LACK OF INTERACTION BETWEEN FLUVASTATIN AND ORAL HYPOGLYCEMIC AGENTS IN HEALTHY-SUBJECTS AND IN PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS

Human drug interaction studies in vivo are conducted when in vitro and /or animal interactions suggest clinical relevance. Studies in vitro h ave indicated that the new, entirely synthetic 3-hydroxy-3-methylgluta ryl coenzyme A reductase inhibitor fluvastatin affects the metabolism of the nonsteroidal anti-inflammatory drug diclofenac and the oral hyp oglycemic tolbutamide. Diclofenac and tolbutamide are both model subst rates of the CYP2C isozymes, suggesting that this enzyme could be invo lved in the underlying mechanism of interaction. The concomitant use o f lipid-lowering drugs with oral hypoglycemic agents has been recommen ded in patients with non-insulin-dependent diabetes mellitus (NIDDM). Therefore, 2 studies were initiated to explore potential pharmacokinet ic and pharmacodynamic interactions between fluvastatin, simvastatin, or placebo and the oral hypoglycemic agents tolbutamide (study I) and glyburide (study II), each in 16 healthy subjects. These compounds wer e selected because of a demonstrated in vitro interaction with tolbuta mide and widespread clinical use of glyburide. A further study (study III) was conducted to investigate the potential pharmacokinetic and ph armacodynamic interactions between fluvastatin and glyburide under the rapeutic conditions in 32 patients with NIDDM. Single and multiple coa dministration of fluvastatin 40 mg or simvastatin 20 mg increased the mean maximum plasma concentration and area under the concentration-tim e curve of glyburide by about 20%. The pharmacokinetics of tolbutamide were influenced to only a minor extent. Fluvastatin concentration-tim e profiles were unaffected by tolbutamide or glyburide coadministratio n. However, the pharmacokinetic interactions between fluvastatin or si mvastatin and tolbutamide and glyburide were not associated with clini cally relevant changes in blood glucose and insulin concentrations and , therefore, are not considered to be relevant in therapeutic practice . The pharmacokinetics of the morning administration of glyburide Idos e range, 5-20 mg) wee unaffected by the preceding evening's intake of fluvastatin. Further, fluvastatin comedication did not influence the h ypoglycemic action of glyburide. Hence, in contrast to study II, in wh ich changes were seen in the pharmacokinetics of glyburide on simultan eous fluvastatin administration in healthy subjects, study III shows t hat fluvastatin and glyburide can be safely combined in patients with NIDDM.