Atorvastatin about

Lipitor is currently one of the best selling drugs for lowering cholesterol. Searching in WDI for Lipitor produces the page shown in Figure 10.1 [46]. The preferred name is Atorvastatin Calcium . WDI has information about the pharmacology, indications, interactions, and so on, hyperlinked for keyword search. 

Note that the warnings in the labeling about interactions with lovastatin, atorvastatin, and pimozide are based on extrapolation from clinical studies with simvastatin and cisapride. 

Itraconazole increases serum concentrations of atorvastatin by inhibiting CYP3A4. In a randomized, double-blind, crossover study in 10 healthy volunteers, itraconazole 200 mg increased the AUC and half-life of atorvastatin 40 mg about three-fold, with a change in Cmax (33). The AUC of atorvastatin lactone was increased about 4-fold, and the Cmax and half-life were increased more than 2-fold. Itraconazole significantly reduced the Cmax and AUC of 2-hydroxyatorvastatin acid and 2-hydroxyator-vastatin lactone and increased the half-life of 2-hydroxyatorvastatin lactone. The concomitant use of itraconazole and other potent inhibitors of CYP3A4 with atorvastatin should therefore be avoided, or the dose of atorvastatin should be reduced accordingly. 

The characteristic effect of inhibitors of HMG-CoA reductase is a profound reduction in LDL cholesterol. The maximal doses of the most effective drugs in this class, simvastatin and atorvastatin, produce reductions by about half in the plasma levels of this atherogenic lipoprotein (Heinonen et al., 1996 Ose et al., 1998 Stein et al., 1998b). The full... 

Since HMG CoA reductase inhibitors (statins) are partially or completely metabolized by CYP3A4, drug interactions with protease inhibitors can be expected. When nelfinavir was combined with atorvastatin and simvastatin, their AUCs increased by 74 and 505% respectively (17). As myopathy and rhabdomyolysis are concentration-related, simvastatin is contraindicated with any protease inhibitor, not just nelfinavir. Based on the data, the starting dose of atorvastatin should be reduced by about 50%. 

After being counseled about lifestyle and dietary changes, the patient was started on atorva-statin. During his treatment with atorvastatin, it is important to routinely monitor serum concentrations of (A) Blood urea nitrogen (BUN)... 

The pH dependence of die interconversion kinetics, equilibrium, and solubilities of die lactone and hydroxyacid forms of calcium (R-(R, R ) )-2-(4-duorophenyl)-p,5-dihydroxy-5-(l-methylethyl)-3-phenyl- 4r((phenylamino)-carbonyl)-lH-pyrrole-l-heptanoate (CI-981 atorvastatin calcium) are described. Over a pH range of 2.1-6.0 and at 30 °C, the apparent solubility of die sodium salt of CI-981 increases about 60-fold, and die profile yields a pKa for die terminal carboxyl group of 4.46. In contrast, over a pH range of 2.3-7.7 at the same temperature, die apparent solubility of die lactone form of CI-981 varies lidle, and die mean solubility is 1.34 meg/ml. The kinetics of interconversion and die equilibrium between the hydroxyacid and lactone forms have been studied as a function of pH, buffer concentration, and temperature at a fixed ionic strength. The rate constant for lactone formation is well described by specific acid-catalyzed and spontaneous lactonization padiways, whereas die rate constant for lactone hydrolysis is well described by specific acid-, water-, and specific base-catalyzed padiways."... 

In the Treat to New Targets (TNT) trial, more intensive therapy with atorvastatin, 80 mg/day, was compared with atorvastatin 10 mg/day in 10,001 patients with stable CHD [46] 15,464 patients were originally recruited with LDL-cholesterol 3.4-6.5 mmol/L. All patients received 8-week run-in therapy with atorvastatin 10 mg/day. If an LDL-cholesterol target <3.4 mmol/L was achieved, patients were rerandomised to take 10 or 80 mg/day. About 5461 patients were excluded because of failure to reach this target. Over a mean follow-up of 4.9 years, LDL-cholesterol in the intensively treated group was... 

A study in 12 healthy women taking a combined oral contraceptive (ethi-nylestradiol/norethisterone 35 micrograms/1 mg) found that atorvastatin 40 mg daily increased the AUC of norethisterone and ethinylestradiol by about 28% and 19%, respectively, and increased their maximum plasma levels by 24% and 30%, respectively. These increases are only moderate and unlikely to be clinically important, but the manufacturers say that they should be considered when selecting an appropriate oral contraceptive dosage for women given atorvastatin. ... 

A case report describes a 76-year-old man taking multiple medications, including pravastatin 80 mg daily with fluconazole 150 mg daily, uneventfully for about 18 months. Due to an inadequate response to the pravastatin he was changed to atorvastatin 40 mg daily. Within one week he developed dyspnoea, myopathy, rhabdomyolysis and renal failure. Although both drugs were stopped he later died of multi-organ failure. The authors considered an interaction between atorvastatin and fluconazole as the most likely explanation for the rhabdomyolysis. ... 

Ten healthy subjects were given itraconazole 200 mg daily for 5 days with a single 40-mg dose of atorvastatin on day 4. The itraconazole increased the AUC of atorvastatin acid and atorvastatin lactone fourfold and threefold, respectively, and increased their half-lives threefold and twofold, respectively. The AUC values of active and total HMG-CoA reductase inhibitors were increased 1.6- and 1.7-fold, respectively. In a similar study the same dose of itraconazole increased the AUC of atorvastatin by 2.5-fold and of atorvastatin lactone by about threefold. Another study has also shown that itraconazole raises atorvastatin levels. ... 

A study in which atorvastatin and colestipol were given concurrently found that although the serum levels of atorvastatin were reduced by about 25%, the total reduction in the LDL-cholesterol levels was greater than when each drug was given alone. ... 

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