Pharmacokinetic and pharmacodynamic interaction trial after repeated oral doses of imidapril and digoxin in healthy volunteers.
OBJECTIVE
To investigate the potential pharmacokinetic and pharmacodynamic interaction between imidapril and digoxin.


METHODS
AUC, Cmax and t(max) of imidapril, imidaprilat and digoxin were calculated and evaluated in a randomized, doubleblind three-period cross-over design in 12 healthy volunteers after 8 days treatment with the following combinations: digoxin 0.25 mg day(-1) + placebo (D + P); imidapril 10 mg day(-1) + placebo (I + P); imidapril 10 mg day)(-1) + digoxin 0.25 mg day(-1) (I + D).


RESULTS
Mean AUC (0, 24 h) of digoxin was 10.4 (+/- 4.9 s.d.) ng ml(-1) h (D + P) and 10.7 (+/- 3.9 s.d.) ng ml(-1) h (I + D), respectively (90%-confidence intervals [CI] for the ratio of (D + P) and (I + D): 0.91-1.27, point estimator [PE]: 1.06). Mean AUC (0, 24 h) of imidapril was 133 (+/- 86 s.d.) ng ml(-1) h (I + P) and 108 (+/- 52 s.d.) ng ml(-1) h (I + D), respectively (90%-CI: 0.76-0.94, PE 0.85). AUC (0, 24 h) of imidaprilat was 215 (+/- 91 s.d.) ng ml(-1) h (I + P) and 194 (+/- 54 s.d.) ng ml(-1) h (I + D), respectively (90%-CI: 0.80-1.08, PE 0.93). Cmax was 19.9 (+/- 8.7 s.d.) ng ml(-1) (I + P) and 15.9 (+/- 5.3 s.d.) ng ml(-1) (I + D) (90%-CI: 0.67-1.00, PE 0.82). The results indicate a slight reduction of imidapril and imidaprilat plasma levels when coadministered with digoxin without any effect on digoxin plasma levels. Maximal ACE-inhibition was 79% (I + P) and 67% (I + D).


CONCLUSIONS
Grouped data analysis of imidaprilat plasma levels vs ACE-activity showed that for maximal inhibition of plasma ACE activity, imidaprilat plasma levels should exceed 10 ng ml(-1). Under digoxin and imidapril, more plasma concentrations of imidaprilat were seen under this level as after imidapril alone, this reduces the integral of the ACE-inhibition/time curves by about 20 to 30%.
Harder
S
S
Institute of Clinical Pharmacology, University Hospital Frankfurt, Germany.
Thürmann
P A
PA
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004077:Digoxin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004311:Double-Blind Method; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D048289:Imidazolidines; D011863:Radioimmunoassay
D000806:Angiotensin-Converting Enzyme Inhibitors; D000889:Anti-Arrhythmia Agents; D007093:Imidazoles; D048289:Imidazolidines; D004077:Digoxin; C065166:imidapril; C078006:imidaprilat