Reinhold Kreutz1, Juliane Bolbrinker, Matthias Huber. 1. Department of Clinical Pharmacology and Toxicology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany. reinhold.kreutz@charite.de
Abstract
BACKGROUND: Hypertension treatment guidelines recommend combination therapy with diuretics and other antihypertensive agents, including angiotensin II type 1 (AT1) receptor antagonists. This trial investigated the possibility of pharmacokinetic interactions between the AT1 receptor antagonist olmesartan medoxomil and the thiazide diuretic hydrochlorothiazide in healthy subjects. METHODS:Twenty-four healthy normotensive adult male subjects underwent three consecutive 7-day treatment periods (A, B and C, respectively) during which they were randomised to receive: olmesartan medoxomil 20 mg once daily (regimen A), hydrochlorothiazide 25 mg once daily (regimen B), or olmesartan medoxomil 20 mg once daily plus hydrochlorothiazide 25 mg once daily (regimen C). Treatment periods were separated by washouts of 7-14 days. The primary pharmacokinetic parameters evaluated were: the area under the plasma concentration versus time curve at steady state (AUCss,tau), the maximum plasma concentration at steady state (Css,max), and the time at which Css,max occurred (tmax). RESULTS: Complete data sets from 17 subjects were available for pharmacokinetic analyses. Mean concentration versus time profiles were similar for monotherapy and combination treatment for both olmesartan (the active metabolite of olmesartan medoxomil) and hydrochlorothiazide. For olmesartan, comparison of monotherapy with combination therapy showed that for AUCss,tau and Css,max point estimates were close to unity, demonstrating bioequivalence. For hydrochlorothiazide, combination therapy resulted in decreases in AUCss,tau and Css,max of approximately 10% versus monotherapy; nevertheless, since 90% CIs were within the acceptance range, bioequivalence was proven. Median tmax values for olmesartan and hydrochlorothiazide for periods A, B and C were identical, indicating bioequivalence. Both olmesartan medoxomil and hydrochlorothiazide were well tolerated. CONCLUSION: These results show that there is little or no potential for a clinically relevant pharmacokinetic interaction between olmesartan medoxomil 20 mg and hydrochlorothiazide 25 mg, and therefore dosage adjustment should not be necessary when they are co-administered.
RCT Entities:
BACKGROUND:Hypertension treatment guidelines recommend combination therapy with diuretics and other antihypertensive agents, including angiotensin II type 1 (AT1) receptor antagonists. This trial investigated the possibility of pharmacokinetic interactions between the AT1 receptor antagonist olmesartan medoxomil and the thiazide diuretic hydrochlorothiazide in healthy subjects. METHODS: Twenty-four healthy normotensive adult male subjects underwent three consecutive 7-day treatment periods (A, B and C, respectively) during which they were randomised to receive: olmesartan medoxomil 20 mg once daily (regimen A), hydrochlorothiazide 25 mg once daily (regimen B), or olmesartan medoxomil 20 mg once daily plus hydrochlorothiazide 25 mg once daily (regimen C). Treatment periods were separated by washouts of 7-14 days. The primary pharmacokinetic parameters evaluated were: the area under the plasma concentration versus time curve at steady state (AUCss,tau), the maximum plasma concentration at steady state (Css,max), and the time at which Css,max occurred (tmax). RESULTS: Complete data sets from 17 subjects were available for pharmacokinetic analyses. Mean concentration versus time profiles were similar for monotherapy and combination treatment for both olmesartan (the active metabolite of olmesartan medoxomil) and hydrochlorothiazide. For olmesartan, comparison of monotherapy with combination therapy showed that for AUCss,tau and Css,max point estimates were close to unity, demonstrating bioequivalence. For hydrochlorothiazide, combination therapy resulted in decreases in AUCss,tau and Css,max of approximately 10% versus monotherapy; nevertheless, since 90% CIs were within the acceptance range, bioequivalence was proven. Median tmax values for olmesartan and hydrochlorothiazide for periods A, B and C were identical, indicating bioequivalence. Both olmesartan medoxomil and hydrochlorothiazide were well tolerated. CONCLUSION: These results show that there is little or no potential for a clinically relevant pharmacokinetic interaction between olmesartan medoxomil 20 mg and hydrochlorothiazide 25 mg, and therefore dosage adjustment should not be necessary when they are co-administered.
Authors: Aram V Chobanian; George L Bakris; Henry R Black; William C Cushman; Lee A Green; Joseph L Izzo; Daniel W Jones; Barry J Materson; Suzanne Oparil; Jackson T Wright; Edward J Roccella Journal: Hypertension Date: 2003-12-01 Impact factor: 10.190