Lack of mutual pharmacokinetic interaction between cerivastatin, a new HMG-CoA reductase inhibitor, and digoxin in healthy normocholesterolemic volunteers

The potential mutual interaction between cerivastatin, a 3-hydroxy-3-methyl glutaryl-coenzyme A reductase inhibitor, and digoxin was assessed in this n onmasked, nonrandomized, multiple-dose study. The effect of cerivastatin 0. 2 mg on mean plasma digoxin levels and the effect of digoxin on the single- dose pharmacokinetics of cerivastatin were assessed in 20 healthy normochol esterolemic men between is and 45 years of age weighing 140 to 200 Ibs (63. 3 to 90.0 kg). Subjects were given a single dose of cerivastatin 0.2 mg. Af ter a 2-day washout period, subjects were given a loading dose of digoxin 0 .5 mg for 3 days followed by 0.25 mg daily for 5 additional days (period 1- digoxin alone). Concurrent dosing with cerivastatin 0.2 mg continued for 14 days (period 2-digoxin and cerivastatin), followed by an 8-day course of d igoxin-only administration and an optional 6-day extension of digoxin-only treatment for a total of 14 days (period 3). Safety was assessed through ph ysical examination, electrocardiography, laboratory tests, and ophthalmolog ic examination. Ratio analyses of mean digoxin plasma trough levels, 24-hou r urinary digoxin levels, and digoxin clearance with and without concurrent cerivastatin dosing also were carried out. In addition, single-dose pharma cokinetic variables for cerivastatin, including area under the curve (AUC(0 -24)), peak concentration (C-max), time to peak concentration (T-max), and elimination half-life (t(1/2)), were examined with and without concurrent d igoxin dosing. Eleven of the 20 subjects completed the entire study. Seven subjects discontinued the study because of treatment-emergent adverse event s or laboratory abnormalities that were mostly unrelated to cerivastatin, a nd 2 subjects were discontinued because of protocol violations. Treatment-e mergent adverse events developed in 12 subjects receiving cerivastatin; 11 of these subjects were receiving digoxin concurrently. Six adverse events t hat led to discontinuation of treatment were unrelated to cerivastatin but were related to digoxin or to a preexisting condition. The most commonly re ported event was headache, which occurred with equal frequency compared wit h placebo groups in large cerivastatin clinical trials. Other events were m ild or moderate and resolved without intervention. Mild and transient eleva tions in hepatic transaminase and creatine kinase values tall <2 times the upper limit of normal) were observed in 7 subjects. After 14 days of concur rent dosing of cerivastatin and digoxin, steady-state digoxin plasma levels , urinary digoxin levels, and urinary digoxin clearance were unchanged comp ared with steady-state digoxin levels when digoxin was given alone. Compare d with dosing with digoxin alone, the AUC(0-24), C-max, and t(1/2) for ceri vastatin increased 3%, 20%, and 7%, respectively, while the T-max was reduc ed by 18% during concurrent treatment with digoxin. These changes are minim al and would not be expected to be clinically relevant. These results demon strate that when cerivastatin is administered concurrently with digoxin, ne ither digoxin nor cerivastatin plasma levels are altered. The combination t herapy was generally well tolerated.