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Pharmacokinetics and Safety of Tiagabine in Subjects with Various Degrees of Hepatic Function
Author(s) -
Lau Alan H.,
Gustavson Linda E.,
Sperelakis Rita,
Lam Nancy P.,
ElShourbagy Tawakol,
Qian Jiang X.,
Layden Thomas
Publication year - 1997
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1157.1997.tb01734.x
Subject(s) - tiagabine , pharmacokinetics , chemistry , liver disease , medicine , liver function , anesthesia , pharmacology , endocrinology , anticonvulsant , epilepsy , psychiatry
Summary: Purpose: To evaluate the pharmacokinetics and safety of multiple oral doses of tiagabine HC1 in subjects with different degrees of hepatic impairment. Methods: Four subjects with mild hepatic impairment, three subjects with moderate hepatic impairment, and six matched normal subjects received twice daily oral tiagabine HCl for 5.5 days. Serial blood specimens were obtained for 48 h after the final dose. Total and unbound tiagabine plasma concentrations were determined by high‐performance liquid chromatography (HPLC) and ultrafiltration, respectively. Pharmacokinetic parameters were compared between the groups by analysis of covariance. Results: For total tiagabine concentrations in normal subjects and subjects with mild and moderate hepatic impairment, C max values (mean i SD) were 117 ± 54, 172 ± 40, and 172 ± 28 ng/ml; C min values were 13 ± 4,27 ± 4, and 28 ± 6 ng/ml; areas under the plasma concentration‐time curve were 396 ± 59, 633 ± 16, and 675 ± 32 ng Wml, and elimination half‐lives (harmonic means) were 7, 12, and 16 h, respectively. Unbound tiagabine coricentrations, area under the unbound plasma concentration‐time curve, and the free fractions were increased in the hepatically impaired subjects. Reduced serum albumin and α 1 ‐acid glycoprotein concentrations may have contributed to increases in the unbound fraction. Adverse events observed included dizziness, tremor, nausea, somnolence, incoordination, and unsteady gait. The frequency of these events was increased in the subjects with liver impairment. Conclusions: Because of the decreased drug elimination caused by liver function impairment, reduced doses or increased dosing interval or both may be needed to attain therapeutic plasma drug concentrations. Time to reach steady state also may be prolonged. The patients should be monitored closely for potential neurologic adverse events.