Where next for antiepileptic therapeutic drug monitoring?

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Da bi se popravila ta situacija, potrebne su dobro dizajnirane kliničke studije koje bi ispitale korelaciju koncentracija ukupnog i slobodnog leka u plazmi ili pljuvačci sa ishodima lečenja kao i efikasnost samog TML-a u kliničkoj praksi.Tehnološki razvoj bi trebalo da omogući brzo i pouzdano merenje slobodne koncentracije leka u plazmi i pljuvačći, pod uslovom da su te metode isplative, kako bi se mogle održati u praksi.Ključne reči: antiepileptici; budući razvoj; terapijski monitoring lekova; epilepsija 1. INTRODUCTION Therapeutic drug monitoring (TDM) is a clinical procedure of adjusting drug dose according to its measured concentrations in plasma or other biological fluid.It makes sense if the following conditions are met: there is correlation between plasma concentration and the drug effect, concentrations in biological fluids vary significantly between subjects (high inter-individual variability), the drug has narrow therapeutic window, suitable method of measuring dtug concentrations exists, and the drug effect cannot be easily and precisely measured in clinical practice [1,2].However, in order to make adjustment of the drug dose according to its plasma concentration,the therapeutic range of plasma concentrations should be known, based on results of previous clinical trials.Some of the first and second generations of anticonvulsants fulfilled all these conditions, and TDM of these drugs is currently conducted in clinical practice as routine procedure: phenobarbital, phenytoin, carbamazepine and valproic acid.Classification of anticonvulsant drugs according to generations (historical development) is usually made in the following way: the first generation drugs (phenobarbital, phenytoin, carbamazepine, ethosuximide and valproic acid), the second generation drugs (lamotrigine, topiramate, oxcarbazepine, tiagabine, pregabaline, vigabatrine, zonisamide, gabapentin, felbamate and levetiracetam) [3] and the third generation anticonvulsants (eslicarbazepine, lacosamide, perampanel, brivaracetam, rufinamide, retigabine and newer drugs) [4] True clinical impact of TDM in patients with epilepsy was rarely investigated in clinical trials [5].One of rare clinical trials published up to date [6] investigated impact of TDM on patients with newly diagnosed epilepsy (partial or idiopathic generalized nonabsence epilepsy) for carbamazepine, valproate, phenytoin and phenobarbital.The TDM kept plasma concentrations within the therapeutic range in more patients than in control group, but neither 12-month remission rate, fractionremaining seizure free since initiation of treatment, nora time to first seizure or 12-month remission were significantly influenced by the TDM.The adverse effects rate was also very similar in TDM and control group.The authors concluded that TDM should be reserved for selected patients and special situations.
For many of the second and third generation anticonvulsants, therapeutic plasma range is still either unknown or uncertain [7][8][9][10].In such cirsumstances measuring plasma concentration of a drug has only exploratory character, i.e. precise recommendations about extent of a dose increase or decrease could not be given.However, clinicians still can adjust the dose of anticonvulsant in particular patient, using both information about measured plasma concentration and clinical presentation of the patient.
Even for anticonvulsants with well established TDM, only total drug concentration in plasma is measured routinely, which may mislead a prescriber.If hypoalbuminemia is present, total drug plasma concentration could be within the therapeutic range, but free drug may be highly elevated and cause serious toxicity, as reported for valproate [11].
Measuring plasma concentrations of anticonvulsants' free fraction should become standard, and therapeutic ranges of free drug should be established if we want to increase precision and usefulness of TDM.These, and several other issues remain unresolved with TDM of anticonvulsants.
The aim of this review was to describe them in sufficient detail, offering basis for planning further developments of TDM.

ISSUES WITH TDM OF PHENOBARBITAL, PHENYTOIN, CARBAMAZEPINE AND VALPROIC ACID
Early after introduction of TDM as routine procedure in patients prescribed with first generation anticonvulsants the clinicans became aware of several issues that make difficulties when deciding about dose adjustment after plasma concentration of the drug is obtained [12].First, they understood that therapeutic ranges of plasma concentrations could not be applied to all patients, without taking into account seizures type and frequency, yet specific data were lacking to guide the prescriber.Importance of measuring unbound fraction of drug within plasma was also perceived, as well as influence of numerous factors which may change pharmacokinetics of anticonvulsants and make dose adjustments wrong if not considered in an individual patient (genetic polymorphisms, drug-drug and drug-food interactions, co-morbidities, noncompliance or special physiological states like pregnancy).
It became clear that in order to choose right dose regimen at least in some patients (sometimes wrongly classified as "therapy resistant-) it is necessary to make objective estimate of long-term seizure frequency, adverse effects on motor and intelectual functions, quality of life, perhaps continuous EEG monitoring and measurement of both total and unbound anticonvulsant plasma concentrations.This led to idea that individual therapeutic threshold value(ITTV) should be searched for in a patient, or the minimum steady-state anticonvulsant concentration that, in thatpatient, results with complete control of seizures and lack of significant adverse drug reactions [13].A clinician should prescribe the lowest dose of an anticonvulsant that achieves through plasma concentrations above the ITTV; however, establishing exact ITTV in a patient is difficult task to achieve in clinical practice, and great majority of clinicians still relies on population therapeutic range of plasma concentrations instead.Nevertheless, we should start treatment of a patient having population therapeutic range in mind, but then, if possible, to adjust interpretation of measured plasma concentrations to individual characteristics of the patient and influences he or she was exposed to, as mentioned before.
Several studies showed that is is not appropriate to consider only one range of steady-state plasma concentrations as therapeutic for certain anticonvulsant, since it depends on the type and the severity of epilepsy, measured by the seizure frequency before the treatment [14,15].In theory, if specific therapeutic ranges of cetrain anticonvulsant are established for each type of epilepsy and severity class, a prescriber would have clear target steady-state concentrations to achieve in every patient, so use of information about measured plasma concentration for adjusting dose regimen would be straightforward.
Unfortunately, to date well designed and large enough studies aimed to establish type-and severity-dependent steady-state plasma therapeutic concentration ranges were not conducted, and we are left without this knowledge.
Phenytoin,carbamazepine and valproic acid were the first anticonvulsants for whom advantage of measuring unbound plasma concentration over total plasma concentration was shown in clinical practice, especially in situations when a patient has low albumin levels [16].However, direct measurement of unbound drug is technically more difficult and demanding, and some clinicians revert to calculation of adjusted phenytoin plasma concentration based on measured total plasma concentration, albumin level and Sheiner-Tozer equation.Although relying on adjusted plasma concentrations give better results than total plasma concentrationswhen deciding about phenytoin dose, using measured free (unbound) plasma concentration of phenytoin for dose adjustment remains gold standard for TDM of this drug [17]; unfotrunately, we are far from achieving that standard in majority of TDM units, even in developed countries.

TDM AND OTHER ANTICONVULSANTS
TDM is only possibly useful for second-generation anticonvulsant lamotrigine, since correlation between plasma concentrations and effect was not proven unequivocally, and therapeutic range was loosely defined [18,19].There is similar experience with topiramate, another second-generation drug, as its average plasma concentrations were not significantlydifferent between responders, non-responders, and patients with toxic reactions [20,21].Unproven plasma concentration-effect correlation and wide or unreliable therapeutic range are commonplace for all other second-generation anticonvulsants, including tiagabine [22], pregabaline [23], vigabatrine [24], zonisamide [25], gabapentin [26], felbamate [27] and levetiracetam [25].Vigabatrine is not significantly bound for plasma proteins and acts as irreversible enzyme inhibitor of gamma-aminobutyric acid aminotransferase, so TDM of this drug is considered useless [24]; additional obstacles for TDM use in patients on levetiracetam therapy are very wide therapeutic range and minimal side effects [25].Measuring free (protein unbound) plasma concentrations of secondgeneration anticonvulsants within the framework of TDM was not even attempted.
For majority of third generation anticonvulsants data about clinical usefulness of TDM are missing [28], or only point to large inter-individual variability, which is just one of the conditions that should be met (e.g.eslicarbazepine, lacosamide) [29,30].Reliable therapeutic range of plasma concentrations is not established for any of these drugs, although assays for measurement of plasma concentrations are developed and validated for many of the newest anticonvulsants, like perampanel [31]or rufinamide [32].
It is clear that use of TDM for the first-generation anticonvulsants could be improved and enlarged, and also many of second and third-generationanticonvulsants have true potential to become drugs where routine use of TDM is mandated.However, there are several obstacles to achievement of this ideal situation, and both technological developments and substantial workforce and financial investments are necessary to overcome the obstacles.Without attempting to be systematic, the obstacles and ways to remove them could be listed as following: (1) unknown seizure type and severity-specific therapeutic ranges of plasma steady-state concentrations of almost all anticonvulsants; (2) lack of simple, rapid and inexpensive methods for measuring plasma concentrations of free drug (unbound for plasma proteins); (3) lack of non-invasive methods for measuring steady-state concentrations of anticonvulsants which correlate well with therapeutic and toxic effects; (4) lack of evidence that TDM for each particular anticonvulsant is improving relevant outcomes of treatment, as seizure control and quality of life, as well as decreasing adverse events rate and overall treatments costs.

SEIZURE TYPE AND SEVERITY-SPECIFIC THERAPEUTIC RANGES
The only reliable way to establish seizure type and severity-specific therapeutic range of steady-state plasma concentrations of an anticonvulsant is to conduct properly designed and adequately powered clinical trial which would include patients with various seizure types and severity of epilepsy.Some of the researchers in their clinical trials analyzed effects of anticonvulsants in various sub-groups according to seizure type and noted different effects with the same plasma concentrations [33], but attempts wererarely made to establish therapeutic ranges, usually because the subgroup analyses were underpowered, but also because statistically significant concentration-dose relationshipis sometimes nonlinear [34].However, indirect prof that there must be seizure typespecific therapeutic ranges are dosing recommendations of topiramate and many other anticonvulsants in their Summaries of product characteristics, which are dependent on seizure type [35].Recently comprehensive systematic review was made (810 full-text articles reviewed, and data extracted from 163)with an aim to establish therapeutic index for anticonvulsants based on published clinical data for five anticonvulsants, but it was possible only for phenytoin, phenobarbital and valproate, regardless of the seizure type or severity [36].This situation could be improved, at least partially and for new anticonvulsants, if guidelines for clinical trials include recommendation that one of the study outcomes should be establishing seizure type (and if possible severity) -specific therapeutic range (or index) of plasma concentrations.Another way is more sophisticated use of observational data for antiepileptics where TDM is already done in clinical practice, through pooling data from different studies and use of statistical techniques for elimination of bias.

MEASURING PLASMA CONCENTRATIONS OF FREE DRUG
Measuring concentrations of free (unbound drug) in vitro is usially done by one the following methods: equilibrium dialysis, ultrafiltration and the Hummel and Dreyer method for gel permeation chromatography.However, when measirung free drug in plasma, only equilibrium dialysis and ultrafiltration are used, because gel permeation chromatography has high measurement "noise-due to abundance of small-size molecules in plasma [37].
Perhaps the most suitable for use in clinical practice is ultrafiltration method.Although up to date enough simple, rapid and inexpensive method for measuring free plasma concentration of anticonvulsants was not developed for routine TDM, it should not be too far away, since something similar was already developed for measuring free plasma concentrations of ten beta lactam antibiotics in critically ill patients [38].

CONCENTRATIONS OF ANTICONVULSANTS
Measuring concentrations of anticonvulsants in saliva was long ago seen as potentially very suitable method for TDM, as it is non-invasive and easy to repeat as many times as necessary from the point of view of patients, who certainly would be much more compliant with such than TDM based on blood samples (injection phobia is highly prevalent in every social milieu) [39].Besides, physicans always prefere painless methods, if available [40].It was early proven for first-generation anticonvulsants that intraindividual variability of measured concentrations in saliva was small enough to be acceptable for the TDM purposes [41], and later significant correlation was found between total plasma concentrations and concentrations in saliva [42] when anticonvulsants were used in monotherapy or combination, but not after polytherapy.In general, concentrations of anticonvulsants in saliva make 10-40% of plasma concentrations, what is enough for routine TDM [43].It was recently shown that valproate concentrations in saliva correlate well with concentrations of free valproate in plasma [44], which is promising because free drug in plasma is considered to be active, and as mentioned earlier, in good correlation with therapeutic effect.However, more recent studies showed that salivary valproate concentration is not reliable to be used for TDM, while the following anticonvulsants could be measured in saliva and steady-state values used for TDM: carbamazepine, ethosuximide, clobazam, gabapentin, lamotrigine, lacosamide, levetiracetam, oxcarbazepine, phenytoin, phenobarbital, primidone, topiramate, and zonisamide [45].Although possible, TDM based on salivary concentrations is far from routine usemuch remain to be done on establishing therapeutic range in saliva for the abovementioned anticonvulsants, including specially designed clinical studies (both clinical trials and observational studies) for each drug separately.

TDM AND TREATMENT OUTCOMES
Ultimate goal of TDM is to improve treatment outcomes of anticonvulsants and minimize occurrence of adverse effects.However, achievement of that goal was surprisingly rarely proven in clinical studies even with the first-generation anticonvulsants.
It was demonstrated for some anticonvulsants that TDM resulted with decreased seizure frequency [46], or that complete seizure control was achieved in some patients previously considered therapy resistant [47].TDM is also very useful to discover non-compliant patients [48], and relationship with decreased frequency of adverse effects was shown in a few studies [49].Decrease in overall treatment costs with use of TDM was not shown, but several studies pointed to generation of unnecessary costs if TDM is improperly used (taking blood samples out of the steady-state, misinterpretation of results, etc.) [50].Effects of TDM on quality of life of patients with epilepsy were not investigated, too.There were some studies, too, which failed to find any connection between TDM and treatment outcomes or adverse effects [51].Considering scarcity and incompleteness of published data, there is obvious need for new clinical trials or observational studies which would explore relation between the TDM of anticonvulsants and treatment outcomes (including costs and quality of life) / adverse effects, for both old and new drugs that fulfill criteria for TDM.

AVAILABILITY OF POINT OF CARE TDM TOOLS
Although intense development of point-of-care (POC) tests were introduced in the past for TDM of anticonvulsants, their use did not widespread because there was not enough patient throughput to justify the costs at that time and quality assurance was questionable [52].However, rapid technological advances in nanosciences and biosensors created an opportunity for development of reliable and less expensive point-of-care tests for measuring concentration of anticonvulsants in blood or saliva and obtaining immediate results [53].This advancement would be useful especially in evaluation of possible toxicity of an anticonvulsant, as it is when we need information about drug concentration as soon as possible.Another possible prospect of POC tests is that establishment of individual therapeutic threshold value could become feasible for more patients than it was case until now (mesurements could be done in the patient's home, during weekends and hollidays, and when staff trained for venepunction is not available).With POCs we could capture concentrations of anticonvulsants immediately after or before a seizure event, and also when a patient is changing diet or being prescribed drugs unrelated to epilepsy.All these advantages should help us to better tailor anticonvulsant therapy for individual patient, and hopefully, improve therapeutic outcomes.

CONCLUSIONS
Despite relatively long history of TDM use within the framework of epilepsy treatment, we are using only small part of possibilities it offers, in the first place because of lack of specific knowledge.In order to use full capacity of TDM in the future for maximal benefit of patients with epilepsy,we need to establish seizure type and severity-specific therapeutic ranges for those anticonvulsants where TDM has clinical significance, as well as to prove positive effects of TDM on wide spectrum of treatment outcomes.Development of non-invasive TDM methods, point-of-care tests and reliable methods for routine measurement of free drug concentrations in plasma are also areas where progress could empower TDM of anticonvulsants and bring new qualities.However, we should acknowledge that for many years TDM was successfully used for adjusting doses of the first-generation anticonvulsants, provided that important confounding factors were taken into account, like hypoalbuminemia, hypervolemia, acid-base disequilibrium, and others.