Bioavailability of two selegiline hydrochloride tablet products.

The bioavailability of two selegiline HCl (CAS 14611-52-0) tablet products was compared in a single-blind, single-dose, randomised, two-way, cross-over study with 25 healthy volunteers. A test preparation of selegiline HCl (4 x 5 mg tablets) was compared to a reference preparation of selegiline HCl (4 x 5 mg tablets). The volunteers were randomised receiving each treatment once. Two clinic days were separated by a wash-out period of between 6 and 14 days. The variable AUC(0-infinity) was the primary characteristic of the extent of formation (bioavailability) of the selegiline metabolites, desmethylselegiline and methamphetamine. For desmethylselegiline the point estimate (90% confidence interval) of the "test/reference" mean ratio for the variable Cmax is 98.4% (91.2% to 106%), for AUC(0-infinity) 103% (97.6% to 109%), and for Cmax/ AUC(0-infinity) 95.6% (89.4% to 102%). For methamphetamine the point estimate (90% confidence interval) of the "test/reference" mean ratio for the variable Cmax is 101% (96.8% to 105%), for AUC(0-infinity) 102% (95.3% to 109%), and for Cmax/AUC(0-infinity) 99.0% (91.5% to 107%). The results of this study indicate that the test preparation is bioequivalent to the reference preparation with respect to both the rate and extent of formation of desmethylselegiline and methamphetamine.

Study of the effect of miglitol on the pharmacokinetics and pharmacodynamics of warfarin in healthy males.

This was a double-blind, randomised, placebo-controlled, cross-over study to determine the possible pharmacodynamic and pharmacokinetic interaction of miglitol (CAS 72432-03-2, Bay m 1099) and warfarin sodium (CAS 129-06-6) in healthy volunteers. The study comprised 2 treatment periods of 8 days each, with a medication-free period of 14 days between the 2 treatment periods. The volunteers received medication for 7 days and were assessed over 8 days in both treatment periods. According to the randomisation, the volunteers received either 100 mg of miglitol or matching placebo, 3 times daily during the treatment periods. On Day 4 of each treatment period the volunteers received a single oral dose of 25 mg warfarin sodium together with miglitol or placebo. The effect of miglitol on both the pharmacokinetics and pharmacodynamics (prothrombin time and clotting factor VII activity) of warfarin sodium was investigated. The study results indicate that the concomitant administration of miglitol and warfarin does not affect the pharmacokinetics of R- and S-warfarin, or the pharmacodynamics of warfarin.

Relative bioavailability of rifampicin, isoniazid and ethambutol from a combination tablet vs. concomitant administration of a capsule containing rifampicin and a tablet containing isoniazid and ethambutol.

Twenty male volunteers who were slow metabolisers of isoniazid, completed this single-blind, single-dose, randomised, cross-over study to compare the bioavailability of rifampicin (CAS 13292-46-1), isoniazid (CAS 54-85-3) and ethambutol (CAS 1070-11-7) from Myrin tablets (test preparation) with the bioavailability of these drugs from a combination of capsules containing rifampicin and tablets containing isoniazid and ethambutol (reference). There were 2 treatment periods and on clinic days volunteers were given either the reference (300 mig rifampicin plus 200 mg isoniazid and 600 mg ethambutol HCl), or the test preparation (300 mg rifampicin, 150 mg isoniazid and 600 mg ethambutol HCl). Serial blood samples were drawn from the volunteers and rifampicin, isoniazid and ethambutol assays were performed. The results of this study indicate that the test preparation is equivalent to the reference with respect to both the rate and the extent of absorption of rifampicin, isoniazid (after adjustment for the different doses of isoniazid and ethambutol).

Lack of effect of pantoprazole on the pharmacodynamics and pharmacokinetics of warfarin.

Twenty-six healthy males took part in this double-blind, randomised, placebo-controlled, two-period, cross-over study. Pantoprazole (40 mg) (test) or placebo (reference) were administered once daily, for 8 days, with a 3 week washout period. A single oral dose of 25 mg warfarin sodium was co-administered with pantoprazole or placebo on Day 2 of each treatment period. The 90% confidence intervals for the 'test/reference' mean ratios of the excess AUC(0.168 h) of prothrombin time and AUC(0.168 h) of factor VII, and of Cmax, AUC and t1/2 of both R- and S-warfarin fell within the equivalence range of 80% to 125%. These results suggest that pantoprazole does not alter the pharmacokinetics or pharmacodynamics of warfarin.

No pharmacokinetic or pharmacodynamic interaction between rivastatin and warfarin.

Twenty-one healthy, male volunteers completed this double-blind, randomized, two-period, crossover study to determine the possible pharmacodynamic and pharmacokinetic interaction of the concomitant administration of rivastatin and warfarin sodium in healthy volunteers. The study comprised 2 treatment periods of 8 days each, with a medication-free period of 14 days between the 2 treatment periods. According to the randomization, the volunteers received either 300 micrograms of rivastatin or matching placebo once daily during the treatment periods. On day 4 of each treatment period, the volunteers also received a single oral dose of 25 mg of warfarin sodium together with rivastatin or matching placebo. The effect of rivastatin on both the pharmacokinetics and pharmacodynamics (prothrombin time and clotting factor VII activity) of warfarin sodium, and the effect of warfarin sodium on the pharmacokinetics of rivastatin were investigated. Blood sample assays included the analysis of both R- and S-warfarin, because it is known that the enantiomers differ in anticoagulant potency. The study results indicate that the concomitant administration of rivastatin and warfarin does not affect the pharmacokinetics of R- and S-warfarin, or the pharmacodynamics of warfarin. Furthermore, the administration of warfarin sodium does not affect the pharmacokinetics of rivastatin.

Relative bioavailability of four controlled-release nifedipine products.

Four controlled-release nifedipine products were investigated in two clinical studies. In study 1, 22 healthy male volunteers took part in an open, multiple-dose, randomized, crossover study to determine the relative bioavailability of two 10 mg controlled-release nifedipine tablets (Adalat Retard, Bayer), administered 12 hourly, and one 20 mg controlled-release nifedipine tablet (Adalat Retard, Bayer) administered 12 hourly. In study 2, 24 healthy male volunteers took part in an open, multiple-dose, randomized, three-period, crossover study to determine the relative bioavailability of (i) two 30 mg nifedipine gastro-intestinal therapeutic system (GITS) tablets (Adalat XL, Bayer) administered once daily; (ii) one 60 mg nifedipine GITS tablet (Adalat XL, Bayer) administered once daily; and (iii) one 20 mg plus one 10 mg nifedipine controlled-release tablet (Adalat Retard, Bayer), administered 12 hourly. In both studies detailed pharmacokinetic data, in particular with respect to the controlled-release characteristics of the different formulations, were collected. Results of both studies indicate that all nifedipine products investigated are bioequivalent with respect to the extent of absorption of nifedipine. The nifedipine GITS products (Adalat XL) have better controlled-release properties than the Adalat Retard product, and are suitable for once-a-day administration.