Authors: Abel, Samantha¹; Nichols, Donald J.¹; Brearley, Christopher J.¹; Eve, Malcolm D.²

Source: British Journal of Clinical Pharmacology, Volume 49, Number 1, January 2000 , pp. 64-71(8)

Publisher: Wiley-Blackwell

Abstract:

Aims The aim of this open-label, placebo-controlled, randomized, four-period crossover study was to determine the effects of cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of a single dose of dofetilide.

Methods Twenty healthy male subjects received 100 or 400 mg twice daily of cimetidine, 150 mg twice daily of ranitidine, or placebo for 4 days. On the second day, a single oral 500 μg dose of dofetilide was administered immediately after the morning doses of cimetidine, ranitidine, or placebo. Treatment periods were separated by 1-2 weeks. Pharmacokinetic parameters were determined from plasma and urinary dofetilide concentrations; prolongation of the QTc interval was determined from three-lead electrocardiograms.

Results Ranitidine did not significantly affect the pharmacokinetics or pharmacodynamics of dofetilide; however, a dose-dependent increase in exposure to dofetilide was observed with cimetidine. When dofetilide was administered with 100 and 400 mg of cimetidine, the area under the plasma concentration-time curve of dofetilide increased by 11% and 48% and the maximum plasma dofetilide concentration increased by 11% and 29%, respectively. The respective cimetidine doses reduced renal clearance of dofetilide by 13% and 33% and nonrenal clearance by 5% and 21%. Dofetilide-induced prolongation of the QTc interval was enhanced by cimetidine; the mean maximum change in QTc interval from baseline was increased by 22% and 33% with 100 and 400 mg of cimetidine, respectively. However, the relationship between the prolongation of the QTc interval and plasma dofetilide concentrations was unaffected by cimetidine or ranitidine; a 1 ng ml⁻¹ increase in plasma dofetilide concentration produced a 17-19 ms prolongation of the QTc interval. Dofetilide was well tolerated, with no treatment-related adverse events or laboratory abnormalities.

Conclusions These results suggest that cimetidine increased dofetilide exposure by inhibiting renal tubular dofetilide secretion, whereas ranitidine did not. This effect is not an H₂-receptor antagonist class effect but is specific to cimetidine. If therapy with an H₂-receptor antagonist is required, it is recommended that cimetidine at all doses be avoided; since ranitidine has no effect on dofetilide pharmacokinetics or prolongation of the QTc interval, it can be seen as a suitable alternative.

Keywords: antiarrhythmic drug; cimetidine; dofetilide; pharmacodynamics; pharmacokinetics; ranitidine

Document Type: Research article

DOI: http://dx.doi.org/10.1046/j.1365-2125.2000.00114.x

Affiliations: 1: Pfizer Central Research, Sandwich, 2: Pfizer Clinical Research Unit, Kent and Canterbury Hospital, Canterbury, UK

Publication date: 2000-01-01

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