Pharmacokinetic Interactions Between the Fixed-Dose Combination of Ezetimibe/Rosuvastatin 10/20 Mg and the Fixed-Dose Combination of Telmisartan/Amlodipine 80/5 Mg in Healthy Subjects

Figures & data

Figure 1 Study design.

Note: The gray box represents admission days.

Abbreviations: ER FDC, fixed-dose combination of 10 mg of ezetimibe and 20 mg of rosuvastatin; TA FDC, fixed-dose combination of 80 mg of telmisartan and 5 mg of amlodipine.

Table 1 Pharmacokinetic Parameters of Total Ezetimibe, Free Ezetimibe, and Rosuvastatin After Multiple Administrations of the Fixed-Dose Combination (FDC) of Ezetimibe (20 Mg) and Rosuvastatin (10 Mg), Both Alone and in Combination with the FDC of Telmisartan (80 Mg) and Amlodipine (5 Mg)

Pharmacokinetic Parameters	Monotherapy (N=34)	Combination Therapy (N=34)	GMR* (90% CIs)
Total ezetimibe
Cmax,ss (µg/L)	118.37 ± 47.68	118.45 ± 44.74	1.0263 (0.8765–1.2017)
AUCtau,ss (h∙µg/L)	805.13 ± 402.99	742.99 ± 367.89	0.9359 (0.7847–1.1163)
Tmax,ss (h)	1.00 [0.50–4.03]	1.00 [0.50–5.00]
t1/2,ss (h)	16.09 ± 11.53	20.87 ± 21.56
CLss/F (L/h)	15.08 ± 6.32	16.00 ± 6.68
Vd,ss/F (L)	330.44 ± 267.87	450.61 ± 489.46
Free ezetimibe
Cmax,ss (µg/L)	8.42 ± 3.31	14.49 ± 7.31	1.5713 (1.2821–1.9257)
AUCtau,ss (h∙µg/L)	97.05 ± 38.21	100.17 ± 40.28	0.9941 (0.8384–1.1788)
Tmax,ss (h)	3.00 [0.50–12.00]	0.75 [0.25–3.50]
t1/2,ss (h)	21.19 ± 15.86	18.88 ± 14.37
CLss/F (L/h)	118.57 ± 49.53	117.03 ± 48.17
Vd,ss/F (L)	3092.44 ± 1654.50	2916.28 ± 2018.26
Rosuvastatin
Cmax,ss (µg/L)	37.61 ± 15.04	86.53 ± 50.96	2.1673 (1.7807–2.6379)
AUCtau,ss (h∙µg/L)	349.76 ± 142.63	404.42 ± 160.65	1.1714 (0.9992–1.3733)
Tmax,ss (h)	4.00 [1.50–5.00]	1.00 [0.50–3.50]
t1/2,ss (h)	8.13 ± 2.11	9.14 ± 2.52
CLss/F (L/h)	66.49 ± 32.39	56.52 ± 21.68
Vd,ss/F (L)	783.99 ± 467.45	743.50 ± 343.66

Notes: Values are presented as the mean ± standard deviation, except for T_max,ss, which is presented as the median [minimum–maximum]; *Geometric mean ratio of combination therapy to monotherapy.

Abbreviations: AUC_tau,ss, area under the plasma concentration-time curve during the dosing interval at steady state; CIs, confidence intervals; CL_ss/F, apparent clearance at steady state; C_max,ss, maximum plasma concentration at steady state; GMR, geometric mean ratio; t_1/2,ss, half-life at steady state; T_max,ss, time to reach maximum plasma concentration at steady state; V_d,ss/F, apparent volume of distribution at steady state.

Figure 2 Mean plasma concentration‒time profiles of the lipid-lowering agents (A) total ezetimibe, (B) free ezetimibe, and (C) rosuvastatin at steady state after multiple administrations of ER-FDC alone and with TA-FDC.

Note: Error bars represent the standard deviation.

Abbreviations: ER FDC, fixed-dose combination of 10 mg of ezetimibe and 20 mg of rosuvastatin; TA FDC, fixed-dose combination of 80 mg of telmisartan and 5 mg of amlodipine.

Figure 3 Comparison of C_max,ss and AUC_tau,ss for lipid-lowering agents, total ezetimibe, free ezetimibe, and rosuvastatin after multiple administrations of ER FDC alone and with TA FDC.

Abbreviations: AUC_tau,ss, area under the plasma concentration-time curve during the dosing interval at steady state; C_max,ss, maximum plasma concentration at steady state; ER FDC, fixed-dose combination of ezetimibe 20 mg and rosuvastatin 10 mg; TA FDC, fixed-dose combination of telmisartan 80 mg and amlodipine 5 mg.

Table 2 Pharmacokinetic Parameters of Telmisartan and Amlodipine After Multiple Administrations of the Fixed-Dose Combination (FDC) of Telmisartan 80 Mg and Amlodipine 5 Mg FDC, Both Alone and in Combination with Ezetimibe 20 Mg and Rosuvastatin 10 Mg

Pharmacokinetic Parameters	Monotherapy (N=34)	Combination Therapy (N=34)	GMR* (90% CIs)
Telmisartan
Cmax,ss (µg/L)	1165.48 ± 821.91	1147.21 ± 620.47	1.0745 (0.8139–1.4186)
AUCtau,ss (h∙µg/L)	4379.39 ± 2808.84	4794.81 ± 2903.07	1.1057 (0.8379–1.4591)
Tmax,ss (h)	0.75 [0.50–3.05]	0.77 [0.50–4.00]
t1/2,ss (h)	13.16 ± 7.90	15.06 ± 8.93
CLss/F (L/h)	28.76 ± 23.73	25.85 ± 20.18
Vd,ss/F (L)	469.07 ± 376.33	500.50 ± 369.63
Amlodipine
Cmax,ss (µg/L)	9.42 ± 1.76	8.83 ± 1.45	0.9421 (0.8764–1.0126)
AUCtau,ss (h∙µg/L)	179.38 ± 34.75	172.20 ± 33.38	0.9603 (0.8862–1.0405)
Tmax,ss (h)	6.00 [3.00–8.00]	6.00 [3.50–10.00]
t1/2,ss (h)	53.43 ± 24.49	55.08 ± 47.08
CLss/F (L/h)	28.72 ± 6.07	30.15 ± 6.12
Vd,ss/F (L)	2125.74 ± 847.45	2273.08 ± 1460.18

Notes: Values are presented as the mean ± standard deviation, except for T_max,ss, which is presented as the median [minimum–maximum]; *Geometric mean ratio of combination therapy to monotherapy.

Abbreviations: AUC_tau,ss, area under the plasma concentration-time curve during the dosing interval at steady state; CIs, confidence intervals; CL_ss/F, apparent clearance at steady state; C_max,ss, maximum plasma concentration at steady state; GMR, geometric mean ratio; t_1/2,ss, half-life at steady state; T_max,ss, time to reach maximum plasma concentration at steady state; V_d,ss/F, apparent volume of distribution at steady state.

Figure 4 Mean plasma concentration‒time profiles of antihypertensive agents, (A) telmisartan, and (B) amlodipine at steady state after multiple administrations of TA FDC alone and with ER FDC.

Note: Error bars represent the standard deviation.

Abbreviations: ER FDC, fixed-dose combination of 10 mg of ezetimibe and 20 mg of rosuvastatin; TA FDC, fixed-dose combination of 80 mg of telmisartan and 5 mg of amlodipine.

Figure 5 Comparison of C_max,ss and AUC_tau,ss for antihypertensive agents, telmisartan, and amlodipine after multiple administrations of TA FDC alone and with ER FDC.

Abbreviations: AUC_tau,ss, area under the plasma concentration-time curve during the dosing interval at steady state; C_max,ss, maximum plasma concentration at steady state; ER FDC, fixed-dose combination of ezetimibe 20 mg and rosuvastatin 10 mg; TA FDC, fixed-dose combination of telmisartan 80 mg and amlodipine 5 mg.

Table 3 Summary of Adverse Drug Reactions

System Organ Class Preferred Terms	ER FDC (N=35)	TA FDC (N=35)	ER FDC + TA FDC (N=34)
Total	3 (8.57) [6]	4 (11.43) [4]	7 (20.59) [9]
Cardiac disorders	–	–	1 (2.94) [1]
Palpitations	–	–	1 (2.94) [1]
Eye disorders	–	–	1 (2.94) [1]
Photopsia	–	–	1 (2.94) [1]
Gastrointestinal System disorders	1 (2.86) [1]	–	–
Nausea	1 (2.86) [1]	–	–
General disorders and administration site conditions	–	–	1 (2.94) [1]
Noncardiac chest pain	–	–	1 (2.94) [1]
Investigations	–	–	1 (2.94) [1]
Electrocardiogram QT prolonged	–	–	1 (2.94) [1]
Musculoskeletal and connective tissue disorders	–	–	2 (5.88) [2]
Musculoskeletal pain	–	–	1 (2.94) [1]
Myalgia	–	–	1 (2.94) [1]
Nervous System disorders	3 (8.57) [5]	2 (5.71) [2]	2 (5.88) [3]
Dizziness	1 (2.86) [1]	1 (2.86) [1]	2 (5.88) [2]
Headache	3 (8.57) [4]	1 (2.86) [1]	1 (2.94) [1]
Skin and subcutaneous tissue disorders	–	2 (5.71) [2]	–
Rash	–	1 (2.86) [1]	–
Skin mass	–	1 (2.86) [1]	–

Note: The number of subjects (percentage of the subjects) (number of events) is presented.

Abbreviations: ER FDC, fixed-dose combination of ezetimibe 20 mg and rosuvastatin 10 mg; TA FDC, fixed-dose combination of telmisartan 80 mg and amlodipine 5 mg.

Data Sharing Statement

The data supporting the published results of this study will be shared upon a reasonable request made to the corresponding author or sponsor.