Chronokinetics of Pravastatin Administered in the PM Compared with AM Dosing

Pravastatin, an HMG CoA reductase inhibitor used in the treatment of hypercholesterolemia, is recommended for bedtime (PM) dosing. Bedtime dosing with pravastatin is slightly more efficacious but not significantly different than morning (AM) dosing in lowering LDL-C and total cholesterol. The pharmacokinetics of pravastatin and its major metabolite SQ 31,906 were determined in 20 healthy men administered a single 20-mg dose either in the morning or at bedtime in an open, randomized, crossover study. Concentrations of pravastatin and SQ 31,906 were measured in serum and urine by gas chromatograph/mass spectrometry methodology. The area under the serum concentration time curve (AUC) of pravastatin was significantly less (40%) following PM dosing compared with AM dosing. Urinary excretion of pravastatin following PM dosing was also significantly decreased. Bioavailability of SQ 31,906 was somewhat higher in the PM group (20% greater following PM administration), and urinary excretion of SQ 31,906 was significantly increased by 60% following PM dosing. The lower AUC of pravastatin following PM dosing does not diminish its efficacy, possibly because PM dosing immediately precedes the diurnal peak period of hepatic cholesterol synthesis. Lower blood levels of pravastatin following PM dosing may contribute to its favorable safety profile.