Evaluation of the influence of antacids and H2 antagonists on the absorption of moxifloxacin after oral administration of a 400mg dose to healthy volunteers.

OBJECTIVE: To determine the effect of concomitant administration of the antacid Maalox 70 or the histamine H2 receptor antagonist ranitidine on the bioavailability of moxifloxacin. DESIGN: These were nonblinded, randomised, crossover studies performed in healthy volunteers. PARTICIPANTS: 24 healthy males aged 22 to 39 years (study 1; n = 12) and 24 to 43 years (study 2; n = 12) were included in these studies. METHODS: In study 1, 12 participants received ranitidine 150mg twice daily during a 3-day pretreatment phase and 1 tablet of ranitidine together with a single 400mg dose of moxifloxacin on the profile day. In study 2, 12 participants received a single 400mg dose of moxifloxacin alone (treatment A), simultaneously with Maalox 70 10ml (treatment B), or with Maalox 70 10ml given 4 hours before (treatment C) or 2 hours after (treatment D) the fluoroquinolone. In treatments B, C and D, administration of the antacid (10ml, 1 hour after each meal) was continued for 2 days. Plasma and urine samples were obtained for determination of the pharmacokinetic parameters of moxifloxacin. RESULTS: Coadministration of moxifloxacin with ranitidine showed lack of interaction for area under the plasma concentration-time curve extrapolated to infinity (AUCinfinity) [35.5 versus 34.3 mg/L x h with versus without ranitidine; relative bioavailability 103%, 90% confidence interval (CI) 97.7 to 109.3%] and maximum plasma concentration (Cmax) [2.98 versus 2.76 mg/L with versus without ranitidine; ratio 107.9%, 90% CI 90.5 to 128.6%]. When moxifloxacin was given simultaneously with Maalox 70, AUCinfinity ( 14.7 mg/L x h) and Cmax (1.00 mg/L) were reduced by approximately 60%. When the antacid was given 4 hours before or 2 hours after the fluoroquinolone, AUCinfinity values (28.0 and 26.7 versus 34.3 mg/L x h) were moderately reduced (by <27%), terminal elimination half-life values declined by approximately 24% (9.4 and 9.3 versus 12.3 hours) compared with moxifloxacin alone and Cmax values were almost unchanged (2.55 and 2.38 versus 2.57 mg/L). The mean bioavailabilities corrected for the elimination rate constants (lambdaz) were 101% (antacid given 4 hours before moxifloxacin) and 98% (antacid given 2 hours after moxifloxacin), indicating that Maalox 70 may interfere with the gastrointestinal recirculation of moxifloxacin. CONCLUSIONS: The bioavailability of moxifloxacin is not affected by concurrent administration of ranitidine. Absorption of moxifloxacin is impaired by concomitant administration of aluminium- and magnesium-containing antacids and administration of these agents should be staggered. An interval of 2 hours before or 4 hours after taking the antacid ensures that the effect of the interaction is not clinically relevant.

Biopharmaceutical profile of cerivastatin: a novel HMG-CoA reductase inhibitor.

The biopharmaceutical properties of cerivastatin were evaluated in a series of worldwide clinico-pharmacological studies. Young healthy males aged 18-45 years were randomized to receive 0.05-0.8 mg cerivastatin orally, given either as single or multiple once-daily doses under fed or fasting conditions in the morning, with evening meal or at bedtime. Following administration, cerivastatin was rapidly and almost completely absorbed into the gastrointestinal tract (> 98%), with maximum plasma concentrations (Cmax) reached at 2-3 h post dose. The plasma concentration/time profile of the tablet is similar to an aqueous oral solution (relative bioavailability is 100%). The dose-proportionality of cerivastatin (0.05-0.8 mg) in area under the curve and Cmax showed low intra- and interindividual variability. The effect of food (single-dose studies testing administration of cerivastatin with a high-fat meal and clinical investigations in patients) or time of administration (single- and multiple-dose once-daily/twice-daily studies) had no clinically relevant effects on the pharmacokinetics of cerivastatin. Marketed tablet strengths and drug formulations from different sources were found to be bioequivalent. Cerivastatin is a noncomplicated drug with respect to its biopharmaceutical profile and bioavailability.

Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients.

OBJECTIVE: The mutual drug-drug interaction potential of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor cerivastatin and cyclosporine (INN, ciclosporin) in kidney transplant recipients receiving individual immunosuppressive treatment was evaluated with respect to pharmacokinetic behavior of either drug and tolerability of concomitant use. METHODS: Plasma and urine concentrations of cerivastatin and its major metabolites were determined after administration of 0.2 mg single-dose cerivastatin to 12 kidney transplant recipients (9 men and 3 women) who were receiving stable individual cyclosporine treatment (mainly 200 mg twice a day). These results were compared with the single-dose pharmacokinetic results obtained from a healthy control group (n = 12, age-comparable men). Cerivastatin steady-state pharmacokinetics were evaluated in the same patients during continued immunosuppressive treatment 4 to 6 weeks later, after a 7-day treatment of 0.2 mg cerivastatin once a day. Cyclosporine steady-state concentration-time profiles were determined in blood with monoclonal (EMIT [enzyme multiplied immunoassay technique] assay, parent drug specific) and polyclonal antibodies (FPIA [fluorescence polarization immunoassay] assay, cyclosporine plus metabolites) during cerivastatin cotreatment and compared with predosing data. RESULTS: Coadministration of 0.2 mg cerivastatin once a day to the kidney transplant recipients treated with individual doses of cyclosporine and other immunosuppressive agents resulted in a 3- to 5-fold increase in cerivastatin and metabolites plasma concentrations. Cerivastatin and metabolites elimination half-lives were unaffected, and no accumulation occurred during multiple-dosing conditions. Cerivastatin had no influence on steady-state blood concentrations of cyclosporine or cyclosporine metabolites in these patients. The concomitant use of both drugs was well tolerated. CONCLUSIONS: Cerivastatin and metabolites plasma concentrations were significantly increased in kidney transplant recipients treated with cyclosporine and other immunosuppressive agents. Displacement from the main site for cerivastatin distribution-the liver-by cyclosporine-inhibited liver transport processes may explain the decrease in both metabolic clearance and volume of distribution for cerivastatin and metabolites.

The effect of omeprazole pre- and cotreatment on cerivastatin absorption and metabolism in man.

OBJECTIVE: Cerivastatin, a novel HMG-CoA reductase inhibitor, is exclusively cleared via cytochrome P450-mediated biotransformation and subsequent biliary and renal excretion of the metabolites. The presented study was performed to determine the influence of the gastric acid secretion inhibitor omeprazole on bioavailability and pharmacokinetics of cerivastatin. METHOD: In a controlled, randomized, non-blind two-way crossover study single oral doses of 0.3 mg cerivastatin were administered in 12 healthy male subjects under fasting conditions either alone or together with 20 mg omeprazole following a 4-day pretreatment with oral 20 mg omeprazole once daily. RESULTS: The mean AUC and Cmax ratios (combination treatment versus monotherapy) including 90% confidence intervals were 1.00 (0.92 - 1.09) and 0.94 (0.80 - 1.16) for cerivastatin. Similar results were obtained for the metabolites of cerivastatin and for omeprazole. CONCLUSION: No metabolic inhibitory interaction was noted for either cerivastatin or its major active metabolites, nor for omeprazole, respectively. In addition, the change in gastric pH as consequence of the inhibition of gastric acid secretion exerted by omeprazole had no influence on cerivastatin absorption.

Lack of drug-drug interaction between cerivastatin and nifedipine.

Cerivastatin is a novel, potent HMG-CoA reductase inhibitor. It is primarily cleared via demethylation and hydroxylation with involvement of cytochrome P450 (CYP) 3A4 and subsequent biliary and renal excretion of the metabolites. Both cerivastatin and the dihydropyridine calcium antagonist nifedipine, which is primarily metabolized by CYP 3A4, are used concomitantly in the prevention and therapy of coronary heart disease. To study the drug-drug interaction potential, the mutual effects of cerivastatin and nifedipine were investigated in a controlled, randomized, non-blind 3-way crossover study in healthy male subjects. Single oral doses of 0.3 mg cerivastatin or of 60 mg nifedipine were administered either alone or concomitantly under fasting conditions. The mean AUC- and Cmax ratios (combination treatment versus monotherapy) including 90% confidence intervals were 1.04 (0.98 - 1.10) and 1.00 (0.93 - 1.07) for cerivastatin, and 0.98 (0.73 - 1.32) and 0.95 (0.80 - 1. 13) for nifedipine, respectively. Our results indicate that no mutual drug-drug interaction between cerivastatin and nifedipine occurs.

Influence of erythromycin pre- and co-treatment on single-dose pharmacokinetics of the HMG-CoA reductase inhibitor cerivastatin.

OBJECTIVE: Cerivastatin is a novel, synthetic, highly potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that effectively reduces serum cholesterol levels at very low doses. It is exclusively cleared from humans via cytochrome P450-mediated biotransformation (demethylation M1; hydroxylation M23) and subsequent biliary/renal excretion of the metabolites. The influence of concomitant administration of erythromycin, a potent CYP3A4 inhibitor, on cerivastatin bioavailability and pharmacokinetics was investigated. METHODS: Twelve healthy young male subjects received single oral doses of 300 microg cerivastatin alone or on the 4th day of a 4-day pre- and co-treatment with erythromycin 500 mg t.i.d. in a randomised, non-blind crossover study. Plasma and urine samples were analysed for cerivastatin and its major metabolites by validated specific high-performance liquid chromatography assays. RESULTS: Cerivastatin was safe and well tolerated. No clinically relevant treatment-emergent changes in laboratory parameters were observed. The pre- and co-treatment with erythromycin 500 mg t.i.d. had a modest influence on cerivastatin clearance, leading to a mean increase in the maximum plasma concentration (Cmax) of 13% and a slightly increased terminal half-life (approximately 10%), resulting in a mean elevation of the area under the curve (AUC) of 21%; time to peak (tmax) remained unchanged. While the mean AUC of the metabolite M1 following the combined dosing was decreased by 60% compared with mono-dosing, the mean AUC of M23 exhibited an increase of approximately 60%. The respective Cmax results paralleled these pronounced effects, whereas the influence on mean terminal half-lives was small (i.e. for M23, an approximate 20% increase) or not observable (i.e. for M1). CONCLUSIONS: Concomitant administration of erythromycin 500 mg t.i.d. affects, to a certain extent, the metabolism of cerivastatin, administered as a single oral dose of 300 microg, resulting in a slightly increased exposure of the parent drug and active metabolites which, however, does not need dose adjustment. In addition, the small increase in cerivastatin half-life does not predict an accumulation beyond steady state. The pharmacokinetic data for the major metabolites suggest that the M1 metabolic pathway is more sensitive to CYP3A4 inhibition than the parallel M23 pathway, supporting recent in vitro findings that further cytochrome P450 isozymes are differently involved in the metabolic pathways of cerivastatin.

Absolute and relative bioavailability of the HMG-CoA reductase inhibitor cerivastatin.

To determine the absolute bioavailability of the HMG-CoA reductase inhibitor cerivastatin, 12 healthy young male volunteers received single doses of either 100 micrograms as a 1-minute bolus infusion or 200 micrograms orally as tablets in a controlled, randomized crossover study. In addition, 8 of the 12 subjects participated in a third treatment period in which 200 micrograms cerivastatin were administered as an oral solution as reference for determining the relative bioavailability of the tablet drug formulation. Plasma samples were analyzed for cerivastatin by a specific HPLC assay with fluorescence detection after post-column irradiation of the eluate, with a limit of quantification of 0.1 microgram/l. Following all treatments, cerivastatin was well tolerated and no clinically relevant adverse events or changes in laboratory parameters were observed. Vital signs and ECG remained unchanged. Plasma concentration/time profiles of cerivastatin following intravenous bolus could be described by a 2-compartment model with a distribution half-life of 3-5 min and an elimination half-life of 1.5-2.4 h. For the 2 oral administrations a 1-compartmental pharmacokinetic model with a first-order absorption process was best to describe the plasma concentration/time data. Based on the AUCnorm values of the 7 subjects, valid for complete pharmacokinetic evaluation, the absolute bioavailability of tablet and oral solution was 60.0 and 59.6% (90% confidence intervals 53-68%), respectively. The relative bioavailability of tablet compared with solution was 100.7% (90% confidence interval 89-114%), with tablet and oral solution showing nearly identical in vivo absorption characteristics and almost superimposable plasma concentration/time curves. The tablet formulation, therefore, can be regarded as an optimal oral formulation with respect to galenic aspects.