Will require Trileptal blood tests

Anti-epileptic drugs

General rules for determining the active substance level

In principle, drug levels should be determined in steady state and trough levels. The steady state is reached after 5 elimination half-lives of the administered drug. You can reach the trough level by taking a blood sample immediately before taking your medication again. In particular, a determination of the active substance concentration in the serum is recommended for:

  • Missing, reduced or delayed therapeutic success
  • Questions regarding patient compliance
  • Comorbidities
  • Adverse drug reactions or signs of toxic effects
  • Polymedication or suspected drug interactions
  • Suspected genetic polymorphisms in drug metabolism.



Modern anti-epileptic drugs act by inhibiting excitatory and increasing inhibitory neuronal activity. At the molecular level, this is achieved via a large number of pharmacological mechanisms of action, whereby the individual active ingredients can be assigned to a main mechanism for simplicity:

  • Inhibition or inactivation of voltage-dependent Na+- and approx2+-Channels
  • Inhibition of NMDA and AMPA receptors
  • allosteric / direct activation of GABAA.Receptors
  • Inhibition of GABA transaminase
  • Interaction with synaptic structural proteins (SV2A, CRMP-2) and
  • Inhibition of carbonic anhydrase.

In some cases, however, undesirable effects can also be derived from the mechanisms of action, e.g. proarrhythmogenic properties through inhibition of cardiac ion channels or psychotic symptoms through NMDA / AMPA receptor antagonism. Structurally similar substances in turn show characteristic side effects, e.g. B. Hyponatremia with carbamazepine, eslicarbazepine, and oxcarbazepine. For some active substances, rare but severe undesirable effects have been described, e.g. B. aplastic anemia and liver failure with felbamate, or visual field restrictions with vigabatrin.



After oral administration, antiepileptic drugs are usually rapidly absorbed with maximum serum concentrations within 1–4 hours; Carbamazepine (T.Max approx. 9 hours) or oxcarbazepine and rufinamide (T.Max approx. 6 hours) are major exceptions. A relevant influence of food on absorption has been described for rufinamide, stiripentol and sultiam.

The excretion of the active ingredients is different:

  • Gabapentin, pregabalin and vigabatrin are largely excreted unchanged by the kidneys.
  • Carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone and stiripentol are mainly metabolized by cytochrome CYP450 enzymes, rufinamide is metabolized independently of CYP450 enzymes.
  • Lamotrigine is predominantly glucuronidated and excreted directly by UDP-glucuronosyltransferases (UGT), the active metabolite of eslicarbazepine and oxcarbazepine licarbazepine is eliminated both via glucuronidation and primarily renally.
  • Valproic acid is glucuronidated directly by UDP-glucuronosyltransferases (UGT) and is also metabolized via mitochondrial beta-oxidation and CYP450 enzymes.
  • Felbamate, lacosamide, levetiracetam, sultiamate, topiramate and zonisamide are primarily eliminated renally and metabolized to varying degrees by various hepatic enzyme systems.

The clinically relevant details on pharmacokinetics, active levels and metabolism are set out in Table 1.


Table 1

Active ingredientParent substance - metaboliteTherapeutic areaElimination half-lifeEarliest steady state timeMain metabolic enzymes (including metabolites)
Carbamazepine1Carbamazepine4 - 12 mg / l10 - 65 h2 - 10 dCYP3A4
Carbamazepine epoxide
Eslicarbazepine1Eslicarbazepine10 - 35 mg / l10 a.m. - 8 p.m.3 - 5 drenal, UGT
Ethosuximide2Ethosuximide40-100 mg / l24 - 66 h8-17 dCYP3A4
Felbamate3Felbamate30 - 80 mg / l3 pm - 11 pm3 - 5 drenal, CYP3A4 & 2E1
Gabapentin5Gabapentin2 - 20 mg / l5 - 10 h2 - 4 dprimarily renal
Lacosamide3Lacosamide1 - 10 mg / l10 a.m. - 3 p.m.3 - 4 drenal, non-CYP
Lamotrigine3Lamotrigine3 - 15 mg / l14-104 h3 - 22 dUGT
Levetiracetam3Levetiracetam20 - 40 mg / l6 - 8 h3 dprimarily renal & non-CYP
Mesuximide1Mesuximide 1 - 3 h8-17 dCYP2C19 & 3A4, UGT
Desmethyl mesxuimide10 - 40 mg / l36 - 45 h 
Oxcarbazepine1OxcarbazepineΣ 10 - 35 mg / l *

5 h

2 - 8 drenal, UGT
10-OH carbazepine10 a.m. - 8 p.m. 
phenobarbital2phenobarbital10 - 40 mg / l75 - 120 h16 - 25 dCYP2C19 & 2C9
Phenytoin4Phenytoin10-20 mg / l20 - 60 h5 - 7 dCYP2C9, 2C19 & 3A4
Pregabalin5Pregabalin2 - 5 mg / l6 h2 - 3 dprimarily renal
Primidon4Primidon5 - 10 mg / l2 - 8 p.m.16 - 25 dCYP2C19 & 2C9
phenobarbital10 - 40 mg / l80 - 120 h 
Rufinamide3Rufinamide5 - 30 mg / l6 - 10 h2 - 3 dnon-CYP
Stiripentol4Stiripentol1 - 10 mg / l4 a.m. - 1 p.m.2 - 3 dCYP1A2, 2C19 & 3A4
Sultiam5Sultiam2 - 8 mg / l3 - 30 h2 - 6 d 
Topiramate5Topiramate2 - 10 mg / l7pm - 11pm4 - 8 dprimarily renal & non-CYP
Valproic acid2Valproic acid50-100 mg / l3 - 30 p.m.3 - 6 dUGT, CYP
Vigabatrin5Vigabatrin2 - 10 mg / l5 - 8 h2- 3 dprimarily renal
Zonisamide2Zonisamide10 - 40 mg / l49 - 77 h10-15 drenal, CYP3A4 & 2C19, non-CYP
*The effective level refers to the sum of the parent substance and the active metabolite.

Depending on the method, the active ingredients are determined at the same time.

Oxcarbazepine and eslicarbazepine work via the same active metabolites 10-OH-carbazepine = licarbazepine


Drug interactions

Because of the narrow therapeutic breadth of anti-epileptic drugs, drug interactions are essential. It should be noted that (I) the active ingredients mostly have several different metabolic and excretion pathways, and (II) the active ingredients can act to different degrees as inducers or inhibitors on different metabolic pathways.

Carbamazepine, phenobarbital, phenytoin and primidone, but also oxcarbazepine and eslicarbazepine are among the active ingredients that induce a clinically relevant induction of enzymes of phase I and phase II drug metabolism (CYP450, UGT, GST, SULT enzymes, P-gp / MDR-1, as well as ALA synthase). This not only accelerates the metabolism of numerous active ingredients, but also, for example, of hormones such as vitamin D3. As a result, the risk of osteoporosis is increased and the effect of immunosuppressive or virostatic therapy as well as oral contraceptives is no longer generally guaranteed.

Interactions are particularly pronounced when the metabolism only proceeds in one way and the active ingredient is not primarily excreted renally. This applies, for example, to lamotrigine or phenytoin. The interaction potential of gabapentin, pregabalin and vigabatrin is therefore low, as these active substances are primarily excreted renally and are hardly metabolized (even when induced by enzymes).

Interactions via CYP3A4 can mainly affect the metabolism of carbamazepine, ethosuximide, stiripentol and sultiam. This also applies to felbamate, topiramate and zonisamide, which are primarily excreted renally in the absence of enzyme-inducing agents. Typical interaction partners are:

  • Inducers of CYP3A4: in particular carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampicin, as well as bosentan, mesuximide, modafinil, eslicarbazepine, efavirenz, oxcarbazepine, oxybutinin, St. John's wort and others
  • Inhibitors of CYP3A4: in particular macrolides, azole antimycotics, protease inhibitors, as well as aprepitant, conivaptan, crizotinib, diltiazem, dronedarone, imatinib, stiripentol, verapamil, naringin / grapefruit juice and others.

Interactions via CYP2C9 can mainly influence the metabolism of phenytoin. Typical interaction partners are:

  • Inhibitors: in particular capecitabine / fluorouracil, fluconazole, gemfibrozil, tegafur and amiodarone, as well as efavirenz, stiripentol, sulfamethoxazole, voriconazole and others
  • Inducers: In particular enzalutamide and rifampicin, but also carbamazepine, nevirapine, phenobarbital, primidone, ritonavir, St. John's wort and others.

Interactions via CYP2C19 can mainly affect the metabolism of primidone, phenobarbital and phenytoin. Typical interaction partners are:

  • Inhibitors: especially fluconazole, as well as eslicarbazepine, felbamate, fluoxetine, fluvoxamine, mesuximide, moclobemide, (Es) omeprazole, oxcarbazepine, stiripentole, topiramate, voriconazole and others
  • Inducers: especially rifampicin and ritonavir, but also carbamazepine, efavirenz, modafinil, primidone, ritonavir, St. John's wort and others.

Interactions via UGT enzymes primarily affect lamotrigine and, to a lesser extent, eslicarbazepine, oxcarbazepine, and valproic acid. The main inhibitor is valproic acid. B. carbamazepine, phenytoin, primidone and phenobarbital, but also lamotrigine and ethinylestradiol or hormonal contraceptives. In particular, it should be noted that lamotrigine and valproic acid influence one another.

Pharmacodynamically, proarrhythmogenic effects can be increased by inhibiting cardiac ion channels, e.g. by (tricyclic) antidepressants / antipsychotics, quinolones, macrolides, fluconazole, lopinavir / ritonavir, cisapride, amiodarone, flecainide and propafenone. The risk of neutropenia / agranulocytosis can be increased primarily by clozapine, cotrimoxazole, carbimazole, popylthiouracil, sulfasalazine, rituximab, or cytostatics (methotrexate, azathioprine, cyclophophamide, etc.).


Drug metabolism genetics (pharmacogenetics)

For CYP2C19 and CYP2D6 of the CYP450 enzyme family, genetic variants have been described in up to 10% of the population that lead to a clinically relevant increase or decrease in enzyme activity. Phenytoin and phenobarbital in particular are metabolized to a relevant extent by CYP2C19, so that their active levels can show an increased individual variation. This can only be reliably monitored by a TDM-controlled therapy. Furthermore, variants have been described for CYP2C9 and UGT enzymes, which can lead to an altered activity. This can have a relevant influence on the active level, especially with phenytoin, lamotrigine and valproic acid.


Requirement and evaluation of findings

The evaluation of drug levels includes both the interpretation of the concentrations in relation to the recommended therapeutic range, as well as the assessment of the applied dose, the concomitant medication and other diseases. In order to obtain the necessary information, we therefore ask you to use the special request form for drug level determinations.

Depending on the method, several active ingredients are determined in one diagnostic run. The groups are shown in Table 1. This gives us the opportunity to provide you with further information on the comedications (without additional charge).


Material and billing

In the curative case, the drug level determination is included without restriction in the range of services of the EBM and the GOÄ. Pharmacogenetic examinations are carried out by private insurers and, for some indications (see request form for determining the drug level / pharmacogenetics), also by statutory health insurers.



Determination of active substance: Serum / whole blood (blood drawn in steady state immediately before taking the medication again)
Pharmacogenetics: EDTA blood or mucosal swab


Contact Person

Your contacts for the determination of active ingredients and pharmacological evaluation:

Dr. med. Dr. rer. nat. Leif Gerrit Hommers
Tel. 030-5604087-31

Dr. med. Frank-Peter Schmidt
Tel. 030-5604087-0

Dr. rer. nat. Steffen Bauer
Tel. 030-5604087-10