Pravachol - Clinical Pharmacology

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In both normal volunteers and patients with hypercholesterolemia, treatment with PRAVACHOL reduced Total-C, LDL-C, and apolipoprotein B. PRAVACHOL also reduced VLDL-C and TG and produced increases in HDL-C and apolipoprotein A. The effects of pravastatin on Lp (a), fibrinogen, and certain other inde-pendent biochemical risk markers for coronary heart disease are unknown. Although pravastatin is relatively more hydrophilic than other HMG-CoA reductase inhibitors, the effect of relative hydrophilicity, if any, on either efficacy or safety has not been established.

In one primary (West of Scotland Coronary Prevention Study Ð WOS) 1 and two secondary (Long-term Intervention with Pravastatin in Ischemic Disease Ð LIPID 2 and the Cholesterol and Recurrent Events Ð CARE 3 ) prevention studies, PRAVACHOL has been shown to reduce cardio-vascular morbidity and mortality across a wide range of cholesterol levels (see Clinical Studies).

Pharmacokinetics/ Metabolism

PRAVACHOL is administered orally in the active form. In clinical pharmacology studies in man, pravastatin is rapidly absorbed, with peak plasma levels of parent compound attained 1 to 1.5 hours following ingestion. Based on urinary recovery of radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces systemic bioavailability, the lipid-lowering effects of the drug are similar whether taken with, or 1 hour prior, to meals.

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.