Pravachol - Clinical Pharmacology

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Systemic bioavailability of pravastatin administered following a bedtime dose was decreased 60% compared to that following an AM dose. Despite this decrease in systemic bioavailability, the efficacy of pravastatin administered once daily in the evening, although not statistically significant, was marginally more effective than that after a morning dose. This find-ing of lower systemic bioavailability suggests greater hepatic extraction of the drug following the evening dose. Steady-state AUCs, C max and C min plasma concentrations showed no evi-dence of pravastatin accumulation following once or twice daily administration of PRAVACHOL (pravastatin sodium) tablets. Approximately 50% of the circulating drug is bound to plasma proteins.

Following single dose administration of 14 C-pravastatin, the elimination half-life (t ) for total radioactivity (pravastatin plus metabolites) in humans is 77 hours. Pravastatin, like other HMG-CoA reductase inhibitors, has variable bioavailability. The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for AUC. Pravastatin 20 mg was administered under fasting conditions in adults. The geometric means of C max and AUC ranged from 23.3 to 26.3 ng/ mL and from 54.7 to 62.2 ng* hr/ mL, respectively. Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces.

After intravenous administration of radiolabeled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes (i. e., biliary excretion and biotransformation). Since there are dual routes of elimination, the potential exists both for compensatory excretion by the alternate route as well as for accumulation of drug and/ or metabolites in patients with renal or hepatic insufficiency. In a study comparing the kinetics of pravastatin in patients with biopsy confirmed cirrho-sis (N= 7) and normal subjects (N= 7), the mean AUC varied 18-fold in cirrhotic patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied 47-fold for cirrhotic patients compared to 6-fold for healthy subjects.