Therapeutic Drug Monitoring of Anticonvulsants

Table 4

Patient Information

Other Information

Name of the patient Hospital identification number Age

Dosage regimen

Time of taking dosage

Type of specimen (serum, urine, saliva, other body fluid). Number of specimens

(if more than one) and type of drug concentration requested (total vs. free)

Time of specimen collection (peak vs.

trough)

Time of last dose Concentration of the drug Pharmacokinetic parameters of the drug

Height and weight

Gender (if female pregnant?a) Ethnicity

Albumin level, creatinine clearancea a Optional information.

Although free drug concentration can be predicted from traditionally measured total drug concentration (free + protein-bound drug), under certain disease conditions, such as uremia and hepatic impairment, free drug concentration may not be predicted from total drug concentration because of impairment of the protein-binding ability of serum for these anticonvulsants. Moreover, monitoring free drug concentration is also recommended for these drugs in elderly patients, critically ill patients, pregnant women, and patients with a low serum albumin concentrations. This topic is discussed in Chapter 2.

Minimally effective serum total phenytoin concentration is considered as 10 ^g/mL, whereas the upper end of the therapeutic range is 20 ^g/mL. Carbamazepine is an iminostilbene derivative structurally similar to the TCA imipramine. It was approved in the USA in 1974 as an antiepileptic for many seizure disorders and in 1979 for use in children over 6 years of age. The current uses of carbamazepine include partial seizures with complex symptomatology, generalized tonic-clonic seizures, and mixed seizures. Carbamazepine and phenytoin are considered as the drugs of choice for treating these seizure disorders (108). Carbamazepine is also frequently added to the existing TCA therapy (109). Carbamazepine, like lithium, may help some individuals with episodic behavioral dysfunction, such as loss of control and aggression, even in the absence of epileptic, affective, or organic features (110,111). TCA and anticonvulsants are also used in the treatment of pain in polyneuropathy (112). The minimally effective serum concentration of carbamazepine is 4 ^g/mL, and the toxicity may be encountered at serum level over 12 ^g/mL. Carbamazepine is metabolized to an active metabolite carbamazepine 10, 11-epoxide. Carbamazepine 10, 11-epoxide is present in 15-20% of the total carbamazepine concentration at steady state. The concentration of metabolite may be significantly higher in carbamazepine overdose and in patients with renal failure. Moreover, concentration of carbamazepine 10, 11-epoxide may be further elevated in patients also receiving valproic acid and lamotrigine. For these patients, measuring both carbamazepine and carbamazepine 10, 11-epoxide is clinically useful (113). Another issue is the cross-reactivity of epoxide with carbamazepine immunoassays. The cross-reactivity of carbamazepine 10, 11-epoxide with different immunoassays may vary between 0% (Vitros Ortho Diagnosics Rariton, NJ) and 94% (Dade Dimension Deerfield, IL) (114). Parant et al. (115) also reported high cross-reactivity of PETINIA (Dade Behring Deerfield, IL) carbamazepine assay with carbamazepine 10, 11-epoxide and negligible cross-reactivity with the EMIT 2000 assay. Ideally, a high-performance liquid chromatography (HPLC) method should be used as a reference method for measuring carbamazepine and carbamazepine 10, 11-epoxide concentrations, but immunoassays are widely used for routine monitoring of serum carbamazepine concentrations in many clinical laboratories. Therefore, caution should be exercised in the interpretation of serum carbamazepine concentrations in light of cross-reactivity of the specific immunoassay with carbamazepine 10, 11-epoxide.

Valproic acid is an antiepileptic drug, which is structurally unrelated to phenytoin, phenobarbital, or carbamazepine. The chemical name of valproic acid is 2-propylpentanoic acid, which was synthesized in 1881, but the antiepileptic property of valproic acid was not discovered until 1963. Other than epilepsy, valproic acid in the form of divalproex sodium is used as a prophylaxis for migraine (116). Valproic acid is also used in treating a variety of psychiatric disorders (117). Therapeutic responses to valproic acid are usually observed at serum concentrations equal to or greater than

40 ^g/mL, and toxicity is encountered at serum levels exceeding 100 ^g/mL. Seizure controls of phenobarbital start with a serum concentration of 15 ^g/mL, and concentrations greater than 40 ^g/mL may cause toxicity.

In the past decade, 10 new antiepileptic drugs have been approved for use. These drugs include felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, prega-balin, tiagabine, topiramate, vigabatrin, and zonisamide. In general, these antiepileptic drugs (except felbamate) have better pharmacokinetic profiles, improved tolerability in patients, and are less involved in drug interactions compared with traditional anticon-vulsants: phenytoin, carbamazepine, phenobarbital, and valproic acid. Gabapentin, levetiracetam, and vigabatrin are mainly eliminated by the renal route with a fraction of unchanged drug in the urine of 65, 66, and 100%, respectively. These anticonvul-sants are not involved in drug interactions. Other new anticonvulsants are metabolized by cytochrome P450 and uridine glucuronosyltransferase enzyme and may be involved in pharmacokinetic drug interactions with conventional anticonvulsants or other drugs (118). Clinical utility of therapeutic drug monitoring as well as guidelines of serum drug concentrations have not been clearly established for these new anticonvulsants. However, careful monitoring of liver function tests and blood cell counts is strongly recommended for felbamate because of its known toxicity (119). The drug is only 20-25% bound to serum protein, and currently, there is no indication for monitoring free felbamate level. There is no systematic study to establish a therapeutic range for gabapentin. A tentative target range of 70-120 ^mol/L has been suggested. There are more indications for therapeutic monitoring of lamotrigine. The therapeutic range suggested is 12-55 ^mol/L. Tiagabine is strongly protein bound and is a candidate for free drug monitoring. However, more studies are needed to establish a therapeutic range. The traditional approach to therapeutic drug monitoring does not apply to vigabatrin (120). Reference ranges and costs of therapeutic drug monitoring of anticonvulsants are given in Table 5.

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