Fosinopril/hydrochlorothiazide: single dose and steady-state pharmacokinetics and pharmacodynamics

Aims Fosinoprilat, the active product of fosinopril, is eliminated by an he patic pathway in addition to thr renal pathway shared by other angiotensin converting enzyme inhibitors (ACEIs). This study aimed to determine whether impaired renal function affects the pharmacokinetics and pharmacodynamics of a combination of fosinopril and hydrochlorothiazide (HCTZ). Methods The study had a parallel-group design comparing patients with renal impairment and body-mass-index-matched normal controls. The study was done in a University clinic in 13 patients with renal impairment (mean creatini ne clearance 55.7 +/- 15.6 ml min(-1) 1.73 m(-2)) and 13 age-, sex-, and bo dy-mass-index-matched normal controls (mean creatinine clearance 102.4 +/- 8.9 mi min(-1) 1.73 m(-2)). All patients and normal controls received fosin opril sodium 20 mg and HCTZ 12.5 mg as a daily oral administration on days 1-5. Non-compartmental pharmacokinetic parameters of fosinoprilat and HCTZ were determined from blood and urine samples obtained over 48 h starting on Day 1 (single dose) and Day 5 (steady state): maximum serum concentration (C-max), time to maximum serum concentration (t(max)), area under the serum concentration-time curve during the dosing interval (AUC), cumulative urin ary excretion (CUE) and the accumulation index (AI; ratio of AUC-day 5/AUC- day 1). Pharmacodynamic parameters were also measured over 24 h on day 1 an d over 48 h on day 5. serum ACE activity and arterial blood pressure. Results Fosinoprilat pharmacokinetic parameters on day 1 in renally impaire d vs normal patients: C-max = 387 +/- 0.19 vs 324 +/- 0.25 ng ml(-1) (P=0.0 7); t(max) = 3.5 vs 3.0 h (P = 0.58); AUC = 3510 +/- 0.29 vs 2701 +/- 0.35 ng ml(-1) h (P = 0.072); CUE = 5.08 +/- 2.70 vs 7.40 +/- 2.56% (P = 0.009). Fosinoprilat parameters on day 5: C-max = 517 +/- 0.40 vs 357 +/- 0.19 ng ml(-1) (P = 0.007); t(max) = 3.0 vs 3.0 h (P>0.99); AUC = 4098 +/- 0.43 vs 2872 +/- 0.30 ng ml(-1) h (P=0.027); CUE=6.81+/-3.53 vs 8.10 +/- 2.80% (P = 0.068). Al = 1.17 +/- 0.33 vs 1.06 +/- 0.23 (P = 0.29). In both groups ACE inhibition and blood pressure response were similar over 24 h and slightly greater 48 h after last dosing. Conclusions In renally impaired subjects fosinopril and HCTZ can be coadmin istered without undue increases in fosinoprilat concentrations or any clini cally significant pharmacodynamic effects. This is probably due to the dual excretory pathways for fosinoprilat.