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 Cmax 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 cirrhosis (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.

Biotransformation pathways elucidated for pravastatin include: (a) isomerization to 6-epi pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906), (b) enzymatic ring hydroxylation to SQ 31,945, (c) ω-1 oxidation of the ester side chain, (d) β-oxidation of the carboxy side chain, (e) ring oxidation followed by aromatization, (f) oxidation of a hydroxyl group to a keto group, and (g) conjugation. The major degradation product is the 3α-hydroxy isomeric metabolite, which has one-tenth to one-fortieth the HMG-CoA reductase inhibitory activity of the parent compound.

In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was approximately 27% greater and the mean cumulative urinary excretion (CUE) approximately 19% lower in elderly men (65 to 75 years old) compared with younger men (19 to 31 years old). In a similar study conducted in women, the mean AUC for pravastatin was approximately 46% higher and the mean CUE approximately 18% lower in elderly women (65 to 78 years old) compared with younger women (18 to 38 years old). In both studies, Cmax, Tmax and t_½ values were similar in older and younger subjects.

After 2 weeks of once-daily 20 mg oral pravastatin administration, the geometric means of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) ng*hr/mL for children (8-11 years, N=14) and adolescents (12-16 years, N=10), respectively. The corresponding values for Cmax were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for children and adolescents, respectively. No conclusion can be made based on these findings due to the small number of samples and large variability.

Clinical Studies

Prevention of Coronary Heart Disease

In the Pravastatin Primary Prevention Study (West of Scotland Coronary Prevention Study - WOS)¹, the effect of PRAVACHOL on fatal and nonfatal coronary heart disease (CHD) was assessed in 6595 men 45 - 64 years of age, without a previous myocardial infarction (MI), and with LDL-C levels between 156 - 254 mg/dL (4 - 6.7 mmol/L). In this randomized, double-blind, placebo-controlled study, patients were treated with standard care, including dietary advice, and either PRAVACHOL 40 mg daily (N=3302) or placebo (N=3293) and followed for a median duration of 4.8 years. Median (25th, 75th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were -20.3 (-26.9, -11.7), -27.7 (-36.0, -16.9), -9.1 (-27.6, 12.5), and 6.7 (-2.1, 15.6), respectively.

PRAVACHOL significantly reduced the rate of first coronary events (either coronary heart disease [CHD] death or nonfatal MI) by 31% [248 events in the placebo group (CHD death=44, nonfatal MI=204) vs 174 events in the PRAVACHOL group (CHD death=31, nonfatal MI=143), p=0.0001 (see figure below)]. The risk reduction with PRAVACHOL was similar and significant throughout the entire range of baseline LDL cholesterol levels. This reduction was also similar and significant across the age range studied with a 40% risk reduction for patients younger than 55 years and a 27% risk reduction for patients 55 years and older. The Pravastatin Primary Prevention Study included only men, and therefore it is not clear to what extent these data can be extrapolated to a similar population of female patients.

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