Exploratory comparative pharmacokinetic study of a fixed-dose combination of telmisartan/amlodipine/chlorthalidone: half-dose (20/2.5/6.25 mg) versus conventional dose (40/5/12.5 mg)

Abstract

Low-dose combination therapies are recommended when monotherapy fails to control hypertension. This exploratory study aimed to compare the pharmacokinetics (PK) of 2 fixed-dose combinations (FDCs) of telmisartan, amlodipine, and chlorthalidone: half-dose test FDC (20/2.5/6.25 mg) and a conventional-dose reference FDC (40/5/12.5 mg). A randomized, open-label, single-dose, parallel-group study was conducted in healthy participants. Each participant received a single oral dose of either the test or reference FDC. Serial blood samples for telmisartan, amlodipine, and chlorthalidone were collected up to 72 hours post-dose, and PK parameters were calculated using noncompartmental analysis. The mean maximum plasma concentrations (C_max) of telmisartan, amlodipine, and chlorthalidone were 41.34 and 155.75 μg/L, 1.74 and 4.42 μg/L, and 39.36 and 104.86 μg/L for the test and reference FDCs, respectively. The mean area under the concentration-time curves to the last measurable time point (AUC_last) were 659.93 and 1,673.51 h·μg/L for telmisartan, 57.98 and 128.75 h·μg/L for amlodipine, and 831.73 and 1,826.86 h·μg/L for chlorthalidone. The test FDC demonstrated systemic exposure levels ranging from 0.27- to 0.39-fold for telmisartan, 0.39- to 0.44-fold for amlodipine, and 0.38- to 0.46-fold for chlorthalidone, compared to the reference FDC. In conclusion, the PK profiles of the half-dose test FDC were consistent with the known characteristics of the individual components. These provide the first PK data for this half-dose test FDC and may support its potential as an alternative treatment option for hypertension. However, as this was an exploratory study, the results should be interpreted with caution.

Trial Registration

Clinical Research Information Service Identifier: KCT0010166

INTRODUCTION

Hypertension is a modifiable risk factor for cardiovascular morbidity and mortality [1]. Adequate blood pressure (BP) control is therefore essential to prevent complications such as stroke, myocardial infarction, and heart failure. Despite the availability of effective antihypertensive agents, more than 60% of patients fail to achieve target BP with monotherapy alone [2]. According to the 2018 European Society of Cardiology and European Society of Hypertension guidelines, initial combination therapy is preferred over monotherapy in most patients, as monotherapy often fails to achieve adequate BP control and combination approaches yield greater BP reduction [3].

The rationale for combination therapy is based on the additive effects of BP reduction across different antihypertensive classes. Most of the antihypertensive effects are achieved at low doses, while adverse effects are mostly dose-dependent [4]. This pharmacological evidence supports low-dose triple combination (LDTC) therapy as an effective initial approach, involving agents with complementary mechanisms, most often an angiotensin receptor blocker (ARB) or angiotensin-converting enzyme inhibitor combined with a calcium channel blocker (CCB) and a thiazide-like diuretic [3]. The TRIUMPH trial showed that a low-dose triple fixed-dose combination (FDC) of telmisartan 20 mg, amlodipine 2.5 mg, and chlorthalidone 12.5 mg achieved BP control in 70% of patients with mild-to-moderate hypertension, compared to 55% with usual care, without a significant rise in adverse events [5]. A subsequent meta-analysis confirmed that LDTC regimens lead to significantly greater BP reductions than monotherapy or usual care, with a favorable tolerability profile [4].

To implement this strategy in clinical settings, LDTC regimens are best delivered as FDCs, as they enhance medication adherence, reduce costs, and simplify treatment regimens [5,6]. The development of such FDCs should involve lower-than-maximal doses in combination, incorporate agents with distinct mechanisms of action, and ensure availability in a range of dose strengths to allow for titration toward optimal blood pressure control [7]. However, not all patients require or tolerate standard-dose therapy at initiation [7,8]. In this sense, a half-dose FDC offers a clinically meaningful option for patients initiating therapy, including elderly patients, those with mild hypertension, or those at risk of orthostatic hypotension, in whom conventional-dose combinations may result in excessive blood pressure lowering [9,10].

The three components of such a triple FDC-telmisartan, amlodipine, and chlorthalidone-each possess distinct pharmacokinetic (PK) profiles. Telmisartan, an ARB, reaches maximum plasma concentration (C_max) within 0.5 to 1 hours after oral administration. It undergoes metabolism primarily through conjugation to an inactive acyl glucuronide, while most of the administered dose is excreted unchanged in feces via the bile [11]. Telmisartan displays a long half-life of approximately 24.6–27.1 hours [12]. It also exhibits nonlinear PK over the 20 to 160 mg dose range, with greater-than-proportional increases in C_max and area under the curve (AUC) at higher doses, thought to be primarily attributable to saturable hepatic uptake mediated by OATP1B3 [11,13]. Amlodipine, a CCB, reaches C_max within 6–12 hours, and is extensively converted (> 90%) to inactive metabolites. It is a known substrate of CYP3A4 and has a long terminal elimination half-life of 30–50 hours [14]. Chlorthalidone, a thiazide-like diuretic, reaches C_max within 1–6 hours after dosing [15]. It is primarily eliminated as an unchanged drug in the urine and has a terminal elimination half-life of 40–60 hours [16].

Considering the metabolic and elimination pathways of these three components, no PK interactions are anticipated. Consistent with this, no clinically relevant PK interactions were observed between telmisartan and amlodipine, nor between telmisartan and chlorthalidone in previous drug-drug interaction studies [17,18]. This is further supported by the absence of clinically relevant PK interactions reported during the development of the conventional reference FDC (True Set Tab; telmisartan/amlodipine/chlorthalidone 40/5/12.5 mg; Yuhan Corporation, Seoul, Korea) [19].

AD-209 (telmisartan/amlodipine/chlorthalidone 20/2.5/6.25 mg) is a newly developed half-dose FDC formulation. However, no PK data in healthy participants have been available, domestically or internationally, for a triple FDC at these dose strengths. The Ministry of Food and Drug Safety (MFDS) of Korea requested characterization of the PK exposure of this newly developed test FDC (AD-209) prior to approval. Therefore, this study was conducted as an exploratory assessment to characterize the PK exposure of the half-dose test FDC and to compare it with that of the conventional reference FDC, containing the same components. The findings of this study are expected to provide the first PK data for this half-dose test FDC in healthy participants.

METHODS

The protocol of this study was reviewed and approved by the MFDS and by the Institutional Review Board of H Plus Yangi Hospital (Seoul, Korea; HYJ 2024-03-004). This study was registered in the public clinical trial registry of Korea (CRIS registration number: KCT0010166). This study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization for Good Clinical Practice in Korea.

Participants

Healthy participants aged 19 to 55 years, who weighed more than 50 kg for men and 45 kg for women with a body mass index (BMI) between 18.0 and 30.0 kg/m², were included. Their health status was assessed based on medical history, vital signs, physical examinations, and clinical laboratory tests conducted within 30 days prior to hospitalization. Primary exclusion criteria were the following: patients with severe hypotension (systolic BP < 90 mmHg or diastolic BP < 60 mmHg), patients with moderate to severe renal impairment (estimated glomerular filtration rate < 60 mL/min/1.73 m²), patients with electrolyte disturbances (refractory hypokalemia, hyponatremia, or hypercalcemia), and patients with anuria.

Study design

A randomized, open-label, single-dose, parallel-group study was conducted in healthy participants. Because the objective of this study was to characterize PK exposure rather than to formally assess dose proportionality or bioequivalence, a randomized parallel design was considered appropriate, and a sample size of 10 participants per group was considered sufficient for this purpose. Participants were randomly assigned to 1 of 2 treatments and received a single oral dose of the test FDC or the reference FDC with 150 mL of water under fasting conditions.

Serial blood samples for PK assessment were collected at predefined time points up to 72 hours following the administration of the study drug. At each PK sampling point, 5, 7, or 9 mL of blood was collected into EDTA-K2 vacutainer tubes. The volume varied according to the number of analytes scheduled for quantification at that time point, as the sampling schedules differed among telmisartan, amlodipine, and chlorthalidone based on their PK characteristics. For telmisartan, blood samples were obtained at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose. For amlodipine, samples were obtained at pre-dose and 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, and 72 hours post-dose. For chlorthalidone, blood samples were obtained at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose. The samples were centrifuged at 3,000 rpm for 10 minutes. The plasma was separated and dispensed into polypropylene tubes and stored at below −70°C until analysis.

Determination of plasma concentration of telmisartan, amlodipine, and chlorthalidone

Plasma concentrations of telmisartan, amlodipine, and chlorthalidone were measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The analysis was conducted using a Waters ACQUITY UPLC™ system coupled to a Waters Xevo™ TQ-XS mass spectrometer (Waters Corp., Milford, MA, USA), following Good Clinical Laboratory Practice guidelines. Electrospray ionization was used for ionization in the LC-MS/MS analysis.

For telmisartan, 50 µL of plasma was mixed with 50 µL of telmisartan-d7 (internal standard, IS) and 400 µL of acetonitrile. The mixture was vortexed for 10 seconds and centrifuged at 12,000 rpm for 5 minutes at 4°C. The supernatant was then analyzed by LC-MS/MS. Chromatographic separation was performed using an Imtakt Unison UK-C18 column (3 µm, 2.0 × 75 mm) at a flow rate of 0.3 mL/min. Multiple-reaction monitoring (MRM) was conducted for telmisartan and telmisartan-d7, with m/z of 515.30 > 276.30 and 522.40 > 280.30, respectively. The calibration curve was constructed over a concentration range of 0.2 to 800 ng/mL, with a correlation coefficient (r²) of ≥ 0.998402. The accuracy for telmisartan ranged from 99.28% to 101.18%, and the precision coefficient of variation was ≤ 3.18%.

For amlodipine, 100 µL of plasma was mixed with 10 µL of the amlodipine-d4 (IS) and 2,000 µL of methyl tertiary butyl ether. The mixture was vortexed at 2,200 rpm for 10 minutes and then centrifuged at 4,000 rpm for 1 minute at room temperature. The supernatant was then analyzed by LC-MS/MS. Chromatographic separation was performed using an Imtakt Unison UK-C18 column (3 µm, 2.0 × 75 mm) at a flow rate of 0.2 mL/min. MRM was conducted for amlodipine and amlodipine-d4, with m/zof 409.40 > 238.20 and 413.40 > 238.20, respectively. The calibration curve was constructed over a concentration range of 50 to 10,000\\xe2\\x80\\xafpg/mL, with a correlation coefficient (r²) of ≥ 0.998886. The accuracy for amlodipine ranged from 100.34% to 102.67%, and the precision coefficient of variation was ≤ 2.77%.

For chlorthalidone, 200 µL of plasma was mixed with 10 µL of the chlorthalidone-d4 (IS) and 2,000 µL of methyl tertiary butyl ether. The mixture was vortexed at 2,200 rpm for 5 minutes and then centrifuged at 4,000 rpm for 5 minutes at room temperature. The supernatant was then analyzed by LC-MS/MS. Chromatographic separation was performed using an Imtakt Unison UK-C18 column (3 µm, 2.0 × 50 mm) at a flow rate of 0.2 mL/min. MRM was conducted for chlorthalidone and chlorthalidone-d4, with m/z of 337.20 > 146.10 and 341.10 > 150.10, respectively. The calibration curve was constructed over a concentration range of 0.5 to 300 ng/mL, with a correlation coefficient (r²) of ≥ 0.998828. The accuracy for chlorthalidone ranged from 98.23% to 98.86%, and the precision coefficient of variation was ≤ 1.34%.

PK assessment

PK parameters of telmisartan, amlodipine, and chlorthalidone were derived by noncompartmental methods using Phoenix WinNonlin^® (version 8.4; Certara, Princeton, NJ, USA). The C_max and time to reach C_max (T_max) were determined from the observed plasma concentration-time profiles. The area under the plasma concentration-time curve from time 0 to the last measurable time point (AUC_last) was calculated using the linear trapezoidal method. The AUC from time 0 to infinity (AUC_inf) was calculated as AUC_last + C_last/λ_z, where C_last is the last measurable concentration and λ_z is the terminal elimination rate constant. The percentage of AUC_last relative to AUC_inf was calculated as (AUC_last/AUC_inf × 100). Apparent clearance (CL/F) was calculated as dose/AUC_inf, apparent volume of distribution (V_z/F) was calculated as dose/(AUC_inf ∙ λ_z), and terminal half-life (t_1/2) was calculated as ln (2)/λ_z. In addition, dose-normalized C_max (C_max/Dose) and dose-normalized AUC_last (AUC_last/Dose) were calculated.

Safety assessment

Safety profiles were assessed by monitoring adverse events (AEs), vital signs, physical examinations, 12-lead electrocardiogram (ECG), and clinical laboratory tests. The investigators determined the clinical significance and relationship with the treatment of all findings.

Statistical analyses

All statistical analyses were performed via SAS^® (version 9.4; SAS Institute Inc., Cary, NC, USA), and p-values < 0.05 were regarded as statistically significant. Descriptive statistics were presented for continuous data, and frequencies and percentages for each category were presented for categorical data. To compare the AUC_last and C_max after a single oral dose of the test and reference FDCs, the geometric mean ratios (GMRs) were estimated using a linear mixed-effects model with treatment as a fixed effect and participant as a random effect. Statistical differences in dose-normalized PK parameters, AUC_last/Dose and C_max/Dose, between the test and reference FDCs were assessed using either Student’s t-test or the Wilcoxon 2-sample test, based on the results of normality testing, and p-values were reported accordingly.

RESULTS

Participants

A total of 21 healthy participants were enrolled and randomized. One participant withdrew consent prior to administration, and thus, a total of 20 participants, 9 males and 1 female in the test FDC group (n = 10) and 8 males and 2 females in the reference FDC group (n = 10), received the study drug and completed the study (Supplementary Fig. 1).

The demographic characteristics were similar between the test and reference groups. In the reference FDC group, the mean age was 28.50 years, with an average height of 172.73 cm, a mean body weight of 64.63 kg, and a mean BMI of 21.56 kg/m². The corresponding values of test FDC group were 31.20 years, 174.42 cm, 72.20 kg, and 23.69 kg/m² (Supplementary Table 1).

PK assessments

PK was assessed in 20 participants who had a complete PK profile for either the test or reference formulation. Given that the test FDC contains half the dose of the reference FDC, 0.5 was used as the reference value for the GMR of PK parameters, against which the 90% confidence intervals (CIs) were evaluated for dose-proportionality. Telmisartan exhibited a delayed absorption profile in the test FDC, whereas its elimination profile was comparable to that of the reference FDC. Amlodipine and chlorthalidone showed similar absorption and elimination profiles between the test and reference FDCs (Fig. 1, Supplementary Fig. 2).

Figure 1. Mean plasma concentration-time profiles of telmisartan, amlodipine, and chlorthalidone after a single dose of test or reference formulation (left: linear scale, right: log scale). (A) Telmisartan, (B) amlodipine, and (C) chlorthalidone. The bars represent the standard deviation.

Test: AD-209 Tab, telmisartan/amlodipine/chlorthalidone, 20/2.5/6.25 mg; Reference: True set Tab, telmisartan/amlodipine/chlorthalidone, 40/5/12.5 mg.

The median T_max of telmisartan in the test FDC was delayed from 1.75 to 3.5 hours, and the mean t_1/2 was comparable between the test and reference FDCs, with corresponding values of 26.0 and 21.0 hours, respectively. The GMR of C_max for telmisartan was 0.27 in the test FDC compared to the reference FDC, and the 90% CI was below 0.5, whereas the AUC_last was 0.39 with a 90% CI including 0.5 (Table 1).

Table 1. Pharmacokinetic parameters of telmisartan, amlodipine, and chlorthalidone after a single dose of test or reference formulation.

Parameters		Treatment		GMR (90% CI)*
		Test (n = 10)	Reference (n = 10)
Telmisartan (reference 40 mg/test 20 mg)
	Tmax (h)	3.5 [1.5–4.1]	1.75 [1.5–4.0]
	Cmax (μg/L)	41.34 ± 26.34	155.75 ± 104.14	0.2705 (0.1709–0.4282)
	AUClast (h·μg/L)	659.93 ± 321.30	1,673.51 ± 753.09	0.3863 (0.2655–0.5620)
	AUCinf (h·μg/L)	773.19 ± 424.18	1,862.48 ± 866.15
	AUClast/AUCinf (%)	87.67 ± 10.86	90.54 ± 5.94
	t1/2 (h)	26.0 ± 13.6	21.9 ± 5.6
	CL/F (L/h)	33.50 ± 17.13	26.07 ± 11.76
	Vz/F (L)	1,177.96 ± 763.04	792.09 ± 370.36
Amlodipine (reference 5 mg/test 2.5 mg)
	Tmax (h)	5.5 [5.0–6.0]	5.0 [5.0–6.0]
	Cmax (μg/L)	1.74 ± 0.42	4.42 ± 0.77	0.3883 (0.3279–0.4598)
	AUClast (h·μg/L)	57.98 ± 16.00	128.75 ± 27.36	0.4440 (0.3624–0.5439)
	AUCinf (h·μg/L)	80.21 ± 24.27	167.53 ± 38.69
	AUClast/AUCinf (%)	77.43 ± 5.47	72.99 ± 4.99
	t1/2 (h)	37.9 ± 5.5	34.3 ± 5.4
	CL/F (L/h)	34.18 ± 11.82	31.65 ± 8.76
	Vz/F (L)	1,829.53 ± 543.61	1,535.08 ± 352.49
Chlorthalidone (reference 12.5 mg/test 6.25 mg)
	Tmax (h)	1.5 [1.05–4]	1.5 [1–4]
	Cmax (μg/L)	39.36 ± 12.14	104.86 ± 36.30	0.3802 (0.2959–0.4885)
	AUClast (h·μg/L)	831.73 ± 152.80	1,826.86 ± 413.65	0.4578 (0.3934–0.5328)
	AUCinf (h·μg/L)	1,399.8 ± 377.00	2,719.98 ± 513.15
	AUClast/AUCinf (%)	67.45 ± 9.48	60.67 ± 6.05
	t1/2 (h)	56.5 ± 11.2	48.1 ± 13.9
	CL/F (L/h)	4.74 ± 1.17	4.74 ± 0.84
	Vz/F (L)	371.93 ± 46.72	324.68 ± 86.22

Data are presented as mean ± standard deviation, except for T_max, which is presented as median [minimum–maximum].

Test: AD-209 Tab, telmisartan/amlodipine/chlorthalidone 20/2.5/6.25 mg; Reference: True Set Tab, telmisartan/amlodipine/chlorthalidone 40/5/12.5 mg.

GMR, geometric mean ratio; CI, confidence interval; C_max, maximum plasma concentration; AUC_last, area under the plasma concentration-time curve from time 0 to last measurable time point; AUC_inf, area under the concentration-time curve from time of 0 to infinity; AUC_last/AUC_inf, percentage of AUC_last relative to AUC_inf; T_max, time to reach C_max; CL/F, apparent clearance; V_z/F, apparent volume of distribution; t_1/2, terminal half-life.

^*GMR and 90% CI of test to reference.

Both the median T_max and mean t_1/2 of amlodipine were similar between the test and reference FDCs, at 5.5 and 5 hours and 37.9 and 34.3 hours, respectively. The GMR of C_max for amlodipine was 0.39 in the test FDC compared to the reference FDC, and the 90% CI was below 0.5, whereas the GMR of AUC_last was 0.44 with a 90% CI including 0.5 (Table 1).

The median T_max of chlorthalidone was 1.5 hours in both test and reference FDCs. The mean t_1/2 was 56.5 and 48.1 hours, respectively. The GMR of C_max for chlorthalidone was 0.38 in the test FDC compared to the reference FDC, and the 90% CI was below 0.5, whereas the GMR of AUC_last was 0.46 with a 90% CI including 0.5 (Table 1).

No statistical differences in dose-normalized C_max were observed between the test and reference FDCs for telmisartan and chlorthalidone (p > 0.05), whereas a statistical difference was noted for amlodipine (p = 0.0184). No statistical differences were observed in the dose-normalized AUC_last between the test and reference FDCs for telmisartan, amlodipine, and chlorthalidone (p > 0.05) (Table 2, Fig. 2).

Table 2. Comparison of dose-normalized C_max and AUC_last of telmisartan, amlodipine, and chlorthalidone after a single dose of test or reference formulation.

Parameters		Treatment		p-value*
		Test (n = 10)	Reference (n = 10)
Telmisartan (test 20 mg/reference 40 mg)
	Cmax/Dose (μg/L/mg)	2.07 ± 1.32	3.89 ± 2.60	0.0596
	AUClast/Dose (h·μg/L/mg)	33.00 ± 16.07	41.84 ± 18.83	0.3955
Amlodipine (test 2.5 mg/reference 5 mg)
	Cmax/Dose (μg/L/mg)	0.70 ± 0.17	0.88 ± 0.16	0.0184
	AUClast/Dose (h·μg/L/mg)	23.19 ± 6.40	25.75 ± 5.47	0.3494
Chlorthalidone (test 6.25 mg/reference 12.5 mg)
	Cmax/Dose (μg/L/mg)	6.30 ± 1.94	8.39 ± 2.90	0.0745
	AUClast/Dose (h·μg/L/mg)	133.08 ± 24.48	146.15 ± 33.09	0.3284

Data are presented as mean ± standard deviation.

Test: AD-209 Tab, telmisartan/amlodipine/chlorthalidone 20/2.5/6.25 mg; Reference: True Set Tab, telmisartan/amlodipine/chlorthalidone 40/5/12.5 mg.

C_max, maximum plasma concentration; AUC_last, area under the plasma concentration-time curve from time 0 to the last measurable time point; C_max/Dose, dose-normalized maximum plasma concentration; AUC_last/Dose, dose-normalized area under the plasma concentration-time curve from time 0 to the last measurable time point.

^*Wilcoxon 2-sample test for telmisartan, Student’s t-test for amlodipine and chlorthalidone.

Figure 2. Comparison of dose-normalized pharmacokinetic parameters (C_max/Dose, AUC_last/Dose) of telmisartan, amlodipine, and chlorthalidone between test and reference formulation (left: C_max/Dose, right: AUC_last/Dose). (A) Telmisartan, (B) amlodipine, and (C) chlorthalidone.

C_max/Dose, dose-normalized maximum plasma concentration; AUC_last/Dose, dose-normalized area under the plasma concentration-time curve from time 0 to the last measurable time point.

Safety assessments

Safety was assessed in all 20 participants who received at least one dose of the study drug. No serious adverse events were reported during the study. One AE (urine ketone body present) occurred in 1 out of 10 participants (10.0%) who received the reference FDC, which was mild. No clinically significant changes were observed in vital signs, laboratory test results, 12-lead ECGs, or physical examinations at the end of the study.

DISCUSSION

This exploratory study was conducted to characterize the PK of a half-dose test FDC of telmisartan, amlodipine, and chlorthalidone (AD-209 Tab; 20/2.5/6.25 mg), for which no prior PK data in healthy participants were available. Existing data have been limited to the highest marketed strength (True Set Tab; 40/5/12.5 mg), and to our knowledge, this study provides the first PK data for this half-dose triple FDC in healthy participants.

Following the FDA guidance for bioequivalence studies, blood sampling was conducted up to 72 hours post-dose. The AUC_last/AUC_inf ratios were 87.67–90.54% for telmisartan, and 72.99–77.43% and 60.67–67.45% for amlodipine and chlorthalidone, respectively. The ratios for telmisartan exceeded 80%, indicating adequate characterization of the terminal phase. Given the long elimination half-lives of chlorthalidone (40–60 hours) and amlodipine (30–50 hours), AUC_0-72h (equivalent to AUC_last in this study) was used as the primary AUC parameter for analysis, consistent with regulatory recommendations for long half-life drugs. In total, at least 12 sampling points were collected, including at least 2 sampling points prior to C_max.

The concentration-time profiles of amlodipine and chlorthalidone were comparable between the test and reference FDCs, indicating similar absorption and elimination characteristics. However, the median T_max of telmisartan was 3.5 hours for the test formulation and 1.75 hours for the reference formulation. This observation is consistent with previous reports showing that the T_max of telmisartan decreases with increasing dose, with values of approximately 3.0 hours at 20 mg and 1.0 hours at 120 mg in healthy participants [11,12]. Although formulation-related differences, such as excipient composition and ratios, cannot be entirely ruled out as contributing factors, their impact is likely to be minimal given that both formulations were manufactured using the same process. Therefore, dose-dependent PK behavior remains the more plausible explanation for these findings.

In the test FDC, the systemic exposure of telmisartan, amlodipine, and chlorthalidone was generally less than half of that in the reference FDC. As this study was not designed to assess bioequivalence, the conventional 80–125% criteria were not applied. Instead, 0.5 was used as the reference value for dose-proportionality, given that the test FDC contains half the dose of the reference FDC. The GMRs of C_max for telmisartan, amlodipine, and chlorthalidone were 0.27-, 0.39-, and 0.38-fold relative to the reference FDC, respectively. As the 90% CIs for all components did not include 0.5, this suggests less-than-dose-proportional peak exposure. In contrast, the corresponding GMRs of AUC_last were 0.39-, 0.44-, and 0.46-fold relative to the reference FDC, respectively. The 90% CIs of AUC_last for all components included 0.5, suggesting dose-proportional systemic exposure. However, given the exploratory nature and limited sample size of this study, these findings should be interpreted with caution.

Among the three components, telmisartan showed particularly low C_max and AUC_last ratios, both of which are consistent with its established nonlinear PK. This finding may be attributed to incomplete saturation of OATP1B3-mediated hepatic uptake at the lower dose. As OATP1B3-mediated uptake becomes less saturated at lower telmisartan concentrations, enhanced hepatic first-pass extraction is expected, which would disproportionately reduce C_max compared with AUC_last [13]. In contrast, the AUC_last ratios of amlodipine and chlorthalidone both approximated the administered dose ratio of 0.5, suggesting dose-proportional systemic exposure for these two components. This finding is consistent with amlodipine’s finding well-established linear, dose-proportional PK across the therapeutic dose range [20]. Chlorthalidone has been reported to exhibit a relatively flat dose-concentration relationship at higher doses (≥ 50 mg), with a 4-fold increase in dose yielding only a 2-fold increase in serum concentrations [21]. However, the PK characteristics of chlorthalidone at low doses, including the 6.25 mg dose used in the present study, have not been established.

No statistically significant differences were observed in the dose-normalized parameters, except for the C_max of amlodipine. The decrease observed in amlodipine C_max was consistent with previously established findings in healthy participants, in which a 2.5 mg dose exhibited approximately 10–20% lower dose-normalized C_max and AUC than higher doses [22]. Therefore, the variability observed in this study may be considered predictable based on these established PK characteristics.

Although the systemic exposure of telmisartan, amlodipine, and chlorthalidone in the test FDC was generally less than half of that in the reference FDC, this does not necessarily imply a proportional reduction in antihypertensive efficacy. The dose-response relationship of antihypertensive agents is well established as non-linear, with higher doses yielding diminishing incremental efficacy while substantially increasing the risk of adverse effects [23]. Furthermore, the additive antihypertensive effects of combining agents with complementary mechanisms of action are largely preserved at low doses [24], and antihypertensive efficacy at the respective doses of each component in the test FDC has also been individually demonstrated [25,26,27].

A phase II randomized trial conducted in Korean patients with essential hypertension assessed various low-dose ranges of a once-daily FDC tablet containing telmisartan, amlodipine, and chlorthalidone. The half-dose combinations (telmisartan/amlodipine/chlorthalidone 20/2.5/6.25 mg) provided superior BP reduction over 8 weeks compared with amlodipine or telmisartan monotherapy, without increasing adverse events [28,29]. These findings collectively support the idea that antihypertensive efficacy and safety are preserved at the lower exposure levels of the test FDC.

This study also has several limitations. Given the exploratory nature of this study, its limited sample size (n = 20), and the adoption of a parallel design, intra-individual variability could not be adequately assessed. While a crossover design would have been more appropriate to minimize intra-individual variability, particularly given the high PK variability of telmisartan, a crossover bioequivalence study was already conducted during the development of the reference FDC [19]. In accordance with regulatory guidelines, additional clinical studies may not be necessary for FDCs developed at proportionally scaled doses of an already-approved formulation [7]. In this context, although the parallel design was considered acceptable given the existing regulatory framework and the exploratory nature of this study, a crossover design would have provided more robust PK comparisons between the 2 formulations.

Another limitation relates to the high PK variability observed in this study, as evidenced by the broad standard deviations in C_max and AUC_last of telmisartan. This is consistent with its classification as a highly variable drug [30]. Furthermore, the potential influence of sex imbalance between the 2 groups (test: 9 males, 1 female; reference: 8 males, 2 females) also cannot be entirely excluded, as plasma concentrations of telmisartan are generally 2 to 3 times higher in females than in males [11]. This imbalance may have influenced telmisartan exposure to some extent, and the results should be interpreted accordingly.

In conclusion, the PK profiles of the half-dose test FDC (AD-209 Tab; telmisartan/amlodipine/chlorthalidone 20/2.5/6.25 mg) were consistent with the known PK characteristics of the individual components [11,12,13,20,21,22]. These provide the first PK data for this low-dose triple FDC and may support its potential as an alternative treatment option for hypertension. However, as this was an exploratory study, the results should be interpreted with caution.

SUPPLEMENTARY MATERIALS

Supplementary Table 1

Demographic characteristics

Supplementary Figure 1

Subjects disposition.

Supplementary Figure 2

Mean plasma concentration-time profiles of telmisartan, amlodipine, and chlorthalidone over the first 12 hours after a single dose of test or reference formulation. (A) Telmisartan, (B) amlodipine, and (C) chlorthalidone. The bars represent the standard deviation.