title: Pharmacokinetics, tolerability, and safety of the single oral administration of AGSAV301 vs Exforge: a randomized crossover study of healthy male volunteers.
abstract: OBJECTIVE
  Valsartan, an angiotensin receptor blocker, is often used with calcium channel blockers (CCBs) such as amlodipine to control hypertension. Recently, the fixed-dose combination (FDC) of amlodipine 10 mg/valsartan 160 mg (Exforge) was approved. Amlodipine is a racemic mixture of CCB; S-amlodipine has higher activity than R-form. Therefore, AGSAV301, the FDC of S-amlodipine 5 mg/valsartan 160 mg was recently developed. The objective of this study was to compare the pharmacokinetic (PK) characteristics of S-amlodipine and valsartan when administered as one tablet each of Exforge and AGSAV301 to healthy male subjects.
  
  
  METHODS
  This was a single-dose, randomized, open-label, two-way, two-period crossover study. Each subject received a single dose of AGSAV301 and Exforge, separated by a 3-week washout period. Plasma samples for the PK analysis of valsartan and S-amlodipine were collected at predose (0) and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120, and 168 h after administration. Tolerability was also evaluated.
  
  
  RESULTS
  A total of 29 subjects were enrolled; 24 completed this study. The S-amlodipine maximum plasma concentration (C max) geometric mean ratio (GMR) between AGSAV301 and Exforge was 0.951 (90 % CI 0.983-1.014), and area under the concentration-time curve from time 0 to last measured time point (AUClast) was 0.917 (90 % CI 0.861-0.976). The GMR of valsartan C max was 0.994 (90 % CI 0.918-1.076), and the AUClast was 0.927 (90 % CI 0.821-1.047). All adverse events (AEs) were resolved without sequelae; no serious AEs were reported. Two drugs showed similar tendencies to lower blood pressure in healthy subjects.
  
  
  CONCLUSIONS
  The PK profiles of AGSAV301 and Exforge were bioequivalent. Both drugs were also well tolerated, with comparable AE profiles and similar blood pressure-lowering tendencies in healthy volunteers, suggesting equivalent therapeutic indications.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea.
authors.forename: Hee Youn
authors.initials: HY
authors.lastname: Choi
authors.forename: Yo Han
authors.initials: YH
authors.lastname: Kim
authors.forename: Mi Jo
authors.initials: MJ
authors.lastname: Kim
authors.forename: Yook-Hwan
authors.initials: YH
authors.lastname: Noh
authors.forename: Shi Hyang
authors.initials: SH
authors.lastname: Lee
authors.forename: Kyun-Seop
authors.initials: KS
authors.lastname: Bae
authors.forename: Hyeong-Seok
authors.initials: HS
authors.lastname: Lim
mesh_terms: D000284:Administration, Oral; D000328:Adult; D017311:Amlodipine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000068838:Amlodipine, Valsartan Drug Combination; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects*; D018592:Cross-Over Studies; D004338:Drug Combinations; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D013237:Stereoisomerism; D013607:Tablets; D013777:Tetrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency; D013997:Time Factors; D055815:Young Adult
chemical_list: D000068838:Amlodipine, Valsartan Drug Combination; D000959:Antihypertensive Agents; D004338:Drug Combinations; D013607:Tablets; D013777:Tetrazoles; D017311:Amlodipine