Tiagabine Concentration, Serum
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Tiagabine (Gabitril) is indicated as adjunctive therapy in adults and children 12 years and older in the treatment of partial seizures. It is frequently administered to patients receiving at least 1 concomitant antiepileptic drug (AED).(1) Tiagabine is a selective blocker of gamma-aminobutyric acid (GABA) uptake into presynaptic neurons. Tiagabine binds to recognition sites associated with the GABA uptake carrier. By this action, tiagabine blocks GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on the surface of post-synaptic cells.(1,2)
Tiagabine has an elimination half-life of 7 to 9 hours in normal volunteers. In patients receiving enzyme-inducing AEDs, the elimination half-life decreases to 4 to 7 hours. Phenytoin, phenobarbital, and carbamazepine are AED enzyme inducers; valproate and gabapentin are not. Tiagabine is not considered to be an enzyme-inducing AED.(2,6)
Tiagabine reaches peak serum concentration approximately 45 minutes following an oral dose in the fasting state. Tiagabine is well absorbed with food slowing the absorption rate but not altering the extent of absorption (high fat diet prolongs peak serum concentrations to about 2.5 hours). Tiagabine is >95% absorbed, with oral bioavailability of about 90%. Tiagabine pharmacokinetics are linear over the typical dose range of 2 to 24 mg. Steady-state is achieved within 2 days. Tiagabine is 96% bound to human plasma proteins, mainly to serum albumin and alpha-1-acid glycoprotein. Coadministration with valproate reduces protein binding to 94%, increasing the free fraction of tiagabine by 40%.(3,6)
Based on in vitro data, tiagabine is likely to be metabolized by the 3A isoform subfamily of hepatic cytochrome P450 (CYP 3A), although contributions to the metabolism from CYP 1A2, CYP 2D06, or CYP 2C19 have not been excluded.(3)
This test is used for monitoring tiagabine therapy. Because tiagabine has a wide therapeutic index and dose-dependent toxicity, routine drug monitoring is not indicated in all patients. Drug monitoring is indicated when initiating concomitant therapy with antiepileptic drug that induce hepatic enzymes and when the patient does not respond to treatment to ascertain whether treatment failure is due to noncompliance or nonresponse to the drug.
Trough tiagabine serum concentrations are in the range of 5 to 35 ng/mL in most patients receiving therapeutic doses. Tiagabine serum concentration is proportional to dose.(2,8) A single 4-mg dose administered to a child produced peak serum concentration in the range of 52 to 108 ng/mL.(5) At steady-state, an adult receiving 40 mg per day is expected to have peak serum concentration in the range of 110 to 260 ng/mL, and an adult receiving 80 mg per day is expected to have peak serum concentration in the range of 220 to 520 ng/mL. Serum concentrations >800 ng/mL indicates excessive dosing associated with adverse effects such as asthenia, ataxia, difficulty concentrating, and depression.
In healthy adults administered tiagabine, steady-state peak serum concentrations within 1 hour of dosing are typically in the following ranges:(2)
-Peak serum concentration (4 mg q.i.d.): 36 to 92 ng/mL
-Peak serum concentration (8 mg q.i.d.): 72 to 184 ng/mL
Pediatric patients (3-10 years) reach peak concentration at approximately 2.4 hours.(5)
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Drugs that may interfere with the internal standard include verapamil, lorazepam, and bupivacaine. Coadministration of these drugs will generate an artifactually decreased tiagabine concentration.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
Peak: 110-520 ng/mL
Trough: 5-35 ng/mL
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Package insert: Gabitril Filmtab, tiagabine hydrochloride. Abbott Laboratories, North Chicago, IL, 1997
2. So EL, Wolff D, Graves N, et al: Pharmacokinetics of tiagabine as add-on therapy in patients taking enzyme-inducing antiepilepsy drugs. Epilepsy Res 1995;22:221-226
3. Benedetti MS: Enzyme induction and inhibition by new antiepileptic drugs: a review of human studies. Fundam Clin Pharmacol 2000;14:301-319
4. Perucca E: The clinical pharmacokinetics of the new antiepileptic drugs. Epilepsia 1999;40:S7-S13
5. Gustavson LE, Soellner SW, Granneman GR, et al: A single-dose study to define tiagabine pharmacokinetics in pediatric patients with complex partial seizures. Neurology 1997;48:1032-1037
6. Cato A 3rd, Gustavson LE, Qian J, et al: Effect of renal impairment on the pharmacokinetics and tolerability of tiagabine. Epilepsia 1998;39:43-47
7. Wiley Cl, Enger RJ, Charlson JC, Moyer TP: Unpublished Mayo information
8. Thompson MS, Groes L, Agerse H, Kruse T: Lack of pharmacokinetic interaction between tiagabine and erythromycin. J Clin Pharmacol 1998;38:1051-1056