EFFECT OF MULTIPLE DOSES OF LOSARTAN ON THE PHARMACOKINETICS OF SINGLE DOSES OF DIGOXIN IN HEALTHY-VOLUNTEERS

1 Losartan (DuP 753, MK-954) is a novel, potent and highly selective A T(1) angiotensin II receptor antagonist. The effect of multiple oral d oses of losartan on digoxin pharmacokinetics was evaluated in healthy male subjects. 2 In a double-blind and randomized fashion, subjects re ceived 50 mg losartan or placebo once daily for 15 days in each period . At least 7 days elapsed between the two treatment periods. On days 4 and 11 of each period, subjects also received a single 0.5 mg dose of digoxin intravenously and orally respectively.3 Eleven of 13 subjects completed the study. Side effects were mild and transient (12 out of 13 subjects reported at least one adverse experience). During the stud y, no laboratory abnormalities were noted. 4 Multiple oral doses of lo sartan (50 mg daily) did not affect the pharmacokinetic parameters of 0.5 mg of digoxin i.v. AUC(0,48h) of immunoreactive digoxin during los artan 28.8 +/- 2.9 vs 28.5 +/- 3.9 ng ml(-1) h during placebo; not sig nificant, and 96 h urinary excretion [% dose] during losartan 54.0 +/- 7.2 us 51.9 +/- 6.5% during placebo; not significant). Geometric mean ratios (90% confidence interval) for AUC and urinary excretion were r espectively, 1.03 (0.98, 1.08) and 1.09 (0.98, 1.21). 5 Multiple oral doses of losartan did not affect the pharmacokinetic parameters of ora l digoxin AUC(0,48h) during losartan 23.6 +/- 3.7 ng ml(-1) h vs 22.4 +/- 2.6 ng ml(-1) h during placebo; not significant, C-max 3.5 +/- 0.7 ng ml(-1) with us 3.1 +/- 0.5 ng ml(-1) without losartan; not signifi cant and t(max) 0.6 +/- 0.2 h with vs 0.9 +/- 0.7 h without losartan; not significant, and 96 h urinary excretion [% dose] during losartan 5 1.2 +/- 6.3 vs 46.3 +/- 2.4% during placebo; not significant). Geometr ic mean ratios (90% confidence interval) for AUC and urinary excretion were respectively, 1.06 (0.98, 1.14) and 1.12 (0.97, 1.28). 6 We conc lude that multiple oral doses of losartan (50 mg daily) do not alter t he pharmacokinetics of immunoreactive digoxin, following either intrav enous or oral digoxin. Furthermore, the co-administration of digoxin w ith losartan is well tolerated by healthy male volunteers.