Pravachol - Clinical Pharmacology

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Biotransformation pathways elucidated for pravastatin include:

(a) isomerization to 6-epi pravastatin and the 3 -hydroxyisomer of pravastatin (SQ 31,906),

(b) enzymatic ring hydroxy-lation to SQ 31,945,

(c) -1 oxidation of the ester side chain,

(d) -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 3 -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, C max , T max and t values were similar in older and younger subjects.

After two 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 C max 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 Ð 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.