Effects of alcohol consumption on pharmacokinetics, efficacy, and safety of fluvastatin

Abstract

Alcohol consumption is known to have beneficial effects on cardiac mortality, probably by increasing high density lipoprotein cholesterol (HDL-C). Alcohol also increases triglycerides and, in some studies, total cholesterol and low density lipoprotein cholesterol (LDL-C). Nothing is known, however, of the effects of alcohol on the pharmacokinetics and efficacy of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Consequently, 2 studies have been carried out to determine the effects of alcohol consumption on the pharmacokinetics and efficacy of the HMG-CoA reductase inhibitor fluvastatin. Firstly, the effects of acute alcohol consumption on a single, oral 40 mg dose of fluvastatin were examined in a reference-controlled, randomized, crossover study in 10 healthy volunteers. Measurements were made after ingestion of 70 g of ethanol diluted to 20% with lemonade and, following a 7-day period, after ingestion of lemonade alone (reference). The half-life ( t 1/2) of a single dose of fluvastatin was significantly reduced by acute alcohol consumption compared with reference, whereas the area under the time—concentration curve (AUC), peak concentration ( C max), and time to peak concentration ( t max) did not differ from the reference group. The lipid profile, measured 8 hr after administration, did not differ significantly from baseline in the reference group, apart from a slight reduction in apolipoprotein (apo)-AI. Triglyceride levels increased with alcohol, probably due to impaired fatty acid oxidation. Surprisingly, total cholesterol and LDL-C fell significantly, possibly due to altered pharmacokinetics, as reflected by the lower t 1/2. To assess the long-term clinical implications of these findings, a 6-week study into the effects of alcohol consumption on fluvastatin pharmacokinetics and lipid-lowering capacity was concluded in 26 patients with primary hypercholesterolemia (LDL-C 4.2 mmol/liter after dietary baseline period). Patients were randomized to 6-week treatment with 40 mg/day of fluvastatin, combined with either 20 g of alcohol diluted to 20% with lemonade, or with lemonade alone (reference). After a 6-week washout period, the 2 groups crossed over for a second 6-week treatment period. Measurements were made at the end of each treatment period. In the 20 patients who completed the study, no serious adverse events occurred. Alcohol did have some effect on fluvastatin pharmacokinetic parameters; a tendency to lengthen t 1/2 and to increase AUC and t max compared with reference, without a difference in C max between reference and alcohol. However, these pharmacokinetic effects did not correlate with differences in lipid parameters. Neither reference nor alcohol showed significant changes in HDL-C or triglyceride levels, but significant decreases in total cholesterol, LDL-C, and apo B were observed; these decreases did not differ significantly between reference and alcohol. In conclusion, alcohol consumption has no effect on the efficacy and safety of fluvastatin treatment in patients with primary hypercholesterolemia.