CQ 12-1

When should serum concentrations of antiepileptic drugs be monitored?

Summary

Measurement of serum concentrations of antiepileptic drugs is useful for the following purposes: (1) to establish individual therapeutic ranges when the desired seizure control is obtained; (2) to diagnose adverse effects; (3) to evaluate adherence at the time of poor seizure control or breakthrough seizure; (4) to adjust doses in situations of pharmacokinetic changes (such as in children, elderly patients, comorbid disorders, and change in dosage form); (5) to adjust doses when change in pharmacokinetics is predicted (such as during pregnancy and addition or removal of drugs having interactions); and (6) to adjust doses of drugs having dose-dependent pharmacokinetics (particularly phenytoin).

Comment

Monitoring serum concentrations of antiepileptic drugs is useful in deciding patient’s medication regimen, if monitoring is done for a clear purpose and the results are interpreted properly along with other clinical factors. Serum concentrations of antiepileptic drugs should not be monitored routinely without intended purposes. However, they should be measured when there are clinical needs (Table 1)¹⁾.

The reference range of serum concentrations of a certain drug is not the same as its therapeutic range. The lower limit of the reference range of serum concentrations is the concentration being more likely to produce an insufficient therapeutic effect, and the upper limit is the concentration being more often associated with adverse effects. That is, the serum concentrations of antiepileptic drugs within the reference range (so-called effective serum concentrations) indicate that they are expected to be effective with fewer adverse effects in most of the patients¹⁾.

The therapeutic range of serum concentrations for a certain patient is the range within which that patient has the best seizure control. In most of the patients, the therapeutic range is within or overlaps with the reference range. However, treatment may be effective even when the serum concentration is lower than the reference range in some cases, or conversely may be effective only when the concentration is higher than the reference range in other cases, because of large inter-individual variability of the therapeutic range. Therefore, it is important to know the therapeutic range for each patient. The dose should not be increased if the patient remains seizure-free at serum concentration lower than the reference range. On the other hand, the dose might be increased to above the reference range if the patient has residual seizures without any adverse effects. The reference range of serum concentration differs depending on age, epilepsy syndrome, and seizure type^1, 2).

The reference range is determined based on the lowest serum concentration (the trough value, which is measured before drug taking in the morning). However, it is difficult to measure the trough value in outpatient clinic, and serum concentration measured at our clinics is usually higher than the trough. Therefore, it is not a concern if the measured value exceeds the upper limit of the therapeutic range. We should interpret the blood concentration considering the blood sampling time, the drug taking time, and the time of maximum concentration (T_max) of each drug (Table 1 in CQ 12-2 on page 104).

Antiepileptic drug exists in two forms in the blood: a protein-bound form and a free form. In patients with hypoproteinemia, pregnancy, hepatic disorders or renal disorders, the amount of drug in the free form is larger than that in healthy subjects even when the measured serum concentration is the same, and the efficacy and adverse effects are not the same as in normal controls. Although the free form possesses antiepileptic effect, measurement of free form is not covered by medical insurance. In general, the total serum concentrations of antiepileptic drugs, including both protein-bound form and free form, are measured and recorded.

▪ References

1) Patsalos PN, Berry DJ, Bourgeois BFD, et al. Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: a position paper by the Subcommission on Therapeutic Drug Monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008; 49(7): 1239-1276.

2) Johannessen SI, Patsalos PN. Individual approach to laboratory monitoring of antiepileptic drugs. In: Wyllie E, Gidal BE, Goodkin HP, et al eds. Willie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia: Wolters Kluwer, 2015. p.568-573.

CQ 12-2

Serum concentration monitoring is useful for which drugs?

Summary

The reference ranges of serum concentrations have been established for carbamazepine, phenytoin, phenobarbital, primidone, valproate, and ethosuximide. Serum concentration monitoring is useful for these drugs. However, for some other drugs, the serum concentration monitoring is not very useful because the reference ranges have not determined for them or they show remarkable fluctuations in serum concentration (Tables 1 and 2)^1-5).

Comment

Because there are large interindividual variabilities in epileptogenesis and response to a given antiepileptic drug, it is difficult to find a general therapeutic range of serum concentrations applicable to all patients. However, it is known that there exists a range of serum concentrations at which seizures are controlled and dose-dependent adverse effects are rarely seen in most of the patients. This range is called the “reference range” (so-called effective blood concentration).

Even for drugs with no established general reference ranges, serum concentration measurement is useful for comparisons within an individual patient. Benzodiazepines play a role as an anti-convulsant by binding with benzodiazepine receptors in the brain. Because the number of benzodiazepine receptors varies from person to person, it is difficult to determine the reference blood concentration range for all persons. The reference ranges for clobazam, nitrazepam and diazepam have not been reported. However, repetitive serum concentration measurements in one patient are useful for monitoring adverse effects such as drowsiness in that patient.

Phenytoin is a drug showing big fluctuations in serum concentration, which requires attention. Because of the non-linear relationship between dosage and serum concentration and the narrow therapeutic window, measurement of serum concentration is critical for setting the optimal dosage. Especially, a rapid rise in serum concentration occurs at high doses¹⁾. The serum concentration of lamotrigine decreases drastically when used concomitantly with enzyme-inducing drugs (phenytoin, carbamazepine, phenobarbital, and primidone), increases greatly when used in combination with valproate, and declines significantly during pregnancy. Serum level of carbamazepine decreases within 1–3 months after start of treatment, due to enzyme self-induction. Therefore, serum concentration has to be monitored shortly after treatment initiation.

▪ References

1) Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015, p.376-700.

2) Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia: Wolters Kluwer, 2015, p.593-768.

3) Patsalos PN, Bourgeois BFD. The Epilepsy Prescriber’s Guide to Antiepileptic Drugs. Cambridge: Cambridge University Press, 2010.

4) Drugs in Japan Forum, ed. Drugs in Japan: Ethical Drugs 2016 Edition. Tokyo: Jiho Inc., 2015 (in Japanese).

5) Johannessen SI, Johannessen-Landmark C, Perucca E. Pharmacokinetic optimization of therapy. In: Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015, p.124-138.

CQ 12-3

Is serum concentration monitoring a requisite in the treatment of patients with hepatic or renal dysfunction?

Summary

Since the pharmacokinetics of antiepileptic drugs may alter in patients with hepatic or renal dysfunction, conduct treatment based on serum concentrations of drugs. Dialysis reduces serum drug concentrations.

Comment

Antiepileptic drugs are mainly metabolized by the liver and excreted by the kidney. But the ratio of hepatic metabolism and renal excretion varies depending on the drug. In patients with liver or kidney disorders, pay attention to the increase in serum concentrations of antiepileptic drugs, bearing in mind the metabolism and excretion routes and the ratio of hepatic metabolism and renal excretion for each drug. Then, the doses should be reduced if necessary. For drugs that are metabolized by the liver, serum concentrations do not change markedly in acute hepatitis since metabolic enzymes do not decrease, but serum concentrations rise in cirrhosis because metabolic enzyme and hepatic blood flow are both reduced. In patients treated with hemodialysis, the blood levels of some drugs decrease, therefore consider dose increment¹⁾ (Table 1)^2-4).

▪ References

1) Singh G. Management of medical comorbidity associated with epilepsy. In: Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015, p.245-258.

2) Spina E, Italiano D. Drug interactions. In: Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2016. p.344-359.

3) Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015. p.376-700.

4) Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia: Wolters Kluwer, 2015. p.593-768.

CQ 12-4

What are the drugs that interact with antiepileptic drugs?

Summary ^1-5)

When addition or removal of a given non-antiepileptic drug results in an increase in seizures or adverse effects, suspect drug interaction with the antiepileptic drugs being used and consider measurement of serum concentrations of the antiepileptic drugs. Conversely, when an antiepileptic drug is being added or removed, pay attention to the possibility that the therapeutic effects of other drugs may alter, which may result in some changes in comorbid symptoms.

Comment

Drug interactions include interactions between antiepileptic drugs (Table 1)^1-3), interactions between antiepileptic drugs and psychotropic drugs (Tables 2 and 3)^1-5), and interactions between antiepileptic drugs and general drugs other than psychotropic drugs (Tables 4 and 5)^1-5). Pay special attention when patients are complicated with psychiatric disease or developmental disorder, or elderly people taking various drugs because of comorbidities.

Among antibiotics, clarithromycin and erythromycin inhibit the metabolism of carbamazepine, resulting in a large increase in serum concentration of carbamazepine, causing dizziness, vertigo, and severe drowsiness. Carbapenem antibiotics (panipenem‒betamipron, meropen, imipenem‒cilastatin, doripenem, biapenem, tebipenem) are contraindicated when taking valproate, as they significantly lower the serum concentration of valproate.

For antithrombotic drugs, warfarin used with phenytoin mutually increase the serum concentrations of each other, and the blood level of rivaroxaban is lowered by carbamazepine, phenytoin or phenobarbital (see CQ 3-8 on page 30).

▪ References

1) Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015. p.376-700.

2) Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia: Wolters Kluwer, 2015. p.593-768.

3) Patsalos PN, Bourgeois BFD. The Epilepsy Prescriber’s Guide to Antiepileptic Drugs. Cambridge: Cambridge University Press, 2010.

4) Drugs in Japan Forum, ed. Drugs in Japan: Ethical Drugs 2016 edition. Tokyo: Jiho Inc., 2015 (in Japanese).

5) Sugai K: Interactions between antiepileptic drugs and other drugs and food. Shoni Naika (Japanese Journal of Pediatric Medicine) 2014; 46(9): 1242-1247 (in Japanese).