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). Thus, the combination of atorvastatin and PHT may result in lower serum concentrations of atorvastatin. This is significant because recent surveys indicate that approximately 10% of newly diagnosed patients with epilepsy are on statin therapy and 23% of those receive PHT as an AED. Little has been published in the literature on this interaction; therefore, a study was undertaken to prospectively assess the effect of PHT on the pharmacokinetics of atorvastatin. Preliminary results from a small number of completed subjects are reported. Methods: Eligible subjects were healthy, non-smoking men or women ≥18 years old with no health problems and not on any medication. Subjects received atorvastatin 40mg orally each morning on days 1 to 28. 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. Phenytoin (~4mg/kg) was added to the daily atorvastatin regimen on day 8 and subjects continued this combination for the next 21 days. On day 28, blood samples were again drawn for serial pharmacokinetic measurements of atorvastatin and its metabolites. Trough PHT levels were drawn on days 26 and 27. 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 PHT. Cmax and AUC(0-τ) of the active metabolites were analyzed as secondary endpoints. Descriptive statistics were utilized for this preliminary subject sample report. Results: A total of 41 healthy subjects have enrolled into the study, and 8 male subjects (mean age 31.6yrs) have completed all required visits to date. In this group, the mean PHT dose was 337.5mg/day (± 51.75mg); mean PHT trough levels were 10.3mcg/ml on days 26 & 27. Mean atorvastatin Cmax and AUC(0-τ) were 11.0ng/ml and 49.4ng.h/ml respectively on day 7 but decreased to 8.1ng/ml and 28.0ng.h/ml on day 28, respectively. Mean Cmax and AUC(0-τ) of 2-OH atorvastatin were 8.4ng/ml and 66.3ng.h/ml respectively on day 7 and 8.0ng/ml and 43.9ng.h/ml on day 28, respectively. Mean Cmax and AUC(0-τ) of 4-OH atorvastatin were 0.86ng/ml and 12.3ng.h/ml respectively on day 7 and 0.95ng/ml and 12.5ng.h/ml on day 28, respectively. Conclusions: In this small, preliminary sample, marked reductions in atorvastatin Cmax (~27%), and AUC(0-τ) (~43%) concentrations were observed when administered with PHT, while, for 2-OH atorvastatin, only a reduction in AUC(0-τ) (~35%) was observed. For 4-OH atorvastatin, Cmax and AUC(0-τ) were unaltered by co-administration with PHT. Complete results from the entire cohort will be presented.