Abstract
Management of hypertension and hyperlipidemia is important to reduce the risk of cardiovascular disease, and a fixed-dose combination (FDC) of antihypertensive and lipid-lowering drugs is expected to reduce the pill burden and increase patient compliance. The aim of this study was to compare the pharmacokinetics (PKs) of candesartan, amlodipine, and atorvastatin FDC versus separate tablets. A randomized, open-label, single-dose, 2-treatment, 3-sequence, 3-period, partial replicated crossover study was conducted in healthy subjects. A total of 51 subjects were randomized into 1 of 3 sequences and received a single dose of either an FDC or separate tablets of candesartan 8 mg, amlodipine 5 mg, and atorvastatin 10 mg, with a 14-day washout period in between. Plasma samples were collected up to 72 hours after dosing. Plasma concentrations of candesartan, amlodipine and atorvastatin were assayed using a validated LC-MS/MS method, and PK parameters were determined by noncompartmental analysis. As a result, 43 subjects were included in PK analysis for candesartan, atorvastatin, and 42 subjects were included in PK analysis for amlodipine. The geometric mean ratios (90% confidence intervals) of the area under the plasma concentration-time curve from time zero to the last sampling time and maximum plasma concentration were 0.9637 (0.9192–1.0104) and 0.9360 (0.8885–0.9861) for candesartan, 0.9694 (0.9417–0.9978) and 0.9930 (0.9575–1.0299) for amlodipine, and 1.0350 (0.9891–1.0831) and 1.0658 (0.9370–1.2123) for atorvastatin, respectively. This study suggested that the FDC formulation of candesartan, amlodipine, and atorvastatin showed PK equivalence compared to separate tablets.
Trial Registration
ClinicalTrials.gov Identifier: NCT04611932
Keywords: Pharmacokinetics, Bioequivalence, Candesartan, Amlodipine, Atorvastatin
INTRODUCTION
Hypertension and hyperlipidemia, 2 major risk factors for cardiovascular disease (CVD), are often reported concurrently in patients and increase the incidence of CVD more than either condition alone [1]. Therefore, strict management of blood pressure and lipid levels is required to reduce the risk of CVD in patients who have both hypertension and hyperlipidemia. However, in South Korea, the percentage of patients whose hypercholesterolemia is adequately controlled remains at 54.1% [2], indicating that a substantial proportion of patients do not achieve target lipid levels despite treatment. Although the rate of lipid-lowering medication use has been increasing continuously [3], problems of non-adherence or discontinuation of medication persist, contributing to suboptimal control rates [4]. Similar statistics are reported for hypertension [5], except that the treatment rate for hypertension is higher (74%) than the treatment rate for hyperlipidemia (61%) in South Korea [2,5]. Hence, it is important to increase the treatment rate and control rates of both hyperlipidemia and hypertension by increasing the adherence to the therapy.
Several guidelines are set to guide the treatment of hyperlipidemia and hypertension, such as the Guideline on the Management of Blood Cholesterol [6] and 2020 International Society of Hypertension Global Hypertension Practice Guidelines [7]. For hyperlipidemia, the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly known as statins, are recommended as lipid-lowering agents [6]. For hypertension, the initial therapy generally includes using primary agents such as thiazide diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) alone or in combination [7]. Evidence supports that the combination of 2 or more antihypertensive drugs is much more effective in lowering blood pressure [8]. Based on these guidelines, combination therapies that include one or 2 antihypertensive agents and one statin are common in practice.
Candesartan/amlodipine and atorvastatin are widely used clinically for the treatment and prevention of hypertension and hyperlipidemia, respectively. Candesartan cilexetil is an ARB with indications for essential hypertension and heart failure, and selectively acts on the angiotensin II receptor, which acts as a potent vasoconstrictor in the renin-angiotensin-aldosterone system, especially affecting the AT1 receptor, which is involved in major physiological functions such as vasoconstriction [9]. Amlodipine, a dihydropyridine CCB with indications for hypertension and angina, relaxes the vascular smooth muscle [10]. Atorvastatin is an inhibitor of HMG-CoA reductase with indications for the prevention of hypercholesterolemia and CVD. Atorvastatin not only effectively lowers low density lipoprotein cholesterol but also prevents cardiovascular events in hypertensive patients [11].
The combination of candesartan/amlodipine/atorvastatin is expected to provide comprehensive management of blood pressure and lipid levels in patients with coexisting hypertension and hyperlipidemia, concurrently improving patient compliance. Thus, the objective of this study was to compare the pharmacokinetic (PK) parameters of a candesartan/amlodipine/atorvastatin fixed-dose combination (FDC) tablet with those of an individual administration of candesartan/amlodipine and atorvastatin, after a single oral administration in healthy subjects with a partial replicated crossover design based on the scaled bioequivalence criteria for highly variable drugs.
METHODS
This study was approved by the Ministry of Food and Drug Safety (Cheongju, Republic of Korea) and the Institutional Review Board (IRB) of Jeonbuk National University Hospital (Jeonju, Republic of Korea). It was conducted according to the principles of the Declaration of Helsinki for biomedical research involving human subjects and the Guidelines for Good Clinical Practice (ClinicalTrials.gov Identifier: NCT04611932, IRB number: CUH2019-10-053). All participants had signed written informed consents after a detailed explanation of the study was provided.
Study population
Healthy Korean adult volunteers aged 19–54 years, with a body mass index (BMI) in the range of 17.5 or more and less than 30.5 kg/m2, and a total body weight of males ≥ 55 kg and females ≥ 45 kg, were enrolled in the study. The volunteers were excluded if they had clinically significant abnormalities identified in their medical history, vital signs, physical examination, 12-lead electrocardiogram (ECG), or clinical laboratory test (i.e., hematology, blood chemistry, urinalysis, and serology). Individuals who had participated in another clinical study within 6 months prior to the first administration of the investigational products or had taken prescription or over-the-counter drugs within 10 days prior to the first administration of the investigational products were excluded. The volunteers were excluded if they had allergies to candesartan, amlodipine, atorvastatin, or dihydropyridine drugs. The subjects were restricted from consuming grapefruit from 7 days before the first administration of the investigational products until the end of PKs sampling. Alcohol was restricted from 24 hours before hospitalization until the end of PK sampling, and caffeine and smoking were prohibited during hospitalization.
Study design
A randomized, open-label, single-dose, 3-sequence, 3-period partial replicated crossover study was conducted. The eligible subjects were randomly assigned to one of 3 sequence groups (Table 1). A partial replicated crossover design was selected instead of a full replicated design to reduce subject burden while maintaining sufficient statistical power for PK equivalence evaluation, and it was also to reduce the duration of the clinical trial and reduce the total blood volume required for PK assessment. The reference drug was separate tablets of candesartan cilexetil/amlodipine FDC and atorvastatin (co-administration of Cantabell Tab. 8/5 mg, Chong Kun Dang Pharmaceutical Corp., Seoul, Republic of Korea, and Lipitor Tab. 10 mg, Pfizer Pharmaceutical Korea Ltd., Seoul, Republic of Korea, or Treatment A), and the test drug was an FDC consisting of candesartan cilexetil 8 mg, amlodipine 5 mg, and atorvastatin 10 mg (CKD-333 8/5/10 mg, Chong Kun Dang Pharmaceutical Corp., or Treatment B). Washout period was 14 days between each period, which was sufficient for the drug to be excreted from the body that was at least 5 times the terminal elimination half-life (t1/2) of candesartan cilexetil, amlodipine, and atorvastatin.
Table 1. Study design by sequence groups.
| Sequence | No. of subjects | Period 1 | Period 2 | Period 3 |
|---|---|---|---|---|
| 1 | 17 | Treatment A | Treatment A | Treatment B |
| 2 | 17 | Treatment A | Treatment B | Treatment A |
| 3 | 17 | Treatment B | Treatment A | Treatment A |
Treatment A: Coadministration of Cantabell Tab. 8/5 mg and Lipitor Tab. 10 mg. Treatment B: Administration of CKD-333 8/5/10 mg.
The subjects were hospitalized in Jeonbuk National University Hospital a day before administration of the investigational products and the investigational products were administered in fasting state (at least 10 hours). Water was restricted from 1 hour prior to the administration to 1 hour after the administration. On day 1, the subjects received investigational products with 150 mL of water in each period according to the assigned sequence group. The subjects were discharged on the morning of day 2 and outpatient visits were conducted on days 3 and 4. PK blood samples for determination of the candesartan concentration were collected at pre-dose (0 hour) and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, and 48 hours post-dose; at pre-dose (0 hour) and 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, and 72 hours post-dose for amlodipine; and at pre-dose (0 hour) and 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose for atorvastatin. The blood samples were centrifuged at 1,800 ×g at 4°C for 10 minutes within 1 hour after collection, and the plasma aliquots were stored at −80 to −60°C until further analysis.
PK assessments
Plasma concentrations of candesartan were determined by a validated ultra performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS; Waters ACQUITY UPLCTM System, Waters, MA, USA). The lower limit of quantitation (LLOQ) was 5.00 ng/mL. A Waters ACQUITY UPLC® BEH C18, 1.7 um (2.1 mm ID × 50 mm L) column was used for chromatographic separation by stationary phase. The mobile phase consisted of a mixture of 0.1% (v/v) formic acid in distilled water (mobile phase A) and 0.1% (v/v) formic acid in acetonitrile (mobile phase B) at a flow rate of 0.4 mL/min. After stirring for 3 minutes at 1,500 rpm and centrifuging for 1 minutes at 4,000 rpm, and injection volume was 10 uL. An electrospray ionization in positive ion mode was used for detection and quantification. The multiple reaction monitoring (MRM) was m/z 440.92 to 262.95 for candesartan and 445.98 to 267.95 for the internal standard (IS). Candesartan-d5 was used as the IS for analytes, and drug-to-IS ratios were used to create a linear calibration curve using a 1/x2 weighted least squares regression analysis. The calibration curve was 5.00–1,000 ng/mL for candesartan (correlation coefficient r2 exceeding 0.9988). The within- and between-run of accuracy and precision for the analyses were within 15% of the theoretical concentration.
For amlodipine, UPLC-MS/MS (Waters ACQUITY UPLCTM System) was used to determine plasma concentrations and the LLOQ was 0.05 ng/mL. A Waters ACQUITY UPLC® BEH C18, 1.7 um (2.1 mm ID × 50 mm L) column was used for chromatographic separation by stationary phase. The mobile phase consisted of a mixture of 0.1% (v/v) formic acid in distilled water (mobile phase A) and 0.1% (v/v) formic acid in acetonitrile (mobile phase B) at a flow rate of 0.6 mL/min. After stirring for 3 minutes at 1,500 rpm and centrifuging for 1 minutes at 4,000 rpm, and injection volume was 20 uL. An electrospray ionization in positive ion mode was used for detection and quantification. The MRM was m/z 409.15 to 237.95 for amlodipine and 413.2 to 237.9 for the IS. Amlodipine-d4 was used as the IS for analytes, and drug-to-IS ratios were used to create a linear calibration curve using a 1/x2 weighted least squares regression analysis. The calibration curve was 0.05–50 ng/mL for candesartan (correlation coefficient r2 exceeding 0.9992). The within- and between-run of accuracy and precision for the analyses were within 15% of the theoretical concentration.
For atorvastatin, UPLC-MS/MS; Waters ACQUITY UPLCTM System) was used to determine plasma concentrations and the LLOQ was 0.1 ng/mL. A Waters ACQUITY UPLC® BEH C18, 1.7 um (2.1 mm ID × 50 mm L) column was used for chromatographic separation by stationary phase. The mobile phase consisted of a mixture of 0.1% (v/v) ammonium acetate in distilled water (mobile phase A) and acetonitrile (mobile phase B). After stirring for 3 minutes at 1,500 rpm and centrifuging for 1 minutes at 4,000 rpm, and injection volume was 5 uL. An electrospray ionization in positive ion mode was used for detection and quantification. The MRM was m/z 559.50 to 440.35 for atorvastatin and 564.50 to 445.40 for the IS. Atorvastatin-d5 was used as the IS for analytes, and drug-to-IS ratios were used to create a linear calibration curve using a 1/x2 weighted least squares regression analysis. The calibration curve was 0.1–200 ng/mL for atorvastatin (correlation coefficient r2 exceeding 0.9993). The within- and between-run of accuracy and precision for each analysis were all within 15% of the theoretical concentration. All these assays were validated according to the Bioanalytical Method Validation Guideline of the Korean Ministry of Food and Drug Safety.
Individual PK parameters were determined by non-compartmental method, using Phoenix® WinNonlin® software (version 8.2, CERTARA, Radnor, PA, USA). The maximum plasma concentration (Cmax) and Tmax were obtained from the plasma concentration-time profiles. The t1/2 was calculated as ln 2/λz, where λz was the elimination rate constant and was estimated by the linear regression of the log-transformed plasma concentration-time in the terminal phase. The area under the plasma concentration-time curve from time zero to the last sampling time (AUCt) was calculated using the linear trapezoidal method. The area under the plasma concentration-time curve to infinity (AUCinf) was estimated using the formula AUCt + Ct/λz, where Ct was the last measured concentration. Apparent total plasma clearance (CL/F) was calculated as Dose/AUCinf. Volume of distribution (Vd/F) was calculated as Dose/(AUCinf ·λz). Only data from subjects who completed the study were included in the statistical analysis of PKs.
Safety assessments
All subjects who received at least one dose of the test or reference drugs were included in the safety analysis. Safety was assessed by adverse events (AEs) monitoring, laboratory tests, vital sign measurements, physical examinations, and 12-lead ECGs. AEs were summarized by treatment groups in terms of severity and relationship to the investigational products. Laboratory tests, vital signs, physical examinations, and ECGs were reviewed for clinical significance in individual subjects and presented using descriptive statistics by treatment groups.
Statistical analysis
Statistical analysis was performed using SAS® (version 9.4; SAS Institute Inc., Cary, NC, USA). The log-transformed PK parameters of AUCt and Cmax were analyzed using a mixed-effects analysis of variance (ANOVA) model, with a fixed effects for sequence, period, and treatment and a random effect for subject nested within the sequence, to compare the PK parameters of the 2 treatments. Based on this analysis, the test and reference drugs were assumed to be bioequivalent when the 90% confidence intervals (CIs) for the geometric mean ratio (test/reference) were in the range of 0.80–1.25 for the AUCt and Cmax for candesartan and amlodipine. For the Cmax of atorvastatin, the 90% CIs was calculated using exp [± 0.760 × (Within-Subject Coefficient of Variation (CVw))], where CVw is the intra-subject standard deviation (SD) of the log-transformed values of Cmax of the reference drug estimated by this study results.
RESULTS
Subjects
A total of 52 healthy Korean subjects were enrolled in the study. Out of these, 51 subjects randomly assigned to one of 3 sequence groups (Table 1). There were 11 drop-out subjects after randomization; 7 subjects withdrew consent, 3 subjects dropped out because the investigator decided that the study should be stopped by other reasons, and 1 subject dropped out because they did not follow the precautions or could not comply with the protocol. PK evaluation was performed on 43 subjects for candesartan, and atorvastatin and on 42 subjects for amlodipine; among the drop-out subjects, 3 subjects who completed the blood collection until period 3 were included in the PK analysis for all components; one subject was excluded from the PK analysis for amlodipine because the pre-dose concentration in period 2 and 3 exceeded 5% of Cmax. The demographic information of the subjects (mean ± SD) included the age of 26.69 ± 7.17 years, height of 173.01 ± 7.09 cm, weight of 72.99 ± 11.39 kg, and BMI of 24.35 ± 3.20 kg/m2. There subjects included 43 male and 8 female participants. There was no significant difference among the sequence groups in demographic characteristics.
PK analysis
The geometric mean plasma concentration-time curves of candesartan and its log transformation of the 2 treatments following a single dose are shown in Fig. 1. Fig. 2 shows the geometric mean plasma concentration-time profiles of amlodipine following a single dose administration. Fig. 3 shows the geometric mean plasma concentration-time profiles of atorvastatin following a single dose administration. The plasma PK parameters (mean ± SD) for candesartan, amlodipine, and atorvastatin, are summarized in Tables 2, 3, 4, respectively. The point estimates (90% CIs) of AUCt and Cmax for candesartan were 0.9637 (0.9192–1.0104) and 0.9360 (0.8885–0.9861), respectively; for amlodipine, the values were 0.9694 (0.9417–0.9978) and 0.9930 (0.9575–1.0299), respectively; for atorvastatin, the values were 1.0350 (0.9891–1.0831) and 1.0658 (0.9370–1.2123), respectively. For all drug constituents, the 90% CIs fell within the bioequivalence criteria (Table 5).
Figure 1. Plasma concentration-time profiles of candesartan in linear (A) and semi-logarithmic (B) scale. Treatment A: Fixed-dose combination of candesartan 8 mg/amlodipine 5 mg + atorvastatin 10 mg. Treatment B: Fixed-dose combination of candesartan 8 mg/amlodipine 5 mg/atorvastatin 10 mg.
Figure 2. Plasma concentration-time profiles of amlodipine in linear (A) and semi-logarithmic (B) scale. Treatment A: Fixed-dose combination of candesartan 8 mg/amlodipine 5 mg + atorvastatin 10 mg. Treatment B: Fixed-dose combination of candesartan 8 mg/amlodipine 5 mg/atorvastatin 10 mg.
Figure 3. Plasma concentration-time profiles of atorvastatin in linear (A) and semi-logarithmic (B) scale. Treatment A: Fixed-dose combination of candesartan 8 mg/amlodipine 5 mg + atorvastatin 10 mg. Treatment B: Fixed-dose combination of candesartan 8 mg/amlodipine 5 mg/atorvastatin 10 mg.
Table 2. Summary of pharmacokinetic parameters of candesartan.
| Parameter (unit) | Treatment A (n = 86) | Treatment B (n = 43) |
|---|---|---|
| AUCt (h·ng/mL) | 957.35 ± 278.08 | 921.84 ± 263.97 |
| Cmax (ng/mL) | 104.70 ± 26.55 | 98.49 ± 28.89 |
| AUCinf (h·ng/mL) | 1,046.29 ± 292.10 | 1,020.45 ± 288.02 |
| Tmax (h) | 5.00 (2.00−7.00) | 5.00 (1.50−7.00) |
| t1/2 (h) | 6.34 ± 1.88 | 6.60 ± 1.91 |
| CL/F (L/h) | 8.30 ± 2.54 | 8.50 ± 2.48 |
| Vd/F (L) | 72.16 ± 19.22 | 78.60 ± 29.77 |
Data are presented as arithmetic mean ± standard deviation, except for Tmax presented as median (minimum–maximum). Treatment A: Coadministration of Cantabell Tab. 8/5 mg and Lipitor Tab. 10 mg (atorvastatin calcium trihydrate). Treatment B: Administration of CKD-333 8/5/10 mg.
AUCt, area under the plasma concentration-time curve from time zero to the last sampling time; Cmax, maximum plasma concentration; AUCinf, area under the plasma concentration-time curve to infinity; Tmax, time to maximum plasma concentration; t1/2, terminal elimination half-life; CL/F, apparent total plasma clearance; Vd/F, volume of distribution.
Table 3. Summary of pharmacokinetic parameters of amlodipine.
| Parameter (unit) | Treatment A (n = 86) | Treatment B (n = 43) |
|---|---|---|
| AUCt (h·ng/mL) | 120.72 ± 24.57 | 116.99 ± 24.45 |
| Cmax (ng/mL) | 3.97 ± 0.81 | 3.93 ± 0.81 |
| AUCinf (h·ng/mL) | 169.36 ± 43.42 | 164.75 ± 41.30 |
| Tmax (h) | 5.00 (3.00−7.00) | 5.00 (5.00−6.00) |
| t1/2 (h) | 40.20 ± 11.40 | 40.43 ± 9.14 |
| CL/F (L/h) | 31.32 ± 7.59 | 32.09 ± 7.72 |
| Vd/F (L) | 1,763.05 ± 437.28 | 1,839.64 ± 484.74 |
Data are presented as arithmetic mean ± standard deviation, except for Tmax presented as median (minimum–maximum). Treatment A: Coadministration of Cantabell Tab. 8/5 mg and Lipitor Tab. 10 mg (atorvastatin calcium trihydrate). Treatment B: Administration of CKD-333 8/5/10 mg.
AUCt, area under the plasma concentration-time curve from time zero to the last sampling time; Cmax, maximum plasma concentration; AUCinf, area under the plasma concentration-time curve to infinity; Tmax, time to maximum plasma concentration; t1/2, terminal elimination half-life; CL/F, apparent total plasma clearance; Vd/F, volume of distribution.
Table 4. Summary of pharmacokinetic parameters of atorvastatin.
| Parameter (unit) | Treatment A (n = 86) | Treatment B (n = 43) |
|---|---|---|
| AUCt (h·ng/mL) | 22.05 ± 7.81 | 22.88 ± 8.93 |
| Cmax (ng/mL) | 4.70 ± 2.75 | 4.74 ± 2.54 |
| AUCinf (h·ng/mL) | 25.28 ± 8.56 | 26.35 ± 9.26 |
| Tmax (h) | 0.75 (0.33−6.00) | 0.75 (0.33−3.00) |
| t1/2 (h) | 9.81 ± 3.56 | 9.55 ± 3.80 |
| CL/F (L/h) | 440.59 ± 146.06 | 419.74 ± 128.56 |
| Vd/F (L) | 5,999.55 ± 2,307.47 | 5,645.05 ± 2,400.31 |
Data are presented as arithmetic mean ± standard deviation, except for Tmax presented as median (minimum–maximum). Treatment A: Coadministration of Cantabell Tab. 8/5 mg and Lipitor Tab. 10 mg (atorvastatin calcium trihydrate), Treatment B: Administration of CKD-333 8/5/10 mg.
AUCt, area under the plasma concentration-time curve from time zero to the last sampling time; Cmax, maximum plasma concentration; AUCinf, area under the plasma concentration-time curve to infinity; Tmax, time to maximum plasma concentration; t1/2, terminal elimination half-life; CL/F, apparent total plasma clearance; Vd/F, volume of distribution.
Table 5. Geometric mean ratio and 90% confidence interval of candesartan, amlodipine and atorvastatin.
| Drug constituents | Pharmacokinetic parameter (unit) | Geometric LS mean | Geometric LS mean ratio (Treatment B/Treatment A) | Acceptance range* | CVWR †(%) | CVW ‡(%) | ||
|---|---|---|---|---|---|---|---|---|
| Treatment B | Treatment A | Point estimate | 90% confidence interval | |||||
| Candesartan | AUCt (h·ng/mL) | 889.76 | 923.24 | 0.9637 | 0.9192–1.0104 | 0.8000–1.2500 | 16.24 | 15.29 |
| Cmax (ng/mL) | 95.31 | 101.82 | 0.9360 | 0.8885–0.9861 | 0.8000–1.2500 | 18.30 | 16.86 | |
| Amlodipine | AUCt (h·ng/mL) | 114.27 | 117.88 | 0.9694 | 0.9417–0.9978 | 0.8000–1.2500 | 10.40 | 9.22 |
| Cmax (ng/mL) | 3.85 | 3.87 | 0.9930 | 0.9575–1.0299 | 0.8000–1.2500 | 11.46 | 11.61 | |
| Atorvastatin | AUCt (h·ng/mL) | 21.54 | 20.81 | 1.0350 | 0.9891–1.0831 | 0.8894–1.1243 | 15.51 | 14.67 |
| Cmax (ng/mL) | 4.31 | 4.04 | 1.0658 | 0.9370–1.2123 | 0.7158–1.3970 | 46.21 | 43.25 | |
Treatment A: Coadministration of Cantabell Tab. 8/5 mg and Lipitor Tab. 10 mg (atorvastatin calcium trihydrate), Treatment B: Administration of CKD-333 8/5/10 mg.
LS, least squares; AUCt, area under the plasma concentration-time curve from time zero to the last sampling time; Cmax, maximum plasma concentration; CVWR, within-subject coefficient of variation of the reference; CVW, within-subject coefficient of variation.
*For atorvastatin only. [Upper Limit, Lower Limit] = exp[± 0.760 × (Within-Subject Coefficient of Variation for Cmax of the Reference Drug)].
†Within-Subject Coefficient of Variation for Cmax of the Reference Drug = sqrt(exp(Within-Subject Standard Deviation of the Log-Transformed Cmax of the Reference Drug) − 1) × 100.
‡Within-Subject Coefficient of Variation = sqrt(exp(Within-Subject Standard Deviation of the Log-Transformed Values) − 1) × 100.
In the mixed-effects ANOVA model, a statistically significant period effect was observed for candesartan (p = 0.0416) and amlodipine (p = 0.0009) Cmax, but not for atorvastatin (p = 0.0820) Cmax. However, since period was included as a fixed effect in the statistical model, the treatment effect was estimated independently of the period effect; therefore, the bioequivalence conclusion was not affected.
Safety analysis
Fifty-one subjects who received at least one dose of the investigational products were included in the safety analysis. A total of 47 AEs occurred in 22 subjects (43.1%); 8 subjects (16.7%) reported AEs with the test dug, and 21 subjects (42.9%) reported AEs with the reference drug. The incidence drug-related AEs (16.7% for the test drug and 38.8% for the reference drug) was statistically higher in reference drug (p = 0.0151). Two of the AEs, red blood cells urine positive and flank pain which were reported from one participant, were moderate in intensity, and all others were of mild intensity.
There were no serious AEs, and the results of laboratory tests, vital sign measurements, physical examinations, and 12-lead ECGs indicated that no clinically significant changes occurred during the study.
DISCUSSION
This study was conducted to evaluate the PK equivalence of an FDC tablet formulation of candesartan 8 mg/amlodipine 5 mg/atorvastatin 10 mg and separate formulations of candesartan 8 mg/amlodipine 5 mg FDC tablet and atorvastatin 10 mg tablet. The Cmax and AUCt values of candesartan/amlodipine/atorvastatin when administered as a FDC tablet were comparable to the values obtained when they were administered as separate tablets.
According to the US Food and Drug Administration guideline [12], a highly variable drug is defined that the CVw is ≥ 30%, as determined using a replicate crossover study design with 3 or 4 periods. In this study, atorvastatin exhibited a higher degree of PK variability compared to candesartan and amlodipine. Specifically, the CVw for the Cmax of atorvastatin was 46.21%, categorizing it as a highly variable drug. This high intra-individual variability is consistent with previously published literature, which attributes the phenomenon to the drug’s low and variable systemic bioavailability and the significant first-pass metabolism it undergoes in the gastrointestinal tract and liver [13]. To account for this inherent variability, the bioequivalence acceptance range for Cmax was widened according to regulatory guidelines (0.7158–1.3970, Table 5), using a scaled-average approach based on the CVw of the reference product. Even with this high variability, the 90% CIs for both AUCt (0.9891–1.0831) and Cmax (0.9370–1.2123) fell well within the pre-defined expanded acceptance limits. This confirms that the formulation of CKD-333 provides consistent delivery of atorvastatin and showed PK equivalence to the reference drugs.
A statistically significant period effect was observed in the ANOVA model for candesartan and amlodipine Cmax, and this may be because the partial replicated crossover design was employed in this study. Period effects can be statistically significant due to various sources, including physiological variations over time, environmental factors, or differences in study conduct between periods, which are not likely related to drugs; hence, the PK equivalence assessment was carried out as planned.
A partial replicated crossover design was used in this study to account for highly variable atorvastatin, but in theory, there was no need to measure and analyze amlodipine concentrations for all 3 periods. In fact, if this study was conducted in a full replicated design, it is most likely that amlodipine concentrations would have been measured in periods 1 and 2 only. However, for operational necessity to match the sampling requirements of atorvastatin and to ensure that all 3 drug constituents in the FDC formulation are evaluated under identical conditions, we have chosen to measure the concentrations across all periods.
Despite the adequate partial replicated crossover design and the successful demonstration of PK equivalence, several limitations of this study must be acknowledged. First, the trial was conducted in healthy adult volunteers rather than the target patient population with hypertension and hyperlipidemia. Factors such as age-related physiological changes, impaired renal or hepatic function, and the presence of metabolic comorbidities could theoretically influence the PKs of these agents in a real-world clinical setting. Second, the study focused on single-dose PKs under fasting conditions to minimize variability and does not fully capture the steady-state dynamics. Finally, this study was not designed to measure long-term clinical outcomes such as blood pressure reduction or lipid-lowering effects.
The use of FDC formulations generally improves adherence in several clinical areas, and similar results were reported for patients who needed blood pressure, cholesterol and platelet control [14]. Because the pill burden is greatly reduced, the patients could adhere to therapies that extend beyond a year. We expect that the newly developed FDC of candesartan, amlodipine and atorvastatin would be beneficial to patients with both hyperlipidemia and hypertension.
In conclusion, the PK parameters of candesartan, amlodipine, and atorvastatin were within the expanded bioequivalence and conventional criteria when administered as a candesartan/amlodipine 8/5 mg and atorvastatin 10 mg or as a candesartan/amlodipine/atorvastatin 8/5/10 mg FDC tablet.
ACKNOWLEDGMENTS
The authors wish to thank the investigators, the participating subjects, and Chong Kun Dang Pharmaceutical Corp., for their assistance in conducting the study.
Footnotes
Conflict of Interest: - Authors: Nothing to declare
- Reviewers: Nothing to declare
- Editors: Nothing to declare
Reviewer: This article was reviewed by peer experts who are not TCP editors.
- Conceptualization: Kim MG, Moon SJ.
- Formal analysis: Moon SJ.
- Investigation: Kim SY, Moon SJ.
- Project administration: Moon SJ.
- Supervision: Kwak YG, Kim MG.
- Writing - original draft: Kim SY, Moon SJ.
- Writing - review & editing: Kwak YG, Kim MG, Moon SJ.
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