Corstat Mechanism of Action

Pharmacology: Pharmacodynamics: The involvement of LDL cholesterol in arthrogenesis has been well documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological studies have been established that high LDL (low-density lipoprotein) and HDL (high-density lipoprotein) cholesterol are both risk factors for coronary heart disease.
Corstat has been shown to reduce both normal and elevated LDL-cholesterol concentrations. LDL is formed from VLDL and is catabolised predominantly by the high-affinity LDL receptor. The mechanism of the LDL-lowering effect of Corstat may involve both reduction of VLDL-cholesterol concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL cholesterol. Apolipoprotein B also falls substantially during treatment with Corstat. Since each LDL particles contains one molecule of apolipoprotein B, and since little apolipoprotein B is found in other lipoproteins, this strongly suggests that Corstat does not merely cause cholesterol to be lost from LDL but also reduces the concentration of circulating LDL particles. In addition, Corstat increases HDL cholesterol and reduces plasma triglycerides. As a result of these changes the ratios of total to HDL cholesterol and LDL to HDL cholesterol are reduced. In studies comparing the efficacy and safety of simvastatin 10, 20, 40 and 80 mg daily, the mean reductions of LDL-C where 30%, 38%, 41% and 47%, respectively. The percent reduction in LDL-C was essentially independent of baseline. In a controlled clinical study, 12 patients 15-39 years of age with homozygous familial hypercholesterolaemia received simvastatin 40 mg/day in a single dose or in 3 divided doses or 80 mg/day in 3 divided doses. The mean LDL-cholesterol reductions for the 40- and 80-mg doses were 14% and 25%, respectively. One patient with absent LDL-cholesterol receptor function had an LDL-cholesterol reduction of 41% with the 80-mg dose.
In the Scandinavian Simvastatin Survival Study (45), the total mortality of therapy with Corstat for a median of 5.4 years was assessed in 4444 patients with coronary heart disease (CHD) and baseline total cholesterol 5.5-8 mmol/L. In this multicentre, randomised, double-blind, placebo-controlled study, Corstat reduced the risk of death by 30%, of CHD death by 42%, and of having a hospital-verified non-fatal myocardial infarction by 37%. Furthermore, Corstat reduced the risk for myocardial revascularisation procedures (coronary artery bypass grafting and percutaneous transluminal coronary angioplasty) by 37%. In a post-hoc analysis performed on fatal plus non-fatal cerebrovascular events (stroke and transient ischaemic attacks), there were 75 patients with such events in the Corstat group and 102 in the placebo group (risk reduction 28%, p=0.033). In a multicentre, placebo-controlled clinical trial in 404 patients using quantitative coronary angiography, Corstat slowed the progression of coronary atherosclerosis and reduced the development of both new lesions and new total occlusions, whereas coronary atherosclerosis lesions steadily worsened over 4 years in patients receiving standard care. Corstat is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyses the conversion of HMG-CoA to mevalonate. However, at therapeutic doses, the enzyme is not completely blocked, thereby allowing biologically necessary amounts of mevalonate to be available. Because the conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway of cholesterol, therapy with Corstat would not be expected to cause an accumulation of potentially toxic sterols. In addition, HMG-CoA is metabolised readily back to acetyl CoA, which participates in many biosynthetic processes in the body.
Pharmacokinetics: Simvastatin is an inactive lactone which is readily hydrolysed in vivo to the corresponding β-hydroxy acid, L-654,969 a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the β-hydroxy acid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors). Both are measured in plasma following administration of simvastatin. In a disposition study with ¹⁴C-labelled simvastatin, 100 mg (20 uCi) of simvastatin was administered as capsules (5 x 20 mg) and blood, urine and in faeces collected. 13% of the radioactivity was recovered in the urine and 60% in the faeces. The latter represents absorbed drug equivalents excreted in bile as well as any unabsorbed drug. Less than 0.5% of the dose was recovered in urine as HMG-CoA reductase inhibitors. In plasma, the inhibitors account for 14% and 28% (active and total inhibitors) of the AUC of total radioactivity, indicating that the majority of chemical species present were inactive or weak inhibitors.
The major metabolites of simvastatin present in human plasma are L-654,969 and 4 additional active metabolites. Both simvastatin and L-654,969 are highly bound to human plasma proteins (>94%). The availability of L-654,969 to the systemic circulation following an oral dose of simvastatin was estimated using IV reference dose of L-654,969; the value was found to be <5% of the dose. By analogy to the dog model, simvastatin is well absorbed and undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. Consequently, availability of active drug to the general circulation is low. In dose-proportionality studies, utilising doses of simvastatin of 5, 10, 20, 60, 90 and 120 mg, there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before a test meal. The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of drug occurred after multiple dosing. In all the aforementioned pharmacokinetic studies, the maximum plasma concentration of inhibitors occurred 1.3- to 2.4-hrs post-dose.