Pravachol Clinical Pharmacology

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Pravachol - Clinical Pharmacology [Pravastatin]

Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66), which is its primary site of action, and the primary site of cholesterol synthesis and of LDL-C clearance. In vitro studies demonstrated that pravastatin is transported into hepatocytes with substantially less uptake into other cells. In view of pravastatin's apparently extensive first-pass hepatic metabolism, plasma levels may not necessarily correlate perfectly with lipid-low-ering efficacy. Pravastatin plasma concentrations [including: area under the concentration-time curve (AUC), peak (C max ), and steady-state minimum (C min )] are directly proportional to admin-istered dose.

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.