Time-of-intake (morning versus evening) of extended-release fluvastatin in hyperlipemic patients is without influence on the pharmacodynamics (mevalonic acid excretion) and pharmacokinetics.

OBJECTIVE: Statins inhibit the rate-limiting step in cholesterol biosynthesis, the conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonate by HMG-CoA reductase. Statins are usually taken in the evening as the HMG-CoA reductase activity is high during the night. This recommendation might not apply if statins are given as extended-release (ER) formulations. The present study investigated the influence of time of intake of fluvastatin 80 mg ER on cholesterol biosynthesis. Main objectives were to measure the change in 24-hour urinary mevalonic acid excretion, to determine plasma concentrations of mevalonic acid and fluvastatin and to monitor triglycerides, total cholesterol, HDL-cholesterol and LDL-cholesterol. METHODS: This was a randomized, 2-period crossover study in 26 hypercholesterolemic patients who received a single daily dose of fluvastatin both in the morning and in the evening. RESULTS: At baseline, the amount of mevalonic acid was 204.9 +/- 68.1 microg/g creatinine. After a single dose of fluvastatin mean urine values of mevalonate were significantly reduced to 129.8 +/- 66.2 micro/g (evening) and to 118.7 +/-34.3 microg/g (morning; n.s. between groups), thus representing a reduction of about 39%. Compared to baseline, plasma mevalonate concentrations were decreased by fluvastatin resulting in similar 24-hour profiles after the morning and the evening dosage. The pharmacokinetics of fluvastatin were similar in both periods of the study, with higher plasma concentrations for several hours following the evening dosage. CONCLUSION: This study demonstrates that fluvastatin ER is equally effective in inhibiting cholesterol biosynthesis when given once daily in the morning and once daily in the evening.

[Pharmacokinetics of theophylline in sustained-release formulation in young asthmatics]. / Pharmakokinetik von Theophyllin in einer Retardformulierung bei jugendlichen Asthmatikern.

Pharmacokinetics of two theophylline (CAS 58-55-9) sustained release preparations (T: Bronchoretard Capsules/R: Capsule formulation from the US market) were investigated in an open randomised two-way crossover design. The capsules of the test formulation were opened and administered on a tablespoonful of apple sauce. Nineteen asthmatics aged 6 to 12 years participated in this study. Following individual dosing of 100-300 mg theophylline twice a day, a pharmacokinetic profile for 24 h was derived after seven days of multiple dosing. All relevant parameters for rate (Cmax ss, Cmin ss, Cav ss, plateau time, peak-trough fluctuation, nocturnal excess, tmax ss) and extent of absorption (AUCss) were calculated for both formulations. With long plateau times (T: 17.3 h) and small peak-trough fluctuations (T: 49.0%), established quality criteria for high quality theophylline preparations were fulfilled by the test formulation. Furthermore, symmetrical peaks resulted after morning and evening administration of the test formulation. In conclusion, smooth and predictable concentration/time profiles were achieved, enabling an efficacious and safe therapy of asthma. This individual mode of administration allows not only a perfect dose titration in young asthmatics, but is also helpful to patients who have difficulty in swallowing large dosage forms.

Pharmacokinetics and bioavailability of tamoxifen in postmenopausal healthy women.

A randomised cross-over study in 24 postmenopausal women was selected to establish bioequivalence of two tamoxifen (CAS 10540-29-1) formulations. In addition, this study compiled pharmacokinetic parameters for the current 30 mg regimen in postmenopausal women, the target population of tamoxifen therapy. Mean Cmax values of 59.1 +/- 8.9 (T) and 63.6 +/0 11.1 (R) ng/ml were attained 3.6 +/- 1.2 (T) and 3.2 +/- 1.1 (R) h after administration of 30 mg tamoxifen for the test (T) and the reference (R) formulation. The mean AUC (0-480) of tamoxifen was calculated as 3299.7 +/- 761.2 (T) and 3370.1 +/- 701.9 (R) ng x h/ml. The corresponding AUC (0-480) of the active metabolite, N-desmethyl-tamoxifen, exceeded that of the parent drug with 4359.7 +/- 830.5 (T) and 4306.3 +/- 835.2 (R) ng x h/ml, whereas maximal concentrations of the metabolite were distinctly decreased with 14.4 +/- 3.3 (T) and 14.3 +/- 2.4 (R) ng/ml. The pharmacokinetic parameters evaluated in this study are well in line with already known pharmacokinetic data generated with young male volunteers and postmenopausal patients with breast cancer. Precise analytics and an extremely long blood sampling period facilitated an accurate determination of tamoxifen's half-life in postmenopausal women with 210.1 +/- 60.8 (T) and 209.8 +/- 59.9 (R) h. Based on the extremely long half-life, the suitability of a cross-over design is discussed and recommended for further studies.