Fluvastatin

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Fluvastatin sodium is a competitive inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols, including cholesterol. The inhibition of cholesterol biosynthesis reduces the cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors and thereby increases the uptake of LDL particles. The end result of these biochemical processes is a reduction of the plasma cholesterol concentration. 12.3 Pharmacokinetics Absorption: Following oral administration of the capsule, fluvastatin reaches peak concentrations in less than 1 hour. The absolute bioavailability is 24% (range 9% to 50%) after administration of a 10 mg dose. At steady state, administration of fluvastatin with the evening meal results in a 50% decrease in C max , an 11% decrease in AUC, and a more than two-fold increase in t max as compared to administration 4 hours after the evening meal. No significant differences in the lipid-lowering effects were observed between the two administrations. After single or multiple doses above 20 mg, fluvastatin exhibits saturable first-pass metabolism resulting in more than dose proportional plasma fluvastatin concentrations. Fluvastatin administered as fluvastatin sodium extended-release 80 mg tablets reaches peak concentration in approximately 3 hours under fasting conditions, after a low fat meal, or 2.5 hours after a low fat meal. The mean relative bioavailability of the extended-release tablet is approximately 29% (range: 9% to 66%) compared to that of the fluvastatin immediate-release capsule administered under fasting conditions. Administration of a high fat meal delayed the absorption (T max : 6h) and increased the bioavailability of the extended-release tablet by approximately 50%. However, the maximum concentration of fluvastatin sodium extended-release tablets seen after a high fat meal is less than the peak concentration following a single dose or twice daily dose of the 40 mg fluvastatin capsule. Distribution: Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VD ss ) is estimated at 0.35 L/kg. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide. Metabolism: Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5 and 6 positions. N-dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Fluvastatin has two enantiomers. Both enantiomers of fluvastatin are metabolized in a similar manner. In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450 (CYP) isozymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (approximately 75%), while CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e., approximately 5% and approximately 20%, respectively. Excretion: Following oral administration, fluvastatin is primarily (about 90%) excreted in the feces as metabolites, with less than 2% present as unchanged drug. Approximately 5% of a radiolabeled oral dose were recovered in urine. The elimination half-life (t 1/2 ) of fluvastatin is approximately 3 hours. Specific Populations Renal Impairment: In patients with moderate to severe renal impairment (CL Cr 10 to 40 mL/min), AUC and C max increased approximately 1.2 fold after administration of a single dose of 40 mg fluvastatin compared to healthy volunteers. In patients with end-stage renal disease on hemodialysis, the AUC increased by approximately 1.5 fold. Fluvastatin sodium extended-release tablets were not evaluated in patients with renal impairment. However, systemic exposures after administration of fluvastatin sodium extended-release tablets are lower than after the 40 mg immediate-release capsule. Hepatic Impairment: In patients with hepatic impairment due to liver cirrhosis, fluvastatin AUC and C max increased approximately 2.5 fold compared to healthy subjects after administration of a single 40 mg dose. The enantiomer ratios of the two isomers of fluvastatin in hepatic impairment patients were comparable to those observed in healthy subjects. Geriatric: Plasma levels of fluvastatin are not significantly different in patients age > 65 years compared to patients age 21 to 49 years. Gender: In a study evaluating the effect of age and gender on fluvastatin pharmacokinetics, there were no significant differences in fluvastatin exposures between males and females, except between younger females and younger males (both ages 21 to 49 years), where there was an approximate 30% increase in AUC in females. Adjusting for body weight decreases the magnitude of the differences seen. Pediatric: Pharmacokinetic data in the pediatric population are not available. Drug-Drug Interactions: Data from drug-drug interactions studies involving coadministration of gemfibrozil, niacin, itraconazole, erythromycin, tolbutamide or clopidogrel indicate that the PK disposition of fluvastatin is not significantly altered when fluvastatin is coadministered with any of these drugs. The below listed drug interaction information is derived from studies using fluvastatin capsules. Table 3: Effect of Coadministered Drugs on Fluvastatin Systemic Exposure Coadministered drug and dosing regimen Fluvastatin Dose (mg) 1 Change in AUC 2 Change in C max 2 Cyclosporine - stable dose (b.i.d.) 3 20 mg QD for 14 weeks ↑90% ↑30% Fluconazole 400 mg QD day 1,200 mg b.i.d. day 2 to 4 3 40 mg QD ↑84% ↑44% Cholestyramine 8 g QD 20 mg QD administered 4 hrs after a meal plus cholestyramine ↓51% ↓83% Rifampicin 600 mg QD for 6 days 20 mg QD ↓53% ↓42% Cimetidine 400 mg b.i.d. for 5 days, QD on Day 6 20 mg QD ↑30% ↑40% Ranitidine 150 mg b.i.d. for 5 days, QD on Day 6 20 mg QD ↑10% ↑50% Omeprazole 40 mg QD for 6 days 20 mg QD ↑20% ↑37% Phenytoin 300 mg QD 40 mg b.i.d. for 5 days ↑40% ↑27% Propranolol 40 mg b.i.d. for 3.5 days 40 mg QD ↓5% No change Digoxin 0.1 to 0.5 mg QD for 3 weeks 40 mg QD No change ↑11% Diclofenac 25 mg QD 40 mg QD for 8 days ↑50% ↑80% Glyburide 5 to 20 mg QD for 22 days 40 mg b.i.d. for 14 days ↑51% ↑44% Warfarin 30 mg QD 40 mg QD for 8 days ↑30% ↑67% Clopidogrel 300 mg loading dose on day 10, 75 mg QD on days 11 to 19 fluvastatin sodium extended-release tablets, 80 mg QD for 19 days ↓2% ↑27% 1. Single dose unless otherwise noted 2. Mean ratio (with/without coadministered drug and no change = 1 fold) or % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively. 3. Considered clinically significant [see Dosage and Administration ( 2 ) and Drug Interactions ( 7 )] Data from drug-drug interaction studies involving fluvastatin and coadministration of either gemfibrozil, tolbutamide or losartan indicate that the PK disposition of either gemfibrozil, tolbutamide or losartan is not significantly altered when coadministered with fluvastatin. Table 4: Effect of Fluvastatin Coadministration on Systemic Exposure of Other Drugs Fluvastatin dosage regimen Coadministered drug Name and Dose (mg) 1 Change in AUC 2 Change in C max 2 40 mg QD for 5 days Phenytoin 300 mg QD 3 ↑20% ↑5% 40 mg b.i.d. for 21 days Glyburide 5 to 20 mg QD for 22 days 3 ↑70% ↑50% 40 mg QD for 8 days Diclofenac 25 mg QD ↑25% ↑60% 40 mg QD for 8 days Warfarin 30 mg QD S-warfarin: ↑7% S-warfarin: ↑10% R-warfarin: no change R-warfarin: ↑6% 1. Single dose unless otherwise noted 2. Mean ratio (with/without coadministered drug and no change = 1 fold) or % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively. 3. Considered clinically significant [see Dosage and Administration ( 2 ) and Drug Interactions ( 7 )]