P O'Grady1, K F Yee, R Lins, B Mangold. 1. Clinical Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, 1410, Waterloo, Belgium. padraig.ogrady@bms.com
Abstract
AIMS: Fosinoprilat, the active product of fosinopril, is eliminated by an hepatic pathway in addition to the 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 creatinine clearance 55.7+/-15.6 ml min-1 1.73 m-2 ) and 13 age-, sex-, and body-mass-index-matched normal controls (mean creatinine clearance 102.4+/-8.9 ml min-1 1.73 m-2 ). All patients and normal controls received fosinopril 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 (Cmax ), time to maximum serum concentration (tmax ), area under the serum concentration-time curve during the dosing interval (AUC), cumulative urinary 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 and over 48 h on day 5: serum ACE activity and arterial blood pressure. RESULTS: Fosinoprilat pharmacokinetic parameters on day 1 in renally impaired vs normal patients: Cmax=387+/-0.19 vs 324+/-0.25 ng ml-1 (P=0.07); tmax=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: Cmax=517+/-0.40 vs 357+/-0.19 ng ml-1 (P=0. 007); tmax=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). AI=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 coadministered without undue increases in fosinoprilat concentrations or any clinically significant pharmacodynamic effects. This is probably due to the dual excretory pathways for fosinoprilat.
AIMS: Fosinoprilat, the active product of fosinopril, is eliminated by an hepatic pathway in addition to the 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 creatinine clearance 55.7+/-15.6 ml min-1 1.73 m-2 ) and 13 age-, sex-, and body-mass-index-matched normal controls (mean creatinine clearance 102.4+/-8.9 ml min-1 1.73 m-2 ). All patients and normal controls received fosinopril 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 (Cmax ), time to maximum serum concentration (tmax ), area under the serum concentration-time curve during the dosing interval (AUC), cumulative urinary 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 and over 48 h on day 5: serum ACE activity and arterial blood pressure. RESULTS:Fosinoprilat pharmacokinetic parameters on day 1 in renally impaired vs normal patients: Cmax=387+/-0.19 vs 324+/-0.25 ng ml-1 (P=0.07); tmax=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: Cmax=517+/-0.40 vs 357+/-0.19 ng ml-1 (P=0. 007); tmax=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). AI=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 coadministered without undue increases in fosinoprilat concentrations or any clinically significant pharmacodynamic effects. This is probably due to the dual excretory pathways for fosinoprilat.