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Effects of lamotrigine and phenytoin on the pharmacokinetics of atorvastatin in healthy volunteers
Author(s) -
Bullman Jonathan,
Nicholls Andrew,
Van Landingham Kevan,
Fleck Richard,
Vuong Alain,
Miller James,
Alexander Sarah,
Messenheimer John
Publication year - 2011
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.1528-1167.2011.03118.x
Subject(s) - atorvastatin , cmax , phenytoin , pharmacokinetics , lamotrigine , pharmacology , dosing , medicine , anticonvulsant , cyp3a4 , drug interaction , epilepsy , cytochrome p450 , metabolism , psychiatry
Summary Purpose: Statins and antiepileptic drugs (AEDs) are frequently coprescribed to individuals with hypercholesterolemia and new‐onset seizures. Statins are metabolized by the cytochrome P450 (CYP) enzyme system. Interactions between statins and agents that undergo CYP metabolism are common. In this study, the effects of two commonly prescribed AEDs, lamotrigine and phenytoin, with different routes of metabolism (CYP3A4 versus glucuronic acid conjugation) on atorvastatin pharmacokinetics were evaluated. Methods: Healthy volunteers (n = 119) received atorvastatin 40 mg/day for 7 days followed by addition of lamotrigine (target 300 mg/day) or phenytoin (target ∼4 mg/kg per day) in this open‐label, single‐sequence, two‐cohort study. Serial pharmacokinetic sampling of atorvastatin was conducted on day 7 of atorvastatin dosing and day 70 of lamotrigine + atorvastatin dosing or day 28 of phenytoin + atorvastatin dosing. Main outcome measures were steady‐state area under the curve over the 24‐h dosing interval (AUC (0–τ) ) and maximum concentration (C max ) of atorvastatin and its metabolites, 2OH‐atorvastatin and 4OH‐atorvastatin, in the presence of lamotrigine or phenytoin. Key Findings: When atorvastatin was administered with lamotrigine compared with when atorvastatin was administered alone, atorvastatin AUC (0–τ) was within bounds indicating no interaction, whereas C max was slightly higher(14%); AUC (0–τ) and C max were 3% and 20% higher, respectively, for 2OH‐atorvastatin and 25% and 21% higher, respectively, for 4OH‐atorvastatin.When atorvastatin was administered with phenytoin compared with when atorvastatin was administered alone, reductions in AUC (0–τ) and C max were observed for atorvastatin (54% and 24%, respectively), 2OH‐atorvastatin (53% and 22%, respectively), and 4OH‐atorvastatin (44% and 52%, respectively). Significance: Pharmacokinetics of atorvastatin were not significantly affected by coadministration with lamotrigine. Phenytoin significantly reduced atorvastatin bioavailability. Consistent with the published literature, these data are consonant with the possibility that atorvastatin does not require dose adjustment when coadministered with lamotrigine at doses to 300 mg/day, whereas atorvastatin coadministered with phenytoin may require atorvastatin dose adjustment to maintain atorvastatin exposure.