By Dr Vinny Naidoo
Bioequivalence is the comparison of the plasma profile between the test and reference product. A generic product is bioequivalent to the innovator product and it thus essentially identical – in a species group. There is no pharmacokinetic evidence to support human medicines being generics for veterinary species.
A good way to start this article, would be for you to close your eyes and contemplate the valuable role veterinarians play in the health and welfare of animals. At this point, you would probably agree that veterinarians play an invaluable role of the diagnosis and treatment of animal disease or disease conditions. However have you ever considered what the function of the veterinarian would be, if we as a profession, had no medication available to treat our patients? Probably very little, and even less so since the profession has moved away from the use of Materia Medica (books describing how to prepare one’s own medicines). So what has changed? The answer is simple and reflects our acceptance of modern pharmaceutical science as the means of treating disease.
These prepared formulations offer a number of benefits over practice-based drug preparations. These include:
- Ready availability (e.g. does not need to be prepared which save times and the need to keep raw ingredients as in an apothecary);
- they have long shelf lives (which means one does not need to keep restocking with new/fresh ingredients);
- one could rely on the use of synthetic chemicals (that would otherwise not be readily available)
- purer formulations (in that they’re not contaminated with foreign material or bacteria);
- potential for parenteral administration for rapid or sustained effect (since they’re sterile and pure) and lastly,
- they control for variable effects that can result from inconsistencies in absorption. All of which is possible through our better understanding of various aspects in pharmacology, such the drug’s pharmacokinetic profile, mechanisms of action, the interaction between pharmacokinetics and effect and the importance of biopharmaceuticals in the effects of medication.
How do drugs produce their effects?
Drugs produce their effects by interacting with receptors in the body. These receptors are typically proteins on the cell surface. When the drugs bind to these receptors, they essentially instruct a cell to bring about a change in function or activity, which we would interpret as a clinical effect. The effect is considered agonistic if it mimics or causes an increase in normal cellular function or antagonistic if it opposes or reverses normal physiological function. While the clinical effect is simple to interpret, at the cellular level, this can take effect at various levels, which is beyond the scope of this publication.
The study of a drug’s effect is known as pharmacodynamics. From pharmacodynamic theory we know that the final effect is dependent on the number of receptors on/in the cell, the concentration of drug achieved at the site of my receptors (biophase) and the internal cellular processes. In the majority of cases we cannot control the number of receptors on the cell surface (I would not say impossible as we do this in certain cases such as COPD management, when a beta agonist and a steroid are used in combination) or the internal cellular processes (One again some drugs can, but rarely). So in pharmacological development we chose drugs that activate our required process, and vary the effect by controlling the concentration of drug reaching the cell receptor and/or we can chose drugs that have an inherent lower/higher ability to activate the receptor. This study is known as the receptor-drug interaction and is commonly referred to as receptor affinity. The effect the drug has on a receptor, would be drug’s intrinsic activity which can be partial activation, full activation or inactivation.
Pharmacokinetics is the study of the movement of drug through the body, from the site of administration, to the site of effect and finally to the method of elimination. Of these absorption is dependent on the site of administration, the amount administered, the ability to body to remove the drug before it is absorbed and drug’s chemical profile. Similar factors determine whether the drug gets to the site of action, while elimination is dependent on the need for the drug to be metabolised or excreted.
The processes involved in the pharmacokinetics of a drug are studied by following the change in concentration of drug in the plasma of time (Figure 1). Using differential calculus, one can follow the change characteristics of the curve and establish mathematically how the drug is absorbed, distributed and/or eliminated. In pharmacokinetics the key controlling aspect is the drug formulation which controls absorption and elimination, and the endogenous/systemic processes which control elimination
Figure 1: A typical plasma concentration versus time that results following extravascular administration of a drug. A: Is the absorptive phase; B: a combination of the absorptive and distributive phase and C: The elimination phase. The dotted line represents the relationship of the plasma concentration with the effect concentration (For the latter, one can see that it’s’ not only the ability to reach said concentration that is important, but the duration of time that the concentration can be achieved).
As one can see, since the drug concentration at the receptor site is important, and that the drug pharmacokinetics determines the drug concentration in the body, these the two process must interact to produce a drug effect. More importantly this principle states that if two drugs achieve the same concentration in the plasma, they should be equally as effective.
Medication that are sold commercially, are sold as a mixture of ingredients that all interact to allow the said drug to have its effect. The formulation is there to ensure that the drug is adequately absorbed into the circulation and it can also control the rate of absorption. To place this into perspective, the formulation controls the time to a drug’s first effect, the degree of effect and thus the degree of side effects. The formulation has a number of potential components, which all fulfil different roles in allowing the active ingredient to be absorbed, as well as the shelf-life of the drug (Table 1).
Another important feature of the formulation is the actual chemical properties of the active ingredient, which also has an impact on drug absorption, chemical stability, interaction with excipients and at times even activity. For the latter it’s’ important to note that the active ingredient can also occur in different forms (e.g. amorphous versus crystalline) with some chemical forms being ineffective. The same can apply for chirals (L and D Isomers) with some isomers being inactive, more active or even toxic (e.g. dexmedetomidine is the active chiral of medetomidine).
Table 1: Some value potential of various excipients in the formulation
(Components of a finished drug other than the active pharmaceutical ingredient)
|Reason for Inclusion|
|Sweeteners and flavourings||Improve the palatability of oral medication, to improve compliance in treatment.|
|Bulking agents||Provides bulk to the formulation to allow for easier handling during dosing or packaging.|
|Diluent||Brings the formulation to the correct volume of drug per ml of solution/suspension|
|Solubilizers||Allows the active ingredient to dissolve in the diluent|
|Stabilizer||Stabilizes the active ingredient and prevents it from chemically degrading and potentially|
|Preservative||Increase the shelf life of the formulation|
|Wetting agents||Allows water to penetrate into a table, so that it can break up and dissolve faster in physiological fluid|
|Lubricants||Allows powders to flow through the machines that produce the tablets, without the formulation getting stuck or separation of the active ingredient from the rest of the formulation|
|Chelators||Binds certain ions and prevents bacterial growth|
|Antimicrobials||Prevent the growth of bacteria|
In the formulation, the actives and inactives will interact with one another to control absorption (Figure 2).
From numerous pharmaceutical studies, we know that a change in the excipients or a change in the ratio of ingredients can result in different absorption profiles between formulations. The same can be said if a different form of the active (e.g. different salt, different size of molecular, different polymorph, different isomer) is in use.
As a given rule, no two formulations are identical until proven i.e. simply being told that formulation has the same active as another product is not sufficient to assume efficacy. This would need to be proven with validate methodology such as bioequivalence testing. Another important factor to be consider is the potential for the inactive and active to interact with one another with resultant inactivation, or change in tabletting pressure that precludes the release of the active ingredient in the same period of time, or even the incorrect pH which can cause pain and tissue damage on administration.
Since we know that the formulation effect is extremely important, drug manufacturers have to ensure that their formulations are as uniform as possible. Most try and keep their drugs within a 5% variation of the expected from batch to batch (e.g a 5mg tablet may have 4.5 to 5.5 mg therein), which is lower than natural variation which can be as high as 10%. This process of control is known as Good Manufacturing Practice (GMP), and involves standardising as many factors as possible, from how the chemicals are sourced to how the equipment is handled, serviced and calibrated. It expects the manufacturer to undertake routine assays of their formulation at various steps in manufacture as well to ensure that staff are adequately trained.
Other important aspects include the source and purity of the chemicals in use e.g. what’s the purity, is it free of endotoxins, it is free of contaminants, it is free of bacteria, etc. While this process does add to the costs of production, it is well known that without these control measures the variation in the formulation can result in unpredictable variations in plasma concentrations, which could translate to ineffective treatment, treatment being toxic or even inconsistent treatment where one dose works and another fails.
Figure 2: Interaction of the formulation effect, pharmacokinetics and pharmacodynamics of the drug. The figure shows the importance of the formulation in controlling the subsequent pharmacokinetic profile of the drug and its effect concentration achieved at the biophase
PD -pharmacodymanics – study of the biochemical and physical effects of a drug
PK – pharmacokinetics – explains how the body affects a specific chemical after administration – through the mechanisms of absorbtion, distribution , changes in enzymes for drug metabolism, and effects and routes of excretion of the drug metabolites
Bioequivalence means that two drugs release their active ingredient into the blood stream in the same amounts and at the same rate.
General types of medicines
In the regulatory system, medicines general fall into three categories: Innovator products, Generic products and Compounded products. These three categories are controlled by the Medicines and Related Substance Control Act (Act 101 of 1965):
- Innovator Products: Are the first products that are brought onto the market. They are tested as the final formulation to prove that the active ingredient is properly released and that the formulation is effective. When registered, each indication is looked at individually and requires testing usually with actual clinical cases. The innovator company is generally allowed a period of 20 years from patenting, to sell their product with no competition. It is during this period that they recoup their investment. At all times, the manufacturer has to meet strict GMP requirements.
- A Generic formulation: Is a formulation that contains the same active ingredient as the innovator, and is registered through an abbreviated process known as bioequivalence or occasionally therapeutic equivalence. For the former process, the pharmacokinetics of the generic and the innovator formulation is compared. If the two formulations can be statistically proven to be bioequivalent, it can be registered as a generic to the innovator product. The underlying principle comes from the pharmacokinetic-pharmacodynamic interactions of the active mentioned above. If the two drugs allow for the same plasma concentration to be consistently achieved, there’s no reason that they won’t have the same effect. Since we do know that the manufacture of the formulation can influence the plasma pharmacokinetics, the formulation has to meet strict GMP conditions, to ensure batch to batch uniformity. Generics are thus cheaper than the innovator because they don’t have to redo the efficacy and toxicity tests, as these have already been undertaken by the innovator company i.e. why retest for aspects that are already known. Since the pharmacokinetics of the generic formulation is unknown, this is what needs to be tested (Figure 3). With this said, the requirements for comparing the pharmacokinetic profiles of the generic to the innovator formulation is still very strict and has to comply with numerous requirements from the study design to the analytical chemistry part of the study.
Figure 3: Illustration of how pharmacokinetics are applied in the process of proving bioequivalence of generic formulations (The graphs in question would be supported by a full statistical evaluation for registration purposes). In this case, two different generic formulations (T) (Each one has its own graph) are compared to the same reference product (R). In each of these cases the test and the reference product were compared to a reference produce in an independent two by two cross over study. As evident, the test generic formulation on the left clearly shows that the formulation is not bioequivalent as their profiles are not sufficiently similar. In contrast, the two formulations on the right are bioequivalent which is evident by the almost superimposed profiles.
The principle of generic registration is considered to be highly sound, and has been used to bring numerous generic medications onto the market over the last 40 years, with no proof existing that a generic is inferior when used for its registered indication. The science is so sound, that the innovator company also relies on the same methodology when they want to change their formulation e.g. when a tablet is changed to a palatable tablet, bioequivalence testing is used to save on costs and prevent retesting as once again, there is no need to repeat all the tests. All in all, if a generic formulation is registered and the company follows GMP, there should be no difference between a generic and an innovator.
Nonetheless an important concept in generic medication development is the concept of switchability and prescribability.
- Generics are interchangeable and any of the registered formulation for a particular species can be considered a valid effective choice at the start or initiation of treatment in a patient. This is known as prescribability i.e. the choice is open when the drug is first prescribed.
- However this scenario changes when one is treating a chronic condition where the patient has been stabilised on treatment with a particular formulation e.g. epilepsy. Under these conditions, it is not advisable to switch formulations acutely (irrespective of whether it a generic or innovator) acutely. This acute switching can only occur if the products are tested for switchability, which most formations are not e.g. one can chose to use formulation A or formulation B initially (at this stage there is no difference). However at the end of the month, stick to the same formulation and don’t change acutely as this can be dangerous and result in destabilisation (i.e. for chronic patients, stock the same formulation). If you do need to change formulation, it’s always safer to phase out the old formulation while the new formulation is phased in.
- Compounded formulations: These are formulations that are meant for use in an individual patient and are tailor made drugs, usually made by a pharmacist on an “as needed” basis. Compounded formulations are generally simple formulations with the active dispersed in an excipient. These compounded products, due to their individualised nature, don’t need to legally comply with GMP requirements, and thus may be open to all the problems mentioned above. For this reason, the use of compounded products from a safety point to the patient and consumer, should not be used when there are alternate registered products i.e. legally one takes responsibility for the use. More importantly, it may be more difficult legally to demonstrate that the use of the compounded product use was prudent when there are GMP approved alternates available. Also of importance to consider is the product’s sterility and purity and shelf life. Since this may be a problem, compounded products should ideally be limited to oral or topical use; and they should not be used in production animals.
Is a Generic, definitely a generic?
This may seem as an odd question, in light of what has been said above. But it’s important to know the constraints of the process of bioequivalence. The foremost principle of bioequivalence is the comparison of the plasma profile between the test and reference product, and show that they’re essentially identical. However as mentioned under pharmacokinetics, the PK of a drug is dependent on a number of factors such as absorption and elimination. This would mean that the profile is dependent on the species of testing and the metabolism of the drug. As such, when bioequivalence is shown, each profile has to be determined for each the different route recommended and in each of the different species it is indicated for. As an example, a drug recommended for use by the subcutaneous and intramuscular in pigs, cattle and horses, will need to be tested in six separate studies to show that all the routes per species are bioequivalent. Since it may not always be possible demonstrate bioequivalence in all these studies, some generic formulations will have curtailed claims. As such it is important to check what the recommendation are on the package instead of assuming that they are the same as the innovator (reference product).
Another important consideration is the use of human medication in animals. Firstly this extra-label use of the drugs has legal implications, as the person recommending this use, takes responsibility if something goes wrong (for registered veterinary drugs used correctly as stated on the package insert, the registration owner takes responsibility). The use of human drug extra-label is nonetheless considered safer than using a compounded product, as good manufacturing practice is still in place as it’s a registered human product (i.e. same liability, but lower risk). As a veterinarian, it is incumbent on you to make use of your professional judgement when choosing to use a human formulation. Firstly consideration must be given to the dose, which means that one needs to take into consideration the studies that have demonstrated that this extra-label use is prudent. For the latter consideration needs to be given to the sample size, as registered product use a substantial number of clinical cases to prove that the effect is real (as large as a few hundred animals) i.e. the published study on extra-label use may only have included a small number of clinical cases and not taken into consideration intra-subject variability in effect and side effects. Another important consideration would be that the product used in the publication, may not necessarily be the same product that is sold locally e.g. There are numerous cases of companies choosing to market different formulations in different countries for various manufacturing reasons even though the name is the same. It is possible that the published formulation may have a different response to the South African available drug, purely because they are of different formulation.
Another important scenario that comes up in South Africa is the cost of the medication. Under some conditions veterinary medications may be more expensive than their medical generics, due to lower costs on the medical side from larger scale production. Can one use these human generics as cheaper therapeutic options? Firstly legally, the onus is on the treating veterinarian to let the owner know that there is a veterinary formulation and give them the option. The reason for this, is that the medical product has been tested in only people and thus the veterinary profile may be unknown i.e. it may be possible that the drug has different profiles in the veterinary patient than in people. (Table2)
When the GIT of man is compared to animals, there are major difference that can influence absorption between the species. These difference may be anatomical in that there are different structure of the GIT; there may be difference in transit times; difference in content and thus non-specific binding; differences in bile salts; differences in pH amongst the different areas; differences in GIT bacterial content and/or species; differences in liver metabolic capacity; and most importantly differences in the transport proteins in the intestinal wall. The latter is also a major reason why veterinary drugs differ so much between species.
To illustrate the process, the innovator veterinary formulation of amoxycillin-clavulanate and Ran-ClavÒ (Ranbaxy) were compared at the same dose and the same route in the same six Beagles (in a cross-over study undertaken by myself).(Figure 4) The result for amoxycillin phase of the study showed a marked difference in absorptive profile between the two formulations. While the small sample size did result in significant variability in both groups, this was much more substantial (>80%) in the Ran-ClavÒ group. This study illustrates the point that the non-veterinary formulation could not only differ in the extent of absorption, but more importantly could result in large intra-subject variability which could mean completely inferior treatment in some individuals. This effect is addition to being potential dangerous, is also generally unknown until tested.
Figure 4: Average plasma concentration versus time profile for amoxycillin for a veterinary (R) and non-veterinary (T) amoxycillin formulation tested in the same group of six dogs in a 2×2 cross over study.
Drug regulation science, is a highly complex science that is focused on allowing the treating veterinarian the best chance of getting therapeutic success in a patient with the least chance of formulation failure. This science extends to both innovator and generic formulations, but only so far as to the species and indication for which the product has been tested. As such, when using a non-veterinary formulation, care should be practiced, as therapeutic success are affected by a number of unknown variables such as added exipients and exact structure of the active chemical / ingredient.
Table 2: Indication of how personal liability increases as different categories of medicines are used
|Innovator Vet Medicine/Stock Remedy||Registered Use||Proven safety, quality and efficacy||Poor storage can change product safety||If used and stored as per instructions: Falls to the manufacturer|
|Generic Vet Medicines/Stock Remedies||Registered Use||Proven safety, quality and efficacy||Poor storage can change product safety||If used and stored as per instructions: Falls to the manufacturer|
|Stock Remedies; Vet Med (innovator or generic) used extralabel||Used for non-registered purposes in the intended species||Proven quality. Safety known in target species if used at the recommended dose||Unknown efficacy when used for a new indication, and potentially safety concerns when used at a different dose.||Vet liable for extralabel use. Lower risk than other extralabel use, since use is in the intended species i.e. species safety usually known.|
|Stock Remedies; Vet Med (innovator or generic) used extralabel||Used for non-registered purposes in a non-indicated species||Quality of the product proven||Unknown efficacy as used for a new indication, and unknown safety concerns as used in an untested species||Vet liable for extralabel use. Risk increases as species safety usually unknown|
|Human Meds||Non-registered use||Quality of the product proven||Unknown efficacy and safety||Vet liable for extralabel use. Risks are the same as use of a veterinary medicine in non-indicated species.|
|Compounded Medicines||Non-registered product||Patient specific treatment option when no registered product is available||Unknown safety, efficacy and quality||Vet liable for use. Greater risk than extralabel use, since quality, safety and efficacy unknown