Combination of losartan and hydrochlorothiazide: in vivo bioequivalence.
Two trials were performed in different groups of volunteers with the aim to compare the bioavailability of 50 mg losartan tablets (Sarvas as test and an originator product as reference formulation; study 1) and losartan/hydrochlorothiazide (50 mg/12.5 mg) (CAS 124750-99-8/CAS 58-93-5) combined formulations (Sarvastan as test and an originator product as reference formulation; study 2), respectively. Each study was conducted according to an open, randomized, single-dose, two-period cross-over design in 24 healthy volunteers with a wash-out period from 7 to 14 days. Blood samples were taken up to 36 h in the first study and up to 48 h in the second study. Concentrations of losartan and its principal active metabolite, i.e. E3174, as well as hydrochlorothiazide were determined by HPLC or LC-MS-MS, respectively. In the first study, the 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of losartan were between 0.91 and 1.03 (AUC0-t) as well as between 0.87 and 1.19 (Cmax), and thus within the acceptance ranges. The 90% confidence interval for intra-individual ratios of AUC0-t, and Cmax of E3174 were between 0.90 and 1.13 for AUC0-t, and between 0.97 and 1.14 for Cmax. In the second study, i.e. after administration of combined losartan/hydrochlorothiazide formulations, the 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of losartan were between 0.90 and 1.04 (AUC0-t) as well as between 0.86 and 1.20 (Cmax). Similarly to the parent compound, no significant differences of bioavailability parameters of E3174 between the two studied formulations were found. The 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of hydrochlorothiazide were between 0.89 and 0.98 (AUC0-t) as well as between 0.82 and 1.00 (Cmax). In the light of the present studies it can be concluded that the losartan as well as losartan/hydrochlorothiazide test formulations are bioequivalent to the respective reference formulations.
Koytchev
Rossen
R
Cooperative Clinical Drug Research and Development, Neuenhagen, Germany. mail@ccdrdag.com
Ozalp
Yildiz
Y
Erenmemisoglu
Aydin
A
van der Meer
Mike John
MJ
Alpan
Recep Serdar
RS
D000293:Adolescent; D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004338:Drug Combinations; D006207:Half-Life; D006801:Humans; D006852:Hydrochlorothiazide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019808:Losartan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D013607:Tablets; D013810:Therapeutic Equivalency
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D004338:Drug Combinations; D013607:Tablets; D006852:Hydrochlorothiazide; D019808:Losartan