title: Lack of mutual pharmacokinetic interaction between cerivastatin, a new HMG-CoA reductase inhibitor, and digoxin in healthy normocholesterolemic volunteers.
abstract: The potential mutual interaction between cerivastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, and digoxin was assessed in this nonmasked, 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 normocholesterolemic men between 18 and 45 years of age weighing 140 to 200 lbs (63.3 to 90.0 kg). Subjects were given a single dose of cerivastatin 0.2 mg. After 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 digoxin-only administration and an optional 6-day extension of digoxin-only treatment for a total of 14 days (period 3). Safety was assessed through physical examination, electrocardiography, laboratory tests, and ophthalmologic examination. Ratio analyses of mean digoxin plasma trough levels, 24-hour urinary digoxin levels, and digoxin clearance with and without concurrent cerivastatin dosing also were carried out. In addition, single-dose pharmacokinetic 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 (t1/2), were examined with and without concurrent digoxin dosing. Eleven of the 20 subjects completed the entire study. Seven subjects discontinued the study because of treatment-emergent adverse events or laboratory abnormalities that were mostly unrelated to cerivastatin, and 2 subjects were discontinued because of protocol violations. Treatment-emergent adverse events developed in 12 subjects receiving cerivastatin; 11 of these subjects were receiving digoxin concurrently. Six adverse events that led to discontinuation of treatment were unrelated to cerivastatin but were related to digoxin or to a preexisting condition. The most commonly reported event was headache, which occurred with equal frequency compared with placebo groups in large cerivastatin clinical trials. Other events were mild or moderate and resolved without intervention. Mild and transient elevations in hepatic transaminase and creatine kinase values (all <2 times the upper limit of normal) were observed in 7 subjects. After 14 days of concurrent dosing of cerivastatin and digoxin, steady-state digoxin plasma levels, urinary digoxin levels, and urinary digoxin clearance were unchanged compared with steady-state digoxin levels when digoxin was given alone. Compared with dosing with digoxin alone, the AUC(0-24), Cmax, and t1/2 for cerivastatin increased 3%, 20%, and 7%, respectively, while the T(max) was reduced by 18% during concurrent treatment with digoxin. These changes are minimal and would not be expected to be clinically relevant. These results demonstrate that when cerivastatin is administered concurrently with digoxin, neither digoxin nor cerivastatin plasma levels are altered. The combination therapy was generally well tolerated.
authors.affiliation: Health & Sciences Research, Inc., Englewood, New Jersey, USA.
authors.forename: P
authors.initials: P
authors.lastname: Weber
authors.forename: J T
authors.initials: JT
authors.lastname: Lettieri
authors.forename: L
authors.initials: L
authors.lastname: Kaiser
authors.forename: A L
authors.initials: AL
authors.lastname: Mazzu
mesh_terms: D000328:Adult; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D004077:Digoxin / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D010352:Patient Dropouts; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D002316:Cardiotonic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; D004077:Digoxin; C086276:cerivastatin