessary to make more definitive conclusions.
Given that there are 3 available formulations of botulinum toxin type A, the physician must decide which product is most appropriate for each patient. We have discussed the differences that exist between these preparations from a molecular and biochemical perspective. Theoretically, these attributes could lead to differences in therapeutic outcomes, and physicians should be aware of how the toxins differ. However, the bottom line is that in terms of practical efficacy, there are currently no studies which show one product being superior to another for a given common therapeutic indication. In our experience, satisfying results may be achieved with any of the type A formulations. Complication rates should be favorable provided the treatment is administered in an appropriate manner using sound technique. Physicians should choose the formulation(s) they feel most comfortable using in order to obtain the best possible result for their patients.
Preparations
Although 5 of the botulinum toxin serotypes are potentially active in human tissue, only types A and B are approved by the FDA for therapeutic injection. There are 4 commercially available preparations of these toxins in the United States, each with its own structure and approved therapeutic indications (Table 1). There are 3 type A formulations (Fig. 4): OnabotulinumtoxinA or Botox (Allergan, Inc., Irvine, CA), IncobotulinumtoxinA or Xeomin (Merz Pharmaceuticals, Frankfurt, Germany), and AbobotulinumtoxinA or Dysport (Ipsen, Paris, France). Only 1 formulation of botulinum toxin type B is available: RimabotulinumtoxinB or Myobloc (Solstice Neurosciences, South San Francisco, CA). Myobloc, mainly used to manage cervical dystonia, has a relatively shorter duration of action compared with the type A toxins and is less commonly used in oculofacial plastic surgery. Therefore, we will be primarily discussing the similarities, differences, and practical utility of the 3 botulinum toxin type A preparations.
(Enlarge Image)
Figure 4.
Front and side-view photographs of the 3 type A toxin preparations available for injection in the United States. A and B, OnabotulinumtoxinA (Botox); C and D, AbobotulinumtoxinA (Dysport); E and F, Incobotulinumtoxina (Xeomin).
Structural Differences
The active neurotoxin derived from C. botulinum is a 150 kDa molecule which is invariably present in each type A formulation. The main structural variability among the available type A formulations is related to the presence and relative amount of complexing proteins associated with the neurotoxin. The function of these proteins has not been clearly delineated, but some studies indicate that they stabilize the structural integrity of the compound in an acidic environment such as the gastrointestinal tract, thereby protecting the toxin as it passes through the stomach until it reaches the small intestine where it can be absorbed. It has also been suggested that they facilitate binding activity in target tissues, although this is likely not true. In fact, it has been shown that there is no difference in diffusion rate among the toxin preparations once in target tissues. Once exposed to physiological pH in the tissues of the neuromuscular junction, the neurotoxin, which is identical in each product, dissociates from the proteins and acts on the presynaptic terminal. A definitive need for the presence of these accessory proteins has not been established. Both onabotulinumtoxinA and abobotulinumtoxinA are associated with complexing proteins in differing amounts, whereas incobotulinumtoxinA, the newest formulation on the market, is pure toxin with the proteins removed.
Pharmacologic Differences
All of the botulinum toxin serotypes interfere with the activity of soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) proteins, which are involved in the release of acetylcholine at the neuromuscular junction. Type A toxin specifically targets and cleaves synapsomal-associated protein (SNAP-25). Although the pure toxin in each type A formulation acts in this way, there are some differences among the products with regard to certain pharmacologic parameters. Type B toxin acts on vesicle-associated membrane protein synaptobrevin, a membrane protein of small synaptic vesicles.
Because each type A preparation has a unique biochemical profile, they vary with regard to their potency. As such, they are not equivalent with regard to dosing. A unit of onabotulinumtoxinA has a potency similar to a unit of incobotulinumtoxinA. Therefore, the dosing units of these toxins are essentially interchangeable, practically speaking. However, onabotulinumtoxinA and incobotulinumtoxinA are about 3 times as potent as abobotulinumtoxinA. Taking into account safety issues and antigenic potential, a conversion factor of 2.5 to 3 has been suggested when calculating a treatment dosage of abobotulinumtoxinA to equate that of onabotulinumtoxinA/incobotulinumtoxinA. A simplifying factor in this situation is the absolute amount of toxin present in each vial. Vials of both onabotulinumtoxinA and incobotulinumtoxinA contain 100 U of toxin. A vial of abobotulinumtoxinA contains 300 U. Therefore, if the same volume of normal saline is used as diluent in all preparations, the resultant concentrations would allow for equal volumes of solution to be administered while maintaining the 3 to 1 dosing ratio.
The type A formulations also differ with regard to their storage requirements. The compounds containing complexing proteins (onabotulinumtoxinA and abobotulinumtoxinA) have shorter shelf lives (3 y for onabotulinumtoxinA and 2 y for abobotulinumtoxinA) and must be stored at 2 to 8°C. In contrast, incobotulinumtoxinA seems to remain stable with retained biological activity at room temperature (25°C) for up to 4 years. This suggests that the stability of the formulations is not enhanced by the presence of complexing proteins.
An often-discussed aspect of botulinum toxin is its potential antigenicity. Treatment with botulinum toxin can occasionally fail as it is possible for patients to develop neutralizing antibodies. Although incobotulinumtoxinA has been available for a much shorter time, recent studies have indicated that it results in the formation of fewer neutralizing antibodies and may have reduced antigenicity in comparison to onabotulinumtoxinA and abobotulinumtoxinA. It has been hypothesized that these results from short-term data may be due to the lack of complexing protein in incobotulinumtoxinA. IncobotulinumtoxinA also contains less inactivated botulinum toxin, which is another potential immunogenic factor. Long-term analyses of development of neutralizing antibodies are necessary to make more definitive conclusions.
Clinical Application: Putting it all Together
Given that there are 3 available formulations of botulinum toxin type A, the physician must decide which product is most appropriate for each patient. We have discussed the differences that exist between these preparations from a molecular and biochemical perspective. Theoretically, these attributes could lead to differences in therapeutic outcomes, and physicians should be aware of how the toxins differ. However, the bottom line is that in terms of practical efficacy, there are currently no studies which show one product being superior to another for a given common therapeutic indication. In our experience, satisfying results may be achieved with any of the type A formulations. Complication rates should be favorable provided the treatment is administered in an appropriate manner using sound technique. Physicians should choose the formulation(s) they feel most comfortable using in order to obtain the best possible result for their patients.
