An open-label, randomized, three-way crossover trial of the effects of coadministration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male volunteers.

BACKGROUND: Rosuvastatin and fenofibrate are lipid-regulating agents with different modes of action. Patients with dyslipidemia who have not achieved treatment targets with monotherapy may benefit from the combination of these agents. OBJECTIVE: The effect of coadministration of rosuvastatin and fenofibrate on the steady-state pharmacokinetics of rosuvastatin and fenofibric acid (the active metabolite of fenofibrate) was assessed in healthy volunteers. METHODS: This was an open-label, randomized, 3-way crossover trial consisting of three 7-day treatment periods. Healthy male volunteers received one of the following treatment regimens in each period: rosuvastatin 10 mg orally once daily; fenofibrate 67 mg orally TID; and rosuvastatin + fenofibrate dosed as above. The steady-state pharmacokinetics of rosuvastatin and fenofibric acid, both as substrate and as interacting drug, were investigated on day 7 of dosing. Treatment effects were assessed by construction of 90% CIs around the ratios of the geometric least-square means for rosuvastatin + fenofibrate/rosuvastatin and rosuvastatin + fenofibrate/fenofibrate for the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (derived from analysis of variance of log-transformed parameters). RESULTS: Fourteen healthy male volunteers participated in the study. When rosuvastatin was coadministered with fenofibrate, there were minor increases in the AUC from 0 to 24 hours and maximum concentration (Cmax) of rosuvastatin: the respective geometric least-square means increased by 7% (90% CI, 1.00-1.15) and 21% (90% CI, 1.14-1.28). The pharmacokinetic parameters of fenofibric acid were similar when fenofibrate was dosed alone and with rosuvastatin: the geometric least-square means for fenofibric acid AUC from 0 to 8 hours and Cmax decreased by 4% (90% CI, 0.90-1.02) and 9% (90% CI, 0.84-1.00), respectively. The treatments were well tolerated alone and in combination. CONCLUSION: Coadministration of rosuvastatin and fenofibrate produced minimal changes in rosuvastatin and fenofibric acid exposure.

Quantification of the N-desmethyl metabolite of rosuvastatin in human plasma by automated SPE followed by HPLC with tandem MS detection.

A selective, accurate and precise assay was developed for the quantification in human plasma of the N-desmethyl metabolite of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor rosuvastatin. The assay-employing automated SPE followed by HPLC with positive ion electrospray tandem MS (HPLC-MS/MS)-was validated. The standard curve range for N-desmethyl rosuvastatin in human plasma was 0.5-30 ng/ml with 0.5 ng/ml being the limit of quantification. Plasma samples were mixed 1:1 with sodium acetate buffer (pH 4.0; 0.1M) soon after separation from red blood cells. N-Desmethyl rosuvastatin was stable in plasma:buffer at room temperature for 24h and at -70 degrees C for 12 months. The assay was applied successfully to the quantification of N-desmethyl rosuvastatin in human plasma following administration of rosuvastatin.

The effect of a combination antacid preparation containing aluminium hydroxide and magnesium hydroxide on rosuvastatin pharmacokinetics.

OBJECTIVE: Rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor used for the treatment of dyslipidaemia, may be co-administered with antacids in clinical practice. This trial assessed the effect of simultaneous and separated administration of an antacid preparation containing aluminium hydroxide 220 mg/5 mL and magnesium hydroxide 195 mg/5 mL (co-magaldrox 195/220) on the pharmacokinetics of rosuvastatin. RESEARCH DESIGN AND METHODS: A randomised, open-label, three-way crossover trial was performed. Healthy male volunteers (n = 14) received a single dose of rosuvastatin 40 mg alone, rosuvastatin 40 mg plus 20 mL antacid suspension taken simultaneously, and rosuvastatin 40 mg plus 20 mL antacid suspension taken 2 h after rosuvastatin on three separate occasions with a washout of > or = 7 days between each. MAIN OUTCOME MEASURES: The primary parameters were area under the rosuvastatin plasma concentration-time curve from time zero to the last quantifiable concentration (AUC(0-t)) and maximum observed rosuvastatin plasma concentration (C(max)) in the absence and presence of antacid. RESULTS: When rosuvastatin and antacid were given simultaneously, the antacid reduced the rosuvastatin AUC(0-t) by 54% (90% confidence interval [CI] for the treatment 0.40-0.53) and C(max) by 50% (90% CI 0.41-0.60). When the antacid was given 2 h after rosuvastatin, the antacid reduced the rosuvastatin AUC(0-t) by 22% (90% CI 0.68-0.90) and the C(max) by 16% (90% CI 0.70-1.01). The effect of repeated antacid administration was not studied and it cannot be discounted that this may have resulted in a stronger interaction than that observed here. CONCLUSIONS: Simultaneous dosing with rosuvastatin and antacid resulted in a decrease in rosuvastatin systemic exposure of approximately 50%. This effect was mitigated when antacid was administered 2 h after rosuvastatin.