Is There a Role for Therapeutic Drug Monitoring of New Anticonvulsants?

Abstract

Despite the fact that all new anticonvulsants have undergone extensive pharmacokinetic scrutiny prior to their introduction to the market, the opportunity to perform good prospective studies on their concentration-effect relationship has been largely missed, in some cases deliberately because therapeutic drug monitoring (TDM) is considered unfavourable for the marketing of a new drug. However, there are reasons to believe that TDM may play a useful role in maximising the therapeutic potential of new anticonvulsants. In fact, these drugs have a narrow therapeutic index, careful individualisation of dosage to optimise response is required, and inter- and intra-individual pharmacokinetic variability may translate into differences in dosage requirements. The wide interindividual variability in the serum concentrations at which therapeutic and toxic effects of these drugs are observed does not necessarily imply that TDM cannot be useful: indeed, a marked pharmacodynamic variability has also been reported for all the currently monitored older anticonvulsants. The new anticonvulsants which, based on their properties, are particularly attractive candidates for TDM include lamotrigine, topiramate, tiagabine, zonisamide and felbamate. However, in the absence on sound information on the target concentration ranges of these drugs, the routine concentration monitoring of these drugs cannot be recommended. Despite this, serial measurements of serum drug concentrations may be useful in selected patients, especially those suspected of poor compliance and those in whom pharmacokinetic changes caused by disease or administration of concomitant medication are anticipated. Even in the presence of marked interindividual pharmacodynamic variability, it is often possible to empirically determine the concentration at which each patient exhibits the best response, and apply that information in subsequent management. Prospective studies, using preferably a randomised concentration-controlled design, are necessary to better characterise concentration-effect relationships for these agents.

Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications

“…Furthermore, many of the newer AEDs were first studied as adjunctive therapy and not as monotherapy. Perucca has promoted the concept of 'individual therapeutic concentrations' for AEDs [25] wherein a patient is treated until good seizure control is achieved. The serum/plasma concentration is determined and then serves as the patient's individual therapeutic concentration.…”

“…The serum/plasma concentration is determined and then serves as the patient's individual therapeutic concentration. TDM can then be applied periodically to determine whether the concentration is staying near the individual therapeutic concentration [25,26]. Drug monitoring can be especially important when changes in the patient occur that alter AED pharmacokinetics, e.g., pregnancy, impaired kidney or liver function, or concomitant therapy with enzyme-inducing or -inhibiting drugs.…”

Cannabinoids and Epilepsy

“…Assessing the side effects of AEDs is especially challenging in patients on long-term AEDs as any 'baseline' may be many years past and even intelligent adults, parents, and physicians may fail to appreciate chronic adverse effects. The available AEDs fail to meet the clinical needs for both efficacy and safety [10], indicating a dire need for novel therapeutics that are targeted, disease-, and age-specific.…”

Interchangeability among therapeutic equivalents of lamotrigine: evaluation of quality of life

“…Seizure control is important in refractory epilepsy, but increasing the dose of AEDs to achieve this goal, usu- ally results in reduced of quality of life due to side effects (Perucca, 2000). Therefore, this study evaluated the impact of interchangeability among therapeutic equivalents of LTG on quality of life of refractory epilepsy patients based on the QOLIE-31.…”