Abstract
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except 4 volunteers (3 withdrawn in part A and 1 withdrawn in part B).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 Cmax,ss and AUCτ,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 Cmax,ss and AUCτ,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. ClinicalTrials.gov identifiers: NCT01356017 and NCT01356043.
Key words
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Article info
Publication history
Published online: June 21, 2012
Accepted:
June 1,
2012
Identification
Copyright
© 2012 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
