Comparative pharmacokinetics of a fixed-dose combination vs concomitant administration of telmisartan and S-amlodipine in healthy adult volunteers

Abstract

Objective: This study compared the pharmacokinetic (PK) and safety profiles of a fixed-dose combination (FDC) formulation of telmisartan and S-amlodipine with those of concomitant administration of the two drugs.

Materials and methods: This was an open-label, randomized, crossover study in healthy male Koreans. All subjects were administered an FDC tablet containing 40 mg telmisartan and 5 mg S-amlodipine and were also coadministered the same dose of both drugs given separately. The crossover study design included a 14-day washout period between the two treatments. Blood samples were collected up to 168 h following drug administration. The plasma concentrations of telmisartan and S-amlodipine were determined by liquid chromatography tandem mass spectrometry. PK parameters and plasma concentration-time curves were compared. Safety was assessed by measuring vital signs, clinical laboratory tests, physical examinations, and patient interviews.

Results: The geometric mean ratios and 90% CIs for the maximum plasma concentration (C_max) and area under the curve from time zero to the last sampling time (AUC_t) were 0.8782 (0.8167-0.9444) and 0.9662 (0.9210-1.0136) for telmisartan and 1.0069 (0.9723-1.0427) and 1.0324 (0.9969-1.0690) for S-amlodipine, respectively. A total of 36 adverse events (AEs) were reported by 23 subjects, but no statistical differences were observed between the two treatments. The most frequently reported AE was a mild-to-moderate headache that was generally self-limiting.

Conclusion: For both telmisartan and S-amlodipine, the C_max and AUC_t 90% CIs were between ln (0.8) and ln (1.25). These results suggest that the FDC formulation is pharmacokinetically bioequivalent and has a similar safety profile to the coadministration of these drugs.

Keywords: S-amlodipine; bioequivalence; fixed-dose combination; pharmacokinetics; telmisartan.

Figure 1

Disposition of volunteers. Abbreviations: AE, adverse event; RT, reference-test; TR, test-reference.

Figure 2

Mean (standard deviation) plasma concentration profiles of telmisartan after administration of FDC tablet (40 mg telmisartan/5 mg S-amlodipine) and coadministration of 40 mg telmisartan with 5 mg S-amlodipine in healthy male subjects. Notes: Linear scale (A); Iog scale (B). Abbreviation: FDC, fixed-dose combination.

Figure 3

Mean (standard deviation) plasma concentration profile of S-amlodipine after administration of FDC tablet (40 mg telmisartan/5 mg S-amlodipine) and coadministration of 40 mg telmisartan with 5 mg S-amlodipine in healthy male subjects. Notes: Linear scale (A); log scale (B). Abbreviation: FDC, fixed-dose combination.

Figure 4

Mean (standard deviation) SBP and DBP after administration of FDC tablet (40 mg telmisartan/5 mg S-amlodipine) and coadministration of 40 mg telmisartan with 5 mg S-amlodipine in healthy male subjects. Notes: SBP (A); DBP (B). Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; FDC, fixed-dose combination.