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 RESULTS:Fifty-six volunteers were enrolled (32 in part A and 24 in part B), and all completed except 4 volunteers (3 withdrawn in part A and 1 withdrawn in part B).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(τ,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(τ,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.
RCT Entities:
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(τ,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(τ,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.
Authors: Eline H Groenland; Monique E A M van Kleef; Michiel L Bots; Frank L J Visseren; Kim C M van der Elst; Wilko Spiering Journal: Hypertension Date: 2020-11-30 Impact factor: 10.190