title: Pharmacokinetic comparison and bioequivalence evaluation of losartan/ hydrochlorothiazide tablet between Asian Indian and Japanese volunteers.
abstract: OBJECTIVE
  To demonstrate the bioequivalence between the test and reference formulations of losartan/hydrochlorothiazide 50 + 12.5 mg tablet and evaluate the effect of ethnicity on pharmacokinetics properties of losartan, losartan carboxylic acid and hydrochlorothiazide on healthy Asian Indian and Japanese volunteers.
  
  
  METHODS
  Randomized, open-label, crossover, bioavailability studies were conducted separately in healthy Asian Indian and Japanese volunteers. One tablet either of test or of reference product was administered after 10 hours of overnight fasting. After dosing, serial blood samples were collected for a period of 48 hours for both the studies. Plasma samples were analyzed for losartan, losartan carboxylic acid and hydrochlorothiazide by a validated liquid chromatographic and mass spectrometric method (LC-MS/MS). The pharmacokinetic parameters AUC0-t, AUC0-∞, Cmax, tmax, and other pharmacokinetics parameters were determined from plasma concentration-time profiles for both test and reference formulations of losartan/hydrochlorothiazide 50 + 12.5 mg tablets. Statistical evaluations were done to evaluate bioequivalence between generic test formulation (EPR0001) and Japanese reference product (Preminent®).
  
  
  RESULTS
  Losartan, losartan carboxylic acid and hydrochlorothiazide were well tolerated by subjects in all periods of each study under fasted conditions. No serious adverse events were observed. The ratios of least square means for AUC0-t and Cmax and the affiliated 90% confidence intervals were within acceptance range recommended by PMDA. Marginal differences were observed in pharmacokinetic values of Asian Indian and Japanese volunteers.
  
  
  CONCLUSIONS
  The results of these bioavailability studies indicate that the test formulation of losartan/hydrochlorothiazide 50 + 12.5 mg (EPR0001) tablets is bioequivalent to marketed Preminent® reference formulation in Asian Indian and Japanese volunteers, when administered under fasting conditions. Both test and reference formulations were well tolerated as a single oral dose when administered to healthy adult subjects under fasted conditions. Although Asian Indian and Japanese volunteers are ethnically different, results of these studies indicate that pharmacokinetic parameters of Asian Indian and Japanese volunteers are comparable to each other in terms of bioavailability of losartan, losartan carboxylic acid and hydrochlorothiazide. Similar least square means ratios were obtained in Asian Indian and Japanese volunteers demonstrating that a bioequivalence study conducted on Japanese volunteers seems to be substituted by Asian Indian volunteers' studies.
authors.forename: Sudershan
authors.initials: S
authors.lastname: Kumar
authors.forename: Tausif
authors.initials: T
authors.lastname: Monif
authors.forename: Arshad
authors.initials: A
authors.lastname: Khuroo
authors.forename: Simrit
authors.initials: S
authors.lastname: Reyar
authors.forename: Rakesh
authors.initials: R
authors.lastname: Jain
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Singla
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kurachi
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People; D001682:Biological Availability; D018592:Cross-Over Studies; D004338:Drug Combinations; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D006852:Hydrochlorothiazide / Q000493:pharmacokinetics*; D007194:India; D019808:Losartan / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D013607:Tablets; D053719:Tandem Mass Spectrometry; D013810:Therapeutic Equivalency
chemical_list: D004338:Drug Combinations; D013607:Tablets; C505809:hydrochlorothiazide, losartan drug combination; D006852:Hydrochlorothiazide; D019808:Losartan