Population Analysis of the Pharmacokinetics of Tiagabine in Patients with Epilepsy

Summary: Purpose: In two open-label long-term safety studies, we determined tiagabine (TGB) pharmacokinetics in patients with epilepsy. Methods: In all, 2,147 plasma samples from 5 1 1 patients who participated in the studies were available. The total daily dose ranged from 2 mg administered once daily to 80 mg administered in four doses. A one-compartment model with first-order absorption and elimination was used to fit the TGB plasma concentration-time data, with a population pharmacokinetic approach. Results: The patients’ average (+SD) weight and age were 73.8 + 20.7 kg and 32.1 k 12.3 years. The most significantly factor affecting TGB pharmacokinetics was concomitant administration of other antiepileptic drugs (AEDs). The central clearance value in patients receiving AEDs known to induce hepatic drug metabolism was 21.4 Llh, a value 67% higher than the central clearance estimate obtained for the patients receiving AEDs not known to affect hepatic drug metabolism (1 2.8 Lh). There was no evidence of any dose or time effect, indicating that TGB pharmacokinetics are linear. TGB pharmacokinetics were not different in white, black, or Hispanic patients, although our ability to explore racial effects was limited since 90% of the patients were white. No other demographic variables (including age and smoking) or any clinical chemistry measurements (including bilirubin, SGOT, and SGPT) were important in explaining the variability in the clearance estimates. Conclusions: TGB pharmacokinetics are linear, influenced by enzyme-inducing AEDs, and largely unaffected by other demographic variables. Key Words: Population-TiagabinePharmacokinetics-Epilepsy . Tiagabine [TGB: (R)-N-(4,4-di(3-methyl-2-thienyl)but-3-enyl-nipecotic acid], is a potent and selective inhibitor of y-aminobutyric acid (GABA) uptake. TGB, a nipecotic acid derivative discovered by Novo-Nordisk A/S (Bagsvaerd, Denmark), was recently approved in the United States as adjunctive therapy in the treatment of partial seizures.