PMID- 22721873 OWN - NLM STAT- MEDLINE DCOM- 20121221 LR - 20220330 IS - 1879-114X (Electronic) IS - 0149-2918 (Linking) VI - 34 IP - 7 DP - 2012 Jul TI - Pharmacokinetic interaction of telmisartan with s-amlodipine: an open-label, two-period crossover study in healthy Korean male volunteers. PG - 1625-35 LID - 10.1016/j.clinthera.2012.05.010 [doi] AB - BACKGROUND: Telmisartan belongs to a class of orally active angiotensin II receptor blockers (ARBs), and S-amlodipine is an enantiomer of amlodipine. Amlodipine is a racemic mixture and the calcium channel blocking (CCB) effect is confined to S-amlodipine, whereas R-amlodipine has a 1000-fold lower activity and no racemization occurs in vivo in human plasma. Combination therapy of ARBs with CCBs provides advantages for blood pressure control and vascular protection over monotherapy. OBJECTIVE: To investigate the effects of coadministration of telmisartan and S-amlodipine on the steady-state pharmacokinetic properties of each drug as a drug-drug interaction study required before developing the fixed-dose combination agent. METHODS: This study comprised 2 separate parts, A and B; each was a multiple-dose, open-label, 2-sequence, 2-period, crossover study in healthy male Korean volunteers. In part A, volunteers were administered 80 mg of telmisartan, either alone or with 5 mg of S-amlodipine. In part B, volunteers were administered 5 mg of S-amlodipine, either alone or with 80 mg of telmisartan. Blood samples were taken on days 9 and 37, following the final dose of each treatment, and at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours after administration in part A, and were taken at 0 (predose), 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, and 24 hours after administration in part B. Plasma concentrations were determined using LC-MS/MS. The pharmacokinetic properties of each drug after coadministration of telmisartan and S-amlodipine were compared with those of each drug administered alone. Tolerability was assessed using measurements of vital signs, clinical chemistry tests, and interviews. RESULTS: Fifty-six volunteers were enrolled (32 in part A and 24 in part B), and all completed except 4 volunteers (3 withdrawn in part A and 1 withdrawn in part B). The geometric mean ratios (GMRs) (90% CI) for the C(max,ss) and AUC(tau,ss) of telmisartan (with or without S-amlodipine) were 1.039 (0.881-1.226) and 1.003 (0.926-1.087), respectively. The GMRs (90% CI) for C(max,ss) and AUC(tau,ss) of S-amlodipine (with or without telmisartan) were 0.973 (0.880-1.076) and 0.987 (0.897-1.085). Total 11 adverse events (AEs) were reported in 7 volunteers (21.9%) in part A. A total of 9 AEs were reported in 6 volunteers (25.0%) in part B. Statistical analysis confirmed that the 90% CIs for these pharmacokinetic parameters were within the commonly accepted bioequivalence range of 0.8 to 1.25, indicating that the extent of bioavailability of S-amlodipine was not affected by telmisartan. The intensity of all AEs was considered to be mild, and there were no significant differences in the prevalences of AEs between the 2 formulations. CONCLUSIONS: Following multiple-dose coadministration of high doses of telmisartan and S-amlodipine, the steady-state pharmacokinetic properties of telmisartan were not significantly affected, and telmisartan had no significant effect on the pharmacokinetic properties of S-amlodipine at steady state in these selected groups of healthy volunteers. Both formulations were generally well-tolerated. CI - Copyright (c) 2012 Elsevier HS Journals, Inc. All rights reserved. FAU - Noh, Yook-Hwan AU - Noh YH AD - Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul, Korea. FAU - Lim, Hyeong-Seok AU - Lim HS FAU - Kim, Mi Jo AU - Kim MJ FAU - Kim, Yo Han AU - Kim YH FAU - Choi, Hee Youn AU - Choi HY FAU - Sung, Hye Ryoung AU - Sung HR FAU - Jin, Seok-Joon AU - Jin SJ FAU - Lim, Jonglae AU - Lim J FAU - Bae, Kyun-Seop AU - Bae KS LA - eng SI - ClinicalTrials.gov/NCT01356017 SI - ClinicalTrials.gov/NCT01356043 PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20120619 PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 0 (Angiotensin II Type 1 Receptor Blockers) RN - 0 (Benzimidazoles) RN - 0 (Benzoates) RN - 0 (Calcium Channel Blockers) RN - 1J444QC288 (Amlodipine) RN - U5SYW473RQ (Telmisartan) SB - IM MH - Adult MH - Amlodipine/adverse effects/*pharmacokinetics/pharmacology MH - Angiotensin II Type 1 Receptor Blockers/adverse effects/*pharmacokinetics/pharmacology MH - Area Under Curve MH - Benzimidazoles/adverse effects/*pharmacokinetics/pharmacology MH - Benzoates/adverse effects/*pharmacokinetics/pharmacology MH - Calcium Channel Blockers/adverse effects/*pharmacokinetics/pharmacology MH - Chromatography, Liquid MH - Cross-Over Studies MH - Drug Interactions MH - Follow-Up Studies MH - Humans MH - Male MH - Republic of Korea MH - Stereoisomerism MH - Tandem Mass Spectrometry MH - Telmisartan MH - Time Factors MH - Young Adult EDAT- 2012/06/23 06:00 MHDA- 2012/12/22 06:00 CRDT- 2012/06/23 06:00 PHST- 2012/03/02 00:00 [received] PHST- 2012/05/30 00:00 [revised] PHST- 2012/06/01 00:00 [accepted] PHST- 2012/06/23 06:00 [entrez] PHST- 2012/06/23 06:00 [pubmed] PHST- 2012/12/22 06:00 [medline] AID - S0149-2918(12)00360-8 [pii] AID - 10.1016/j.clinthera.2012.05.010 [doi] PST - ppublish SO - Clin Ther. 2012 Jul;34(7):1625-35. doi: 10.1016/j.clinthera.2012.05.010. Epub 2012 Jun 19.