patic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL; atorvastatin also reduces LDL production and the number of LDL particles.
12.2 PharmacodynamicsClinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
Atorvastatin as well as some of its metabolites are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration (2)].
12.3 PharmacokineticsLIPTRUZET
LIPTRUZET 10/10 and 10/80 tablets have been shown to be bioequivalent to coadministration of corresponding doses of ezetimibe and atorvastatin tablets. LIPTRUZET 10/20 and 10/40 tablets have been shown to be clinically equivalent in LDL-C response to the corresponding coadministered doses of ezetimibe and atorvastatin tablets. [See Clinical Studies (14.1).]
Absorption
Ezetimibe
After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide).
Atorvastatin
Maximum plasma atorvastatin concentrations after oral administration occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration.
Effect of Food on Oral Absorption
LIPTRUZET
A high-fat meal decreased atorvastatin AUC and Cmax 11% and 35%, respectively, of the LIPTRUZET 10/80 tablet. A high-fat meal decreased unconjugated ezetimibe AUC 2% and increased unconjugated ezetimibe Cmax 10% of the LIPTRUZET 10/80 tablet.
LIPTRUZET can be taken with or without food [see Dosage and Administration (2.1)].
Distribution
Ezetimibe
Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.
Atorvastatin
Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in r
