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Pharmacokinetic and pharmacodynamic interaction trial after repeated oral doses of imdapril and digoxin in healthy volunteers
Author(s) -
Harder Sebastian,
Thürmann Petra A.
Publication year - 1997
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1997.00588.x
Subject(s) - digoxin , pharmacokinetics , cmax , pharmacodynamics , placebo , pharmacology , confidence interval , chemistry , medicine , heart failure , alternative medicine , pathology
Aims To investigate the potential pharmacokinetic and pharmacodynamic interaction between imidapril and digoxin. Methods AUC, C max 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). C max 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%.