Fluvastatin administered as Lescol XL 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 XL tablet is approximately 29% (range: 9%-66%) compared to that of the Lescol immediate-release capsule administered under fasting conditions. Administration of a high-fat meal delayed the absorption (Tmax: 6H) and increased the bioavailability of the XL tablet by approximately 50%. Once Lescol XL begins to be absorbed, fluvastatin concentrations rise rapidly. The maximum concentration seen after a high-fat meal is much less than the peak concentration following a single dose or twice daily dose of the 40 mg Lescol capsule. Overall variability in the pharmacokinetics of Lescol XL is large (42%-64% CV for Cmax and AUC), and especially so after a high-fat meal (63%-89% for Cmax and AUC). Intrasubject variability in the pharmacokinetics of Lescol XL under fasting conditions (about 25% for Cmax and AUC) tends to be much smaller as compared to the overall variability. Multiple peaks in plasma fluvastatin concentrations have been observed after Lescol XL administration.

Distribution

Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VDss) is estimated at 0.35 L/kg. The parent drug is targeted to the liver and no active metabolites are present systemically. 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. Both enantiomers of fluvastatin are metabolized in a similar manner.

In vitro studies demonstrated that fluvastatin undergoes oxidative metabolism, predominantly via 2C9 isozyme systems (75%). Other isozymes that contribute to fluvastatin metabolism are 2C8 (~5%) and 3A4 (~20%). (See PRECAUTIONS: DRUG INTERACTIONS Section).

Elimination

Fluvastatin is primarily (about 90%) eliminated in the feces as metabolites, with less than 2% present as unchanged drug. Urinary recovery is about 5%. After a radiolabeled dose of fluvastatin, the clearance was 0.8 L/h/kg. Following multiple oral doses of radiolabeled compound, there was no accumulation of fluvastatin; however, there was a 2.3- fold accumulation of total radioactivity.

Steady-state plasma concentrations show no evidence of accumulation of fluvastatin following immediate release capsule administration of up to 80 mg daily, as evidenced by a beta-elimination half-life of less than 3 hours. However, under conditions of maximum rate of absorption (i.e., fasting) systemic exposure to fluvastatin is increased 33% to 53% compared to a single 20 mg or 40 mg dose of the immediate- release capsule. Following once daily administration of the 80 mg Lescol XL tablet for 7 days, systemic exposure to fluvastatin is increased (20%-30%) compared to a single dose of the 80 mg Lescol XL tablet. Terminal half-life of Lescol XL was about 9 hours as a result of the slow-release formulation.

Single-dose and steady-state pharmacokinetic parameters in 33 subjects with hypercholesterolemia for the capsules and in 35 healthy subjects for the extended-release tablets are summarized below:

Table 1 Single-Dose and Steady-State Pharmacokinetic Parameters

Special Populations

Renal Insufficiency:

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