Absorption: Atorvastatin is rapidly absorbed after oral administration; maximum plasma
concentrations 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. Although food
decreases the rate and extent of drug absorption by approximately 25% and 9%,
respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whethe
atorvastatin is given with or without food. 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 (see DOSAGE AND ADMINISTRATION).
Distribution: 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 rats,
atorvastatin is likely to be secreted in human milk (see CONTRAINDICATIONS,
Pregnancy and Lactation, and PRECAUTIONS, Nursing Mothers).
Metabolism: Atorvastatin is extensively metabolized to ortho- and parahydroxylated
derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA
reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin.
Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is
attributed to active metabolites. In vitro studies suggest the importance of atorvastatin
metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of
atorvastatin in humans following coadministration with erythromycin, a known inhibitor
of this isozyme (see PRECAUTIONS, Drug Interactions). In animals, the ortho-hydroxy
metabolite undergoes further glucuronidation.
Excretion: Atorvastatin and its metabolites are eliminated primarily in bile following
hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo
enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans
is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase
is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of
atorvastatin is recovered in urine following oral administration.
Special Populations
Geriatric: Plasma concentrations of atorvastatin are higher (approximately 40% for
Cmax and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young
adults.Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the
elderly patient population compared to younger adults (see PRECAUTIONS section;
Geriatric Use subsection).
Pediatric: Pharmacokinetic data in the pediatric population are not available.
Gender: Plasma concentrations of atorvastatin in women differ from those in men
(approximately 20% higher for Cmax and 10% lower for AUC); however, there is no
clinically significant difference in LDL-C reduction with Lipitor between men and
women.
Renal Insufficiency: Renal disease has no influence on the plasma concentrations or
LDL-C reduction of atorvastatin; thus, dose adjustment in patients with renal dysfunction
is not necessary.
Hemodialysis: While studies have not been conducted in patients with end-stage renal
disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin
since the drug is extensively bound to plasma proteins.
Hepatic Insufficiency: In patients with chronic alcoholic liver disease, plasma
concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold
greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-
fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease.