Abstracts

Rationale: Statins are frequently prescribed to treat hypercholesterolemia and some have been associated with lowering the risk of stroke and myocardial infarction. Atorvastatin, one of the most widely prescribed statins, is metabolized in the liver by CYP3A4. Several antiepileptic drugs (AEDs) induce CYP3A4, the most potent of which is phenytoin (PHT). Phenytoin may affect the metabolism of atorvastatin by induction of CYP3A4 and glucuronidation; therefore, it is hypothesized that PHT will induce the metabolism of atorvastatin. Conversely, little to no interaction between lamotrigine (LTG) and atorvastatin would be expected, although both drugs are glucuronidated to some extent by UGT1A3. The primary goals of this study were to evaluate the effect of LTG on the pharmacokinetics of atorvastatin and to estimate the effect of PHT on the pharmacokinetics of atorvastatin. Methods: Eligible subjects received either lamotrigine extended release tablets (LTG XR) or PHT. These were healthy, non-smoking men or women aged ≥18 ≤ 55 years with no health problems and not taking any medication. Subjects in both cohorts received atorvastatin 40mg orally each morning on days 1 to 7. On day 7, blood samples for the measurement of atorvastatin and its two active metabolites (2-OH and 4-OH atorvastatin) were drawn pre-dose and serially over the next 24 hours after the morning dose. In Cohort 1, atorvastatin was discontinued after day 7, and LTG XR was escalated over 7 weeks to 300mg; atorvastatin was then resumed for an additional 3 weeks. In Cohort 2, PHT (~4mg/kg) was added to the daily atorvastatin regimen on day 8 and subjects continued this combination for the next 3 weeks. At the end of the combined drugs’ regimens in both cohorts, blood samples were again drawn for serial pharmacokinetic measurements of atorvastatin and its metabolites. The primary endpoint was the steady-state maximum concentration (Cmax) and area under the curve (AUC(0-τ)) of atorvastatin in the absence and presence of LTG or PHT. Cmax and AUC(0-τ) of the active metabolites were analyzed as secondary endpoints. Mixed effects models were used for the analyses. Results: A total of 119 healthy subjects enrolled [75 in Cohort 1 (LTG XR); 44 in Cohort 2 (PHT)]. The pharmacokinetic parameters of atorvastatin (geometric mean values) and the summary endpoints are presented in the tables below: Conclusions: Marked reductions in atorvastatin Cmax (~24%), and AUC(0-τ) (~54%) concentrations were observed when administered with PHT, while for LTG XR, Cmax was actually ~14% higher, and AUC(0-τ) was comparable. The metabolites 2-OH atorvastatin and 4-OH atorvastatin were affected in a similar order. This suggests that statin levels should be carefully monitored when taken concurrently with some AEDs. Adjustments of statin dosing, especially with concomitant PHT, may be necessary.