Influence of the antacid Maalox and the H2-antagonist cimetidine on the pharmacokinetics of cerivastatin.

ABSTRACT

The possible influence of Maalox 70, an antacid based on magnesium-aluminum hydroxide, and the H2-antagonist cimetidine, both commonly prescribed in hypercholesterolemic patients, on the pharmacokinetics of the new HMG-CoA reductase inhibitor cerivastatin was investigated in 2 separate studies in 8 healthy young male subjects each. Cerivastatin plasma concentration/time profiles were assessed by a specific HPLC assay; in addition, total immunoreactive drug (cerivastatin plus metabolites) was determined by RIA. Single oral doses of 200 micrograms cerivastatin were administered under fasting conditions without or with 10 ml Maalox 70 suspension. The mean AUC and Cmax ratios (combined dosing/monodosing) including 90% confidence intervals were 0.92 (0.73-1.15) and 0.89 (0.72-1.10) for the HPLC data, and 0.99 (0.85-1.14) and 1.03 (0.82-1.30) for the RIA data, respectively. Thus, no interaction of the simultaneous administration of Maalox 70 on the pharmacokinetics of cerivastatin was observed. In a similar controlled, randomized nonblind 2-way crossover design the influence of the H2- antagonist and well-known cytochrome P450 enzyme inhibitor cimetidine was investigated. Eight healthy young male volunteers received single oral doses of 200 micrograms cerivastatin alone or on the fourth day of a 4-day cimetidine 400 mg b.i.d. pretreatment. The mean AUC and Cmax ratios (combined dosing/monodosing) including 90% confidence intervals were 0.98 (0.90-1.08) and 0.91 (0.78-1.07) for the RIA data, and 0.89 (0.82-0.96) and 0.93 (0.80-1.09) for the HPLC data, respectively, clearly indicating that cimetidine and cerivastatin did not interact pharmacokinetically. These results do not only reflect the apparent insensitivity of cerivastatin absorption to possible changes in gastric pH, but demonstrate that the metabolic pathways of cerivastatin, involved in its first-pass metabolism and elimination, are rather insensitive to cytochrome P450 enzyme inhibition induced by cimetidine.