Pharmacokinetic interaction of telmisartan with s-amlodipine: an open-label, two-period crossover study in healthy Korean male volunteers.

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Fifty-six volunteers were enrolled (32 in part A and 24 in part B), and all completed except 4 volunteers (3 withdrawn in part A and 1 withdrawn in part B).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.