Patient-tailored antiepileptic drug therapy: predicting response to antiepileptic drugs

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Abstract

Antiepileptic drugs (AEDs) are characterized by a narrow therapeutic index, requiring tailoring of therapy to the individual patient. When choosing an AED, the most important predictors of therapeutic response are seizure type and epilepsy syndrome. Some AEDs have a broad spectrum of efficacy against all seizures while others have a narrow spectrum and may even aggravate certain seizure types. Preliminary data suggest that expression of multiple drug resistance genes may be a cause of intractability to certain AEDs.

Because AEDs differ in their side effect profiles, tolerability is a major factor in drug selection. Hypersensivity reactions to certain AEDs are related to genetic defects in drug metabolism, and may be predicted by in vitro tests. Many other predictors of susceptibility to specific adverse drug reactions have been identified empirically.

AEDs exhibit a large pharmacokinetic variability, and individualizing dosage is as essential as choosing the correct drug. Pharmacokinetic variability is related primarily to differences in rate of drug metabolism due to genetic and developmental factors, drug interactions and associated disease. Methylphenobarbital, mephenytoin and, to a lesser extent, phenytoin and phenobarbital are substrates for the genetically polymorphic enzyme CYP2C19. Mutations in genes encoding for CYP2C19 and/or CYP2C9 may predict reduced dosage requirements for these drugs. Measurement of serum drug levels can be of value in individualizing AED dosage, even though the value of therapeutic drug monitoring for newer generation AEDs remains unclear.

Introduction

With over 50 million people affected worldwide, epilepsy is the most common serious neurological disorder. Uncontrolled epilepsy is a major medical problem, being associated with a significant risk of mortality, including sudden unexpected death, as well as morbidity, including seizure-related injuries [1]. Patients with uncontrolled seizures are not entitled to a driving license, and may suffer from widespread stigma, prejudice and discrimination in the workplace and in society at large. These considerations highlight the importance that persons with epilepsy be assured optimal treatment.

Fortunately, a wide range of effective antiepileptic drugs (AEDs) are available, and their correct utilization allows achievement of complete seizure control in the majority of patients [2]. However, AEDs are not easy to use, for a number of reasons: (i) they have different activity spectra, and drugs which are efficacious in certain epilepsy syndromes may be ineffective or even aggravating in others; (ii) they have a narrow therapeutic index, i.e. the dosage which is required to control seizures is often close to the toxic dosage; (iii) there are wide interindividual differences in the dosage which is required to control seizures; (iv) therapeutic response cannot be immediately measured because utilization of AEDs is primarily prophylactic; and (v) signs of toxicity are not always easy to recognize on purely clinical grounds [1], [3]. Therapeutic success is dependent on the physician's ability to tailor drug choice and drug dosage to the need of the individual patient. This requires considerable skills, and an understanding of those factors that may predict the efficacy and toxicity of individual drugs.

The purpose of the present article is to highlight the main sources of variability in response to AEDs, and to discuss knowledge and tools that are available to predict and to control such variability. Because these proceedings focus on pharmacogenetics, genetic factors as a source of pharmacokinetic and pharmacodynamic variability will be given special attention. In the discussion below, four different aspects will be considered in some detail: (i) variability in therapeutic response to different AEDs; (ii) variability in susceptibility to the toxic effects of different drugs; (iii) pharmacokinetic sources of variability in dose requirements; and (iv) pharmacodynamic sources of variability in dose requirements. The former are important in determining which AED to choose in the individual patient, whereas the latter are important for dose tailoring.

Section snippets

Tailoring drug choice: predicting therapeutic response to specific AEDs

AEDs cannot be used interchangeably, and several aspects need to be considered in choosing the drug which is most likely to benefit the individual patient. Some of these relate to expected tolerability, while others relate to the need to ensure adequate efficacy in specific seizure types. As discussed below, AEDs differ in their mode of action (Table 1) and efficacy spectrum (Table 2), and many patient-specific factors also modulate drug response at pharmacodynamic level.

Tailoring drug choice: predicting adverse reactions to specific AEDs

Because AEDs differ in their side effect profiles, tolerability considerations are a major factor in drug selection. The implications of any given adverse effect vary considerably depending on the characteristics of the individual patient, and it is essential that among drugs with similar efficacy preference be given to the one whose side effects are least likely to interfere with the patient's quality of life [1]. For example, phenytoin's propensity to cause hirsutism and gingival hypertrophy

Tailoring drug dosage: prediction and control of pharmacokinetic variability

Because AEDs have a narrow therapeutic index, identifying the optimal dosage in an individual patient is at least as important as choosing the correct drug. Available AEDs exhibit considerable pharmacokinetic variability and, as a result, there is a large variation in steady-state serum drug concentrations among patients receiving the same dosage. This translates into marked differences in clinical response because patients with high concentrations are more susceptible to adverse effects,

Tailoring drug dosage: prediction and control of pharmacodynamic variability

As discussed above, there is a considerable interindividual variability in the pharmacological response that is achieved at any serum drug concentration. While to some extent this can be ascribed to pharmacokinetic factors such as differences in drug distribution or drug binding to plasma proteins, pharmacodynamic variability, i.e. differences in drug responsiveness at the site of action, can be prominent in patients with epilepsy.

In general, patients with easy to control forms of epilepsy and

Conclusions

The successful management of epilepsy requires patient-tailored AED therapy. Drug choice needs to be individualized for epilepsy syndrome and seizure types, and a drug should be selected whose tolerability profile is least likely to affect adversely the patient's quality of life. Drug dosage also needs to be carefully individualized to compensate for a large interindividual and, at times, intraindividual variability in pharmacokinetics and pharmacodynamics.

In recent years, there has been an

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