Safety, tolerability, and pharmacokinetics of an extended-release formulation of fluvastatin administered once daily to patients with primary hypercholesterolemia

Fluvastatin sodium (Lescol (R), Novartis Pharmaceutical Corp., East Hanover , NJ, U.S.A.). a potent 3-hydroxy-3-methylglutnryl coenzyme A (HMG Co-A) re ductase inhibitor that limits cholesterol biosynthesis, is available as a 4 0-mg immediate-release formulation capsule. An extended-release formulation for once-daily administration has been developed for patients with primary hypercholesterolemia who may benefit from doses higher than 40 mg/day. Thi s phase I study evaluated the safety, tolerability, and pharmacokinetics of a new fluvastatin extended-release formulation at doses ranging from 80-64 0 mg/day in 40 hypercholesterolemic patients. After a 2-week dietary stabil ization phase, patients (Fredrickson type IIa/IIb), 18-55 years of age, wer e randomly assigned to four groups to receive oral fluvastatin extended-rel ease (80, 160, 320, or 640 mg) or matching placebo once daily for 13 days. Fluvastatin extended-release was generally safe and well tolerated at doses of 80-320 mg/day. Within this dose range, linear pharmacokinetics was obse rved after single and multiple dosing. At 630 mg, fluvastatin extended-rele ase was not well tolerated. Six of the seven actively treated patients at t his dose experienced adverse events, including diarrhea, headache, and clin ically relevant elevations in serum transaminase concentrations. In additio n, nonlinear pharmacokinetics, possibly due to saturation of first-pass met abolism, was observed at this dose, causing higher than expected serum drug concentrations. Once-daily administration of fluvastatin extended-release at doses of 80-320 mg/day was generally safe and well tolerated in patients with primary hypercholesterolemia over a 13-day dosing period.