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 (NYH A class II or III, ejection fraction less than or equal to 40%) were e nrolled from three hospitals in Taiwan. Interventions: Immediately fol lowing a lead-in period of fosinopril 10mg daily, patients received th ree consecutive oral dosage regimens of fosinopril (10, 20 or 40mg onc e daily) for 10 to 14 days per period without intervening washout peri ods. Serum and urine were analysed for fosinoprilat (the pharmacologic ally active diacid) concentrations by liquid chromatoeraphy/tandem mas s spectrometry. Results: All treatment periods were completed by 23 pa tients. Five patients experienced adverse events of numbness, syncope, oedema or mouth ulcers that were possibly related to fosinopril. Hear t disease was considered the cause of sudden death in one patient 19 d ays after completion of the study. At all doses, fosinopril almost com pletely inhibited serum ACE activity. Statistical analysis of pharmaco kinetic data showed no significant differences among doses in any of t he following parameters: dose-adjusted maximum serum concentration (C- max) and area under the serum concentration-time curve values (as asse ssed by 90% confidence intervals of the mean ratios at steady-state), ti me to reach Cmax, Serum elimination half-life, cumulative urinary e xcretion (expressed as a percentage of the administered dose), and ren al clearance. At the higher dose levels, there was a somewhat greater fluctuation in steady-state fosinoprilat concentrations. Conclusion: F osinopril is a potent, well-tolerated ACE inhibitor in Chinese patient s with mild to moderate heart failure, and exhibited dose-proportional pharmacokinetics in the 10 to 40mg dose range.