Uncontrolled seizures or suspected toxicity
In patients who develop breakthrough seizures after a prolonged period of seizure control, management can be facilitated by knowledge of the individual therapeutic concentration. In particular, the finding of a concentration much lower than the individual therapeutic concentration in a sample collected within hours of a breakthrough seizure provides suggestive evidence for suboptimal compliance or for a clinically important change in the pharmacokinetics of the AED (Specht et al., 2003). This information is clearly useful in establishing the cause for the loss in seizure control, and taking the appropriate corrective action. Persistence of seizures on an apparently adequate dosage of an appropriate AED is a clear indication for serum AED concentration monitoring (Eadie, 1997). Measurement of serum drug concentrations in these patients is useful to identify potential causes of therapeutic failure, and to differentiate between poor compliance (typically characterized by highly variable serum concentrations, which increase following supervised drug intake) and low-serum drug concentrations due to poor absorption, fast metabolism, or drug interactions. Moreover, determining what concentrations at any dose have been associated with lack of efficacy (or with toxicity) can be used to characterize the concentration-response profile within each individual patient, which is the premise upon which the use of the “individual therapeutic concentration” concept is built.
In patients in whom toxic symptoms are suspected, serum AED concentrations can aid in confirming a diagnosis of AED toxicity, though clinicians should be aware that relatively low concentrations do not necessarily exclude such a diagnosis. Serum AED concentration monitoring can also be useful in differentiating whether poor seizure control is due to insufficient dosing or rather reflects a paradoxical worsening of seizures due to an excessive drug load (Perucca et al., 1998). The finding of serum AED concentrations below the upper limit of the reference range, however, does not allow the clinician to exclude the possibility of paradoxical intoxication, particularly in patients receiving complex polytherapies (Perucca, 2002b). The measurement of serum AED concentrations as an aid to the diagnosis of suspected toxicity may also be valuable in patients whose status is difficult to assess clinically, such as young children and subjects with mental disability.
In patients with difficult-to-treat epilepsy, determination of serum AED concentrations aids in determining the magnitude of the required dose increment, particularly with drugs showing dose-dependent pharmacokinetics such as phenytoin (Richens, 1979). These patients may also require multiple drug therapy, and monitoring serum AED concentrations is useful in identifying pharmacokinetic drug interactions and in making compensatory dosage adjustments. In polytherapy patients who exhibit signs of overdosage, measuring the concentration of the individual AEDs can aid in determining which drug is more likely to be responsible for the toxicity. Interpretation of AED concentrations in this situation, however, should be cautious because in the presence of polytherapy adverse effects are often encountered at unusually low serum AED concentrations (Shorvon & Reynolds, 1979).
During pregnancy, maternal serum concentrations not only reflect concentrations that determine therapeutic and adverse effects in the woman, but also the extent of drug exposure to the embryo or fetus. Drug concentrations and alterations thereof are therefore of particular importance in this specific situation. The pharmacokinetics of many AEDs undergo important changes during pregnancy, due to a combination of factors such as modifications in body weight, altered serum composition, hemodynamic alterations, hormonal influences, and contribution of the fetoplacental unit to drug distribution and disposition (Perucca, 1987). Pregnancy may affect drug absorption, binding to serum proteins and distribution, metabolism, and renal elimination (Pennell, 2003). These alterations need to be taken into consideration in order to optimize AED treatment. The aim is to maintain seizure control with the lowest effective serum drug concentration, in order to avoid harm from seizures and from drugs to the mother and the foetus. The effect of pregnancy on drug disposition varies with different AEDs, and the extent of this effect will also vary between patients (Pennell, 2003). TDM during pregnancy aims at facilitating individualized dosing by identifying pregnancy-induced pharmacokinetic changes.
Pregnancy-associated pharmacokinetic changes have been reasonably well characterized for the old generation AEDs (Yerby et al., 1992; Pennell, 2003). At constant dosages, serum concentrations of most of these AEDs tend to decrease during pregnancy, and return to prepregnant concentrations within the first month or two after delivery. These alterations appear to be due mainly to decreased drug binding to serum proteins and increased metabolism and elimination. A decrease in protein binding per se will result in lower total (protein bound plus unbound) drug concentrations, but may leave unchanged the unbound, pharmacologically active, concentration of the drug.
By the end of pregnancy, total and unbound concentrations of phenobarbital decline by up to 50–55% (Yerby et al., 1992). Primidone concentrations are only slightly affected decreasing by 10–30%, whereas there is a pronounced decrease in the order of 70% or more in metabolically derived phenobarbital concentrations in late pregnancy (Battino et al., 1984). Total serum concentrations of carbamazepine decline to a lesser extent (0–40%) and the changes in unbound carbamazepine concentrations are insignificant (Yerby et al., 1992; Tomson et al., 1994). Marked decreases in total phenytoin concentrations to about 40% of prepregnancy concentrations have been reported (Yerby et al., 1992; Tomson et al., 1994), whereas free concentration decrease to a lesser extent (20–30%). For valproic acid, no significant changes are noted in unbound concentrations despite a fairly marked decrease (sometimes 50% or even more) in total concentrations (Koerner et al., 1989; Yerby et al., 1992). Hence, for highly protein bound drugs such as valproic acid and phenytoin, total serum concentrations may be misleading during pregnancy, underestimating the pharmacological effects of the drugs.
Several studies have demonstrated pronounced alterations in the pharmacokinetics of lamotrigine during pregnancy (Tomson et al., 1997; Öhman et al., 2000; Tran et al., 2002; de Haan et al., 2004; Pennell et al., 2004; Öhman et al., 2007; Pennell et al., 2007). The decrease in serum concentrations during pregnancy appears to be more pronounced for lamotrigine (with a fall sometimes down to 30% of prepregnancy concentrations) than for other AEDs, is probably the consequence of an increased metabolism of lamotrigine by glucuronidation and can result in increased seizures (de Haan et al., 2004; Pennell et al., 2007), prompting the need for more frequent dose adjustments. Recent observations indicate that clinically important declines (30–50%) in serum drug concentrations during pregnancy also occur with levetiracetam (Tomson et al., 2007b) and with the active MHD derivative of oxcarbazepine (Christensen et al., 2006; Mazzucchelli et al., 2006). Much less is known about the pharmacokinetics of other new generation AEDs during pregnancy and clearly more data are needed.
The pharmacokinetic changes quoted above represent average changes, but the effect of pregnancy varies between individuals. The decline in serum drug concentration may be insignificant in some patients and pronounced in others, requiring dosage adjustments to maintain seizure control. Monitoring drug concentrations is therefore recommended during pregnancy. For highly protein bound AEDs such as valproic acid and phenytoin, there may be advantages in monitoring the unbound drug concentrations. A single drug concentration is of limited value, since the optimal concentration is individual. When pregnancy is planned in advance, it is therefore advisable to obtain one or, preferably, two serum concentration values when seizure control is optimal, before pregnancy, for future comparison. The timing and frequency of drug concentration monitoring during pregnancy also needs to be individualized based on the type of AED used and the patient's characteristics. Once each trimester is often recommended and is probably sufficient in most women with stable seizure control. More frequent sampling is advisable in patients with complicated epilepsy, in those previously known to be sensitive to modest alterations in dose and serum concentrations, and in those under treatment with lamotrigine and oxcarbazepine. In the latter patients, sampling once a month is sometimes justified. The need for monitoring in the postpartum period will depend on the clinical situation and on whether dose changes have been made during pregnancy. Lamotrigine pharmacokinetics, for example, appears to revert to prepregnancy conditions within a few days after delivery. In order to avoid toxicity, monitoring every second day for a week after delivery could be justified if the lamotrigine dose was increased during pregnancy.
Suboptimal compliance such as underdosing, overdosing, missed doses, or make-up doses are common in older patients and alter serum AED concentrations and, potentially, clinical response (Cramer et al., 1989). TDM is useful in identifying noncompliance, but caution must be exercised because age-related alterations in absorption and protein binding mimic the effect of noncompliance on serum AED concentrations.
Advancing age alters both the way in which the body responds to medications and the way it absorbs, binds, and eliminates drugs (Perucca, 2006). Although there is a general pattern in these age-related changes, substantial inter- and intraindividual variability exists in all pharmacokinetic parameters. Changes in pharmacokinetics affect serum drug concentration, while changes in pharmacodynamics affect response to any given serum concentration, which may complicate the interpretation of TDM data.
Alterations in gastrointestinal function, body mass composition, serum proteins, and hepatic and renal function are all associated with advancing age (Hammerlein et al., 1998). Reduced intestinal motility, altered gastric and intestinal pH, and altered intestinal structure can affect both the rate and extent of absorption. Serum albumin declines gradually with age while the reactive protein alpha1-acid glycoprotein modestly increases in healthy elderly and markedly increases with many diseases common with aging. For AEDs that are highly bound to serum proteins (carbamazepine, phenytoin, valproic acid, and tiagabine), decreased albumin binding due to hypoalbuminemia will result in lower total drug concentration, whilst an increased binding due, for carbamazepine, to increased alpha1-acid glycoprotein will result in higher total drug concentrations. As an example of the latter circumstance, Rowan et al. (2005) found that the mean carbamazepine unbound fraction in elderly patients enrolled in their study was 12.5%, a much lower value than that reported for younger adults with epilepsy. Although unbound drug concentrations will not be affected by changes in serum proteins, changes in protein binding need to be taken into account when interpreting total serum drug concentrations in these patients. For example, due to the increase in unbound phenytoin fraction, the therapeutic and toxic effects of phenytoin will occur in the elderly at total drug concentrations lower than usual.
Renal function, as measured by creatinine clearance, and CYP–mediated oxidative metabolism decrease by approximately 1% a year after age 40, although there is considerable variability and limited data in individuals 80 or older for both routes of elimination (Vestal et al., 1975; Hammerlein et al., 1998). There is emerging evidence that glucuronidation reactions undergo a similar decline with age (Perucca et al., 1984a; van Heiningen et al., 1991). The effect of advancing age on induction of CYP-mediated metabolism is controversial. Some studies suggested that the degree of enzyme induction in the elderly is attenuated (Salem et al., 1978), while Battino et al. (2004) provided evidence that phenobarbital increases the apparent carbamazepine clearance to a similar extent in elderly and nonelderly adults.
Despite the widespread use of AEDs in the elderly, there is limited information on their pharmacokinetics in this age group, and the available data is largely based on studies in the young-old (65–74 years) (Bernus et al., 1997; Perucca, 2006). The AEDs most extensively studied in the elderly are phenytoin, valproic acid, and carbamazepine. A recent report by Birnbaum et al. (2003) described widely fluctuating serum phenytoin concentrations in a large percentage of elderly nursing home residents. The frequency and direction of change suggests that altered bioavailability is the most likely cause of this phenomenon. Several studies have found higher and more variable phenytoin free fractions in elderly patients, even in the presence of normal serum albumin (Bernus et al., 1997). Phenytoin half-lives are prolonged and metabolism is approximately 20% slower in the elderly (Bauer & Blouin, 1982; Perucca et al., 1984a). As a consequence of Michaelis-Menten kinetics, a modest age-related decline in phenytoin metabolism can be clinically significant, because very small changes in dose or absorption can result in disproportionately large changes in serum concentration. Perucca et al. (1984a) compared the pharmacokinetics of a single dose of valproic acid in six elderly and six younger individuals. Total serum valproic acid concentrations were similar between the two groups, but the free fraction of the drug in older subjects was twice that in the younger group (11% vs. 6%) and the unbound drug concentrations were approximately 60% greater. This study further exemplifies the pitfalls of monitoring highly protein bound AEDs in the elderly. Measurement of total valproic acid concentrations may not provide an accurate estimate of unbound concentrations, leading either to inappropriate increases in dose or to failure to decrease dose in the presence of concentration-dependent side effects such as tremor. Information about carbamazepine absorption is unavailable, but apparent protein binding may increase, presumably due to elevated alpha1-acid glycoprotein concentrations, while clearance declines by 20–40% in old age, and half-life is likely to be prolonged (Cloyd et al., 1994; Battino et al., 2004; Rowan et al., 2005). Although much less is known about the effect of advancing age on newer AEDs, available data suggest that the pharmacokinetic changes observed with these agents in the elderly are similar to those described for the older AEDs (Perucca et al., 2006a).
Elderly individuals with epilepsy take more medications than other patients in the same age group, resulting in a greater risk of drug interactions (Linjakumpu et al., 2002). In a recent US study investigating the safety and efficacy of carbamazepine, gabapentin, and lamotrigine in elderly patients with seizure disorders, the mean number of prescription comedications per patient was 6.7 (Ramsay et al., 2004). In contrast, the average number of comedications in a similar study in elderly patients with newly diagnosed epilepsy in Europe was 3.0 (Saetre et al., 2007). The most commonly used medications in the elderly are cardiovascular, CNS, and analgesic agents, all of which have a high potential for interactions with AEDs (Perucca et al., 2006). The elderly also often take natural products such as St. John's wort which are known to interact with AEDs (Kaufman et al., 2002). The addition or discontinuation of enzyme-inducing and inhibiting drugs may have a particularly important impact on older patients, because these patients are at a high risk of adverse events (Gurwitz et al., 2003). For example, the addition of fluoxetine, an antidepressant frequently prescribed for older patients, can increase both carbamazepine and carbamazepine-10,11-epoxide concentrations by as much as 50% (Grimsley et al., 1991).
In conclusion, TDM may be particularly helpful in guiding AED therapy in elderly patients. Greater morbidity, poor medication compliance, variable age-related changes in pharmacodynamics and pharmacokinetics, and an increased likelihood of drug interactions affect the safety and efficacy of both AEDs and concomitant therapy in these patients. TDM can assist the clinician in attaining targeted concentrations and maintaining these concentrations over time, especially as comedications are added or discontinued. Measurement of unbound concentrations may be indicated for highly protein bound AEDs. Interpretation of drug concentrations in the elderly should also take into account the fact that these patients may show increased pharmacodynamic sensitivity to AEDs, and therefore therapeutic and toxic effects may develop at relatively low concentrations (Perucca, 2006).
Changes in AED formulation and generic substitution
When an AED formulation is changed, e.g., when switching to/from generic formulations, measuring the serum concentration of the AED before and after the change may help in identifying potential alterations in steady-state drug concentrations resulting from differences in bioavailability (Perucca et al., 2006b). As in other situations involving intrapatient comparison of drug concentrations obtained at different times, interpretation of data must take into account alternative explanations for a change in reported values, including day-to-day assay variability, differences in sampling times, and background day-to-day pharmacokinetic variation.
When patients are switched to a formulation with modified-release characteristics (for example, from an immediate-release to a sustained-release formulations), or when dosing schedule is changed (for example, from twice daily to once daily administration), interpretation of TDM data should also take into account the expected variation in diurnal drug concentration profile. In some instances, collection of two or more blood samples at different intervals after drug intake may be desirable to fully assess the concentration profile change.
The absorption, distribution, and elimination of AEDs can be markedly affected by the changes in homeostasis caused by various illnesses, including hepatic or renal failure, infections, burns, stroke, cardiac failure, and other conditions (Boggs, 2001). In addition to the alterations caused by the pathological state per se, drugs used to treat these conditions can cause interactions that also affect AED concentrations. The monitoring of serum AED concentrations is valuable in helping the clinician to identify these pharmacokinetic changes and enabling him or her to make dose adjustments whenever appropriate.
Measurement of unbound drug concentrations is essential for highly protein bound AEDs whenever the associated condition is known or suspected to alter the degree of protein binding (Perucca, 1984). This was first demonstrated for phenytoin in cases of renal failure, where binding is markedly diminished and total concentrations are misleading (Hooper et al., 1974). Serum protein binding changes shortly after dialysis or renal transplantation, but clearance may not change markedly (Kang & Leppik, 1984), and failure to monitor unbound concentrations can lead to errors in dosing. Although other highly bound AEDs such as valproic acid have not been as extensively studied, it would be prudent to measure free concentrations of all highly bound AEDs during renal failure or other states in which endogenous binding sites may be altered, such as hypoalbuminemia, or in patients receiving drugs competing for protein binding sites such as aspirin, naproxen, tolbutamide, phenylbutazone, and other highly protein-bound agents (Perucca et al., 1985).
Many AEDs are excreted in part or primarily by the kidneys (Asconape & Penry, 1982; Perucca, 1999). The concentrations of primidone, levetiracetam, pregabalin, gabapentin, and vigabatrin are particularly dependent on renal clearance, and although formulas exist for calculating dose based on creatinine clearance, these calculations are not always easy or accurate. A better approach is to measure concentrations of these drugs and adjust the doses based on actual concentrations whenever there is a compromised renal function. TDM can also help in guiding the magnitude of replacement dosages for patients receiving AEDs, which are efficiently removed during dialysis. For highly bound drugs, the unbound fraction increases markedly in patients with renal disease, and therefore monitoring total serum concentrations can be misleading in this situation (Perucca et al., 1985).
Burns extensive enough to require admission to a burns unit may result in significantly impaired serum protein binding of phenytoin, phenobarbital, and diazepam (Bloedow et al., 1986; Pugh, 1987). Other AEDs have not been studied. However, it would be advisable to monitor AED concentrations in patients with severe burns, and to determine unbound concentrations when highly protein bound drugs such as phenytoin and valproic acid are monitored.
Phenytoin clearance can be accelerated by various illnesses. This was first observed in a case of mononucleosis and later shown to occur with febrile illnesses and even with vaccination (Leppik et al., 1986). Anyone treated with phenytoin having breakthrough seizures should if possible have the phenytoin concentration measured, and, if low, the dose should be increased for the duration of the illness. Studies for other AEDs during febrile illnesses have not been undertaken, but it may be prudent to monitor their serum concentrations during illnesses. Certainly diarrheal illnesses may be associated with decreased absorption, and even without monitoring concentrations, strategies to supplement drug intake should be considered.
Because many AEDs are metabolized by the liver, hepatic disease may alter their clearance (Asconape & Penry, 1982; Perucca, 1999). In addition, as the liver is the source of many proteins, serum protein binding may also be affected. Only a few studies evaluating serum AED concentrations during hepatic illness have been undertaken, and it is not possible to predict the degree of change in clearance (Asconape & Penry, 1982). Thus, in any person with hepatic failure, total concentrations (and unbound concentrations for highly bound drugs) should be monitored.
Some studies have shown that carbamazepine clearance is altered by surgery for epilepsy (Gidal et al., 1996). Other AEDs have not been well studied. Head trauma may also be associated with changes in unbound drug fraction and drug metabolism, as shown for example for phenytoin (Stowe et al., 2000). Therefore, it is useful to monitor AED concentrations after surgery or head trauma.
In summary, although only a few studies have been undertaken, it is apparent that renal failure, infectious diseases, hepatic failure, burns, surgery, and illness severe enough to warrant placement in an intensive care unit do alter physiology to the degree that AED concentrations can be affected. AED concentrations should be monitored in these situations. Specific guidelines for extent of monitoring are not available, but clinical judgment with an awareness of the potential changes in serum protein binding, absorption, and clearance should guide the clinician caring for ill patients.
An important objective of AED treatment is to anticipate and minimize the risks of clinically relevant pharmacokinetic interactions (Patsalos & Perucca, 2003a, 2003b). An unexpected loss of seizure control or development of toxicity during AED therapy may accompany the addition or removal of a concurrently administered drug. Prevention of AED interactions is best achieved by avoiding unnecessary polytherapy, or by selecting alternative agents that have less potential to interact. The management of interactions begins with anticipating their occurrence and with being familiar with the mechanisms involved.
Pharmacokinetic interactions involve a change in the absorption, distribution, metabolism, or elimination of the affected drug. If an interaction is anticipated, it makes sense to obtain a drug concentration measurement before adding a new drug, in order to establish a baseline. Further measurements should be taken at appropriate times after the potentially interacting agent has been added, and the need for a dose adjustment can then be assessed (Patsalos & Perucca, 2003a).
Serum protein binding interactions usually do not modify clinical response, because as a general rule compensatory changes in drug clearance lead to a new situation whereby the total serum concentration of the displaced drug is reduced, but the concentration of unbound, pharmacologically active drug is unaffected (MacKichan, 1989). Nevertheless, these interactions need to be considered when interpreting TDM data in the clinical setting; in fact, in the presence of a displacing agent, therapeutic and toxic effects of the affected drug will be obtained at total serum concentrations lower than usual. Such a situation applies, for example, to the interpretation of total serum phenytoin concentrations in the presence of valproic acid, a displacing agent (Mattson et al., 1978). Patient management in this situation would benefit from monitoring unbound drug concentrations (Perucca et al., 1985).
The most important and prevalent pharmacokinetic AED interactions are those associated with induction or inhibition of drug metabolism. With the exception of gabapentin, pregabalin and vigabatrin, all AEDs undergo some degree of hepatic metabolism and consequently their clearance is susceptible to enzyme inhibition and/or induction. An elevation in enzyme activity, consequent to enzyme induction, results in an increase in the rate of metabolism (particularly oxidation and/or glucuronide conjugation) of the affected drug (Patsalos & Perucca, 2003a). This will lead to a decrease in its serum concentration and possibly a reduction in therapeutic response. If the affected drug has a pharmacologically active metabolite, induction can result in increased metabolite concentrations and possibly an increase in efficacy and in drug toxicity, as it can occur with induction of the conversion of carbamazepine to carbamazepine-10,11-epoxide. The magnitude of interaction and the time it takes for the serum concentration of the affected drug to stabilize at a new steady-state concentration after adding an enzyme inducer depend on a number of factors, including the half-life of the affected drug and the dose, enzyme-inducing potency and half-life of the enzyme-inducing agent. For example, studies that assessed the time course of enzyme induction by carbamazepine by investigating the degree of autoinduction demonstrated that induction is dose-dependent (Kudriakova et al., 1992), is already present after 1 to 2 days after initiation of carbamazepine treatment, (McNamara et al., 1979; Bernus et al., 1994b) but may require from 1 week (Mikati et al., 1989) to 5 weeks (Bertilsson et al., 1986) to develop fully. Of the AEDs presently used in clinical practice, carbamazepine, phenobarbital, phenytoin, and primidone are associated with clinically important enzyme-inducing properties (Perucca et al., 1984b). Other inducing agents include felbamate, oxcarbazepine, and topiramate (at doses ≥200 mg/day), but these AEDs stimulate the activity of fewer isoenzymes and they induce the metabolism of only a restricted number of substrates such as, most notably, oral contraceptive steroids (Patsalos & Perucca, 2003a, 2003b). Lamotrigine, at a dose of 300 mg/day, can also stimulate the metabolism of contraceptive steroids (Sidhu et al., 2006). Felbamate and oxcarbazepine may also inhibit some CYP enzymes, underlining the fact that induction and inhibition are not mutually exclusive phenomena (Patsalos, 2005).
Enzyme inhibition results in a reduction of enzyme activity which leads to a decrease in the rate of metabolism of the affected drug and, consequently, an increase in its serum concentration and, potentially, clinical toxicity. Inhibition is usually competitive in nature and therefore dose-dependent, and begins as soon as sufficient concentrations of the inhibitor are achieved (Levy et al., 2003). This usually occurs within 24 h of the inhibitor's addition, and the maximal increase in serum concentrations of the affected drug is determined by the time required to attain steady-state conditions for both the inhibitor and the affected drug, which will now have a more prolonged half-life (Patsalos & Perucca, 2003a). After discontinuation of the inhibitor, the time course for the decrease in serum concentrations of the affected drug depends on the same factors. When enzyme inhibition is noncompetitive and irreversible in nature, the rate of synthesis of the enzyme may also play a role in determining the time required to reach a new steady state. The relative contribution of the inhibited pathway to the elimination of the affected drug is also important. If the inhibited pathway accounts for only a small fraction (e.g., <30%–40%) of the total clearance of a drug, the impact of the interaction on the drug serum concentration and clinical effect will be minimal. Among available AEDs, valproic acid, oxcarbazepine, and felbamate have been most frequently associated with causing inhibitory interactions (Hachad et al., 2002; Patsalos & Perucca, 2003a). Furthermore, whilst oxcarbazepine and felbamate are primarily selective inhibitors of CYP2C19, valproic acid is a broader spectrum inhibitor because it reduces the activity of CYP2C9, uridine glucuronyl transferases (UGTs), and microsomal epoxide hydrolases.
It should be stressed that many important AED interactions involve medications used in the management of concurrent nonepilepsy-related conditions (Patsalos, 2005). Many such drugs, including antimicrobials (e.g., erythromycin, ketoconazole, rifampicin, and ritonavir), cardiovascular drugs (e.g., amiodarone, verapamil, and diltiazem) and psychotropic drugs (e.g., fluoxetine and sertraline) can substantially affect the pharmacokinetics of AEDs, resulting in significant changes in serum AED concentrations (Patsalos & Perucca, 2003b). In these settings TDM can be an invaluable tool in guiding patient management.