The role of therapeutic drug monitoring in managing epilepsy

If you are living with epilepsy, or are close to somebody who is, you will be all too aware of the importance of antiseizure medications (ASMs) in stabilizing the condition and preventing future seizures. We’re all different, and the optimal treatment strategy will vary from one person to another, so it is crucial to establish the smallest dose of the fewest ASMs to effectively control your seizures with the fewest side effects.

The right dose for the right person

The effectiveness of ASM depends on getting the right dose to the desired site of action in the body. While the dose you take will affect the concentration of the drug that is in your body, not all of the drug you take will get into your blood. Some may be bound to proteins in the blood and unable to pass the blood-brain barrier to exert its effect on seizures. No two people are the same, with drug metabolism and response differing from person to person, as well as being affected by age, gender, any other existing medical conditions you have, and any additional medications you take. This means that, if several people all take the same dose of the same drug, they will not necessarily have the same amount of drug circulating in their blood. For this reason, it is better to measure the effectiveness of an ASM based on the concentration in the blood rather than the dose taken.

Typically, circulating drug concentrations are measured a few days after you start taking a new or increased dose of an ASM, to ensure a reliable measure of the ‘steady state' concentration – the concentration that is maintained when the drug is taken regularly. Ideally, a blood sample is taken just before your next dose of ASM is due. This is when you have the least amount of drug in your body, allowing your ‘trough level’ to be determined. Although this is the best time to take a blood sample, it is not always possible. In this situation, your doctor will estimate how close you are to your trough level, based on the time you took your last dose. If it is not possible to take a blood sample – for example, in children, people with learning disabilities, or people who do not like having blood taken – saliva testing or, more recently, breath analysis can often be used instead.

Therapeutic drug monitoring

Establishing and maintaining the best combination of ASMs for seizure control involves monitoring and tracking the medication you take, and how it affects you and your seizures. Reference ranges – the range of drug concentrations in the body where an ASM is most likely to work – established using data from a group of people provide an indication of potentially successful dosages. They provide an estimate of the lowest concentration expected to control seizures, as well as an upper limit above which toxic effects are likely. However, this is just a guide, and individual responses to treatment vary. The individual therapeutic concentration (ITC) is the drug concentration that has the best result for a particular individual. You can have an ITC below, within or above the reference range, and this is where therapeutic drug monitoring (TDM) comes to the fore.

Blood sampling

TDM allows your ITC to be determined, rather than relying on reference ranges that may not provide the most effective dose with the fewest side effects for you. When you start taking an ASM, you are usually prescribed a low dose to begin with, which is gradually increased until your seizures are controlled. If your seizures do not respond well to a single ASM, you may be prescribed more than one drug. Some ASMs interact or interfere with each other. This can affect how well they work and may require dosage adjustments to be made. TDM can be used to help guide any necessary changes in dose to maintain a stable drug concentration in the body, and to identify which ASM – and at what concentration – might be the cause of any side effects or toxicity experienced.

Blood levels can change over time for many reasons, including developing another medical condition, starting other medications, or with age, causing previously controlled seizures to restart. Having another medical condition or taking other therapeutic drugs may affect how your ASM is metabolized, as can aging. Other medications may interact with ASMs, while people with memory problems may forget to take them – or take too much or too little. All these things can affect drug concentrations and seizure control. If seizures reoccur, TDM can confirm whether or not the circulating drug concentration is still at the ITC, as deviations due to the above-mentioned issues could be the cause. Furthermore, changing from one ASM to another, such as from a branded drug to a generic version, can influence the circulating blood concentration and, therefore, seizure control; the active pharmaceutical ingredient (API) and dose may be the same for both ASMs, but variations in the formulation can result in differences in effectiveness. This can be established by TDM before and after changing the ASM, to see if the new formulation is affecting the drug concentration in the blood.

Breath analysis – an exciting new complementary approach to blood testing

Breath testing with DBI-EPIbreath® is a recently developed complementary approach to traditional TDM, designed to assist in the management of ASM dosing regimens. It is the first non-invasive test for real-time measurement of the drug concentration and response for valproic acid (VPA). VPA passes through the blood-gas barrier in the lung, and so the API is measurable in human breath. All you have to do is exhale into the instrument, and the results are available within minutes, rather than days.