Pharmacokinetics of fosinopril in Chinese patients with mild to moderate congestive heart failure

Objective: This study evaluated the steady-state pharmacokinetics and dose proportionality of fosinopril in Chinese patients with congestive heart failure in an open-label, randomised, three-way crossover study design. Patients: Chinese patients with congestive heart failure (NYHA class II or III, ejection fraction less than or equal to 40%) were enrolled from three hospitals in Taiwan. Interventions: Immediately following a lead-in period of fosinopril 10mg daily, patients received three consecutive oral dosage regimens of fosinopril (10, 20 or 40mg once daily) for 10 to 14 days per period without intervening washout periods. Serum and urine were analysed for fosinoprilat (the pharmacologically active diacid) concentrations by liquid chromatoeraphy/tandem mass spectrometry. Results: All treatment periods were completed by 23 patients. Five patients experienced adverse events of numbness, syncope, oedema or mouth ulcers that were possibly related to fosinopril. Heart disease was considered the cause of sudden death in one patient 19 days after completion of the study. At all doses, fosinopril almost completely inhibited serum ACE activity. Statistical analysis of pharmacokinetic data showed no significant differences among doses in any of the following parameters: dose-adjusted maximum serum concentration (C-max) and area under the serum concentration-time curve values (as assessed by 90% confidence intervals of the mean ratios at steady-state), ti me to reach Cmax, Serum elimination half-life, cumulative urinary excretion (expressed as a percentage of the administered dose), and renal clearance. At the higher dose levels, there was a somewhat greater fluctuation in steady-state fosinoprilat concentrations. Conclusion: Fosinopril is a potent, well-tolerated ACE inhibitor in Chinese patients with mild to moderate heart failure, and exhibited dose-proportional pharmacokinetics in the 10 to 40mg dose range.