Potential pharmacokinetic interactions in fixed-dose combinations of perindopril/indapamide/amlodipine compared with perindopril/indapamide and amlodipine in healthy Chinese volunteers

Abstract

S05590 is a fixed-dose combination of perindopril tert-butylamine 4 mg/indapamide 1.25 mg, and S06593 is a fixed-dose combination of perindopril arginine 5 mg/indapamide 1.25 mg/amlodipine 5 mg. The purpose of this study was to determine whether pharmacokinetic interactions exist among the components of S06593, compared with S05590 and amlodipine as reference drugs, in healthy Chinese male volunteers after a single oral administration under fasting conditions. A single-center, open-label, randomized, three-period, six-way crossover study was conducted. A total of 42 participants were enrolled and randomized to receive S05590 plus amlodipine, or S06593. The doses of perindopril were 3.34 mg in both S05590 and S06593, calculated as free acid. Blood samples were collected in each treatment period to determine the plasma concentrations of perindopril, indapamide and amlodipine, as well as perindoprilat, the main metabolite of perindopril. A total of 39 participants completed this study. The 90% confidence intervals of the geometric mean ratios of C_max, AUC_0-t and AUC_0-∞ for perindopril, perindoprilat, indapamide and amlodipine were all within 80.00–125.00%, thus indicating that S05590 plus amlodipine and S06593 were pharmacokinetically equivalent. During the study, only one serious emergent adverse event was reported, which was deemed not to be associated with the study drug. No serious treatment-associated adverse events were observed.

Main article text

1. INTRODUCTION

Hypertension, a major modifiable risk factor for cardiovascular diseases, is aggravated in patients with prior cardiovascular events, comorbid diabetes mellitus, microalbuminuria and renal impairment [1, 2]. Cardiovascular risk can be decreased through antihypertensive therapy. Angiotensin receptor blockers, thiazide diuretics, alpha and beta blockers, calcium antagonists and angiotensin converting enzyme (ACE) inhibitors are commonly used classes of antihypertensive agents [2]. However, in more than two-thirds of patients with hypertension, blood pressure cannot be adequately controlled by monotherapy, and two or more antihypertensive agents of different classes are required [3, 4]. Trials have studied different classes of drugs in combination for treatment of hypertension, taking advantage of their complementary action. Combination therapy is currently recommended as a first-line treatment in patients with grade 2 or 3 hypertension, or hypertension with high cardiovascular risk [5]. Triple therapy has been recommended by the European Society of Cardiology/European Society of Hypertension guidelines [6]. Several studies have indicated that three different mechanisms of triple-therapies to prevent arterial hypertension pathogenesis are increasingly being used to provide optimal blood pressure control [7–12] with diminished dose-associated adverse reactions [13]. The combination of angiotensin II receptor blockers or ACE system inhibitors combined with calcium channel blockers and diuretics is recommended in some guidelines [14–16].

Perindopril is an ACE inhibitor approved in all European countries (except Sweden and Norway) and in various other countries for the treatment of hypertension, heart failure and stable coronary artery disease [17, 18]. ACE inhibitors, compared with other regimens, have favorable metabolic, renal, cardiovascular and quality-of-life effects [19–21]. Indapamide, an orally administered thiazide-like chlorosulfamoyl derivative [22], is commonly used in hypertension at a dosage of 2.5 mg (immediate release) or 1.5 mg (slow release) once per day. Amlodipine, a calcium channel blocker, is used primarily in the treatment of hypertension and angina. Amlodipine is administered orally in tablets at dosages of 5 or 10 mg once per day [23].

Perindopril, indapamide and amlodipine are a typical triple-therapy combination. An immediate-release fixed-dose combination (FDC) of perindopril and indapamide (S05590) has been developed in two dosages: perindopril tert-butylamine 2 mg/indapamide 0.625 mg, and perindopril tert-butylamine 4 mg/indapamide 1.25 mg. The rationale for the use of an FDC of these two active substances is based on their well-demonstrated individual safety and efficacy profiles; their antihypertensive effects over 24 hours; their complementary pharmacodynamic and pharmacokinetic activities; and their overlapping risk factors [24, 25].

In Europe, perindopril is generally used as a tert-butylamine salt at a dose of 4–8 mg salt. Recently, in another formulation of perindopril registered in Europe and other countries worldwide, including China, the tert-butylamine salt is substituted by a more stable arginine salt at equimolar doses (5 and 10 mg of perindopril arginine, corresponding to 4 and 8 mg of perindopril tert-butylamine salt, respectively) [26–28]. S06593, a new FDC of perindopril arginine salt/indapamide/amlodipine, exploits the complementary effects of each component in protecting hypertension target organs, such as the heart, kidney, brain and blood vessels (intima-media thickness), in addition to decreasing blood pressure [13].

This study was designed to investigate whether pharmacokinetic interactions exist among the compounds of S06593 in healthy Chinese male volunteers after a single oral administration under fasting conditions.

2. METHODS

This clinical trial was registered with chinadrugtrials in 2019 (registration number CTR20190562) and was conducted from 17 June 2019 to 25 October 2019 at Peking Union Medical College Hospital (PUMCH), in compliance with the clinical study protocol, Good Clinical Practice, the Declaration of Helsinki [29, 30] and regulatory requirements. The study protocol and informed consent forms for participants were approved by the Ethics Committee of PUMCH. Signed hard copies of the informed consent forms were obtained from all participants before their participation in the study. Tablets of the study drugs S05590, amlodipine and S06593 were supplied by Institut de Recherches Internationales Servier.

2.1. Participants

Eligible healthy Chinese male volunteers were 18–50 years of age (inclusive), weighed 50–100 kg (inclusive) and had a body mass index (BMI) of 19–28 kg/m². Before enrollment, all participants were evaluated on the basis of a review of their medical history, physical examination and clinical laboratory findings. The participants were excluded if they had a positive result on an alcohol/nicotine test; had used any drugs known to have hepatic or renal toxicity, or substances that inhibit or induce hepatic drug metabolism and/or transport within 1 month before the screening; or had participated in another interventional clinical trial within 3 months before informed consent was granted for this study. A total of 42 participants were allocated to one of the six randomly assigned treatment sequences, with seven participants in each sequence, as follows.

Sequence 1: S05590/amlodipine/S06593

Sequence 2: S05590/S06593/amlodipine

Sequence 3: amlodipine/S05590/S06593

Sequence 4: amlodipine/S06593/S05590

Sequence 5: S06593/S05590/amlodipine

Sequence 6: S06593/amlodipine/S05590

During the study, participants were required to abstain from strenuous physical exercise, smoking, and consumption of certain products, such as alcohol, coffee, tea, cola, chocolate (and other beverages containing xanthine or quinine) and fruit juice.

2.2. Study design

This study was a single-center, open-label, randomized, three-period, six-way crossover phase I study. The sample size was evaluated according to historical data, which indicated that the intra-individual coefficient of variation (CV%) of C_max was 26%, 29% and 18% for indapamide perindopril and amlodipine, respectively [31–35]. According to an expected theoretical ratio of geometric means of C_max, an AUC of 1 and an acceptance range of [0.8, 1.25], at least 38 participants were estimated to be necessary for the study to allow a reasonable chance (power of 90%) of drawing a statistically supported conclusion of an absence of pharmacokinetic interaction among perindopril/indapamide FDC S05590 plus amlodipine within the FDC of perindopril 5 mg/indapamide 1.25 mg/amlodipine 5 mg (S06593), on the basis of assessment of confidence [36].

Three treatments were investigated: single oral administration of one tablet of S06593 (FDC of perindopril arginine 5 mg/indapamide 1.25 mg/amlodipine 5 mg), one tablet of S05590 (tert-butylamine 4 mg/indapamide 1.25 mg) and one tablet of amlodipine 5 mg. Each participant was randomized to one of three sequential treatment periods—period 1 (P001), period 2 (P002) and period 3 (P003)—with a wash-out time of 3 weeks between treatments. A detailed study flowchart is shown in Figure 1 .

Figure 1 |

Study flow diagram.

2.3. Safety evaluation

A standard electrocardiogram (12 leads) was performed on the screening day to verify an absence of contraindications and on the final visit day to detect the onset of any abnormalities (rhythm disorders, conduction disorders or repolarization disorders). Clinical laboratory tests, including hematology, biochemistry and urinalysis, were performed in the central laboratory on the screening day and final visit day. On the screening day, day 1, day 21, day 42 and the follow-up days, vital signs were measured. The relationships and severity of all adverse events (AEs) associated with the study medications were assessed. All AEs were recorded throughout the study.

2.4. Sample collection

Blood samples were collected for pharmacokinetic (PK) assessment of perindopril, perindoprilat, indapamide and amlodipine before treatment administration (pre-dose) and over a period of 240 hours after each treatment administration. Twenty-two blood samples were collected per participant per period, including pre-dose, and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 144, 192, and 240 hours post-dose. Blood samples were collected into labeled lithium heparinized tubes. Centrifugation (10 minutes, 1600 g, 4°C) was performed within 30 minutes after sampling. Subsequently, the plasma was separated into polypropylene tubes and frozen at −30 ± 5° until analysis.

2.5. Bioanalytical methods

Plasma concentrations of perindopril, perindoprilat and indapamide were determined through a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method at PUMCH [37]. Another LC-MS/MS method was independently developed and validated for amlodipine at the Centre for Drug Metabolism and Pharmacokinetics Research (DMPK Centre), Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences. The lower limits of analytical quantification were 0.250 ng/mL for perindopril, perindoprilat and indapamide. The lower limit of quantification for amlodipine was 0.0500 ng/mL. These two analytical methods were fully validated for selectivity (absence of endogenous interference), linearity (r > 0.995), intra- and inter-day accuracy and precision, matrix effects, and recovery, and a calibration curve was constructed according to the National Medical Products Administration (NMPA) guidance regarding bioavailability and bioequivalence study techniques for drugs in humans [38]. All results met the requirements of the NMPA, the Food and Drug Administration (FDA), European Medicines Agency (EMA) and International Council of Harmonisation (ICH) [39–42]. All standard curves and QC samples met the acceptance criteria, as defined in the bioanalytical study plans.

2.6. Pharmacokinetic evaluation

A non-compartmental analysis was performed on the individual plasma concentration-time profiles of perindopril, perindoprilat, indapamide and amlodipine obtained for each treatment, in Phoenix™ WinNonlin Version 8.2 (Pharsight Corp., Mountain View, CA, USA). The following PK parameters were calculated and reported for each substance, as analyzed on the basis of the actual sampling times after administration: peak concentration (C_max), time at which C_max occurred (t_max), area under the plasma concentration time curve from 0 to the last quantifiable time point (AUC_0-t) and to infinity (AUC_0-∞), and terminal half-life (t_1/2). C_max and t_max values are presented as directly observed data from the plasma concentration time profiles. The AUC was calculated with the linear and logarithmic trapezoidal method (linear interpolation in the ascending part of the curve and logarithmic interpolation in the descending part).

2.7. Statistical analysis

Bioequivalence tests were used to compare the pharmacokinetic parameters of perindopril, perindoprilat, indapamide and amlodipine administered as S05590, amlodipine 5 mg or S06593. If the bioequivalence criteria were met for each compound when administered as S06593, S05590 or amlodipine 5 mg, pharmacokinetic interaction was concluded to be absent between S05590 and amlodipine 5 mg within S06593.

Bioequivalence was evaluated by comparison of the PK parameters (C_max and AUC_0-t, as well as AUC_0-∞ if available) of perindopril, perindoprilat, indapamide and amlodipine after administration of S06593 versus S05590 or amlodipine. Statistical analysis was performed in SAS^® Version 9.4 (SAS Institute, Inc., Cary, NC, USA). Natural-log-transformed PK parameters were analyzed with the following linear mixed-effect model by using the procedure PROC MIXED with fixed effects for treatment, sequence and period, and a random effect of participant in the sequence. The geometric mean ratio and 90% confidence interval (CI) for all the above parameters were calculated from the corresponding residual errors and inverse-log transformed. The two treatments were considered bioequivalent if the 90% CIs for these parameters were within the range of 80.00%–125.00% [43]. Additionally, because t_max did not conform to a normal or log-normal distribution, this parameter was evaluated statistically with Koch’s stepwise nonparametric testing procedure. The best nonparametric estimate (Hodges-Lehmann estimate) for the difference in t_max between treatments was derived, together with a nonparametric confidence interval. The nonparametric test of t_max for treatment effects was independent of the treatment period.

3. RESULTS

3.1. Participant disposition and baseline characteristics

Overall, 172 participants were screened. Among them, 44 (two alternate participants included) were enrolled, and 42 participants were randomized and allocated to one of the treatment sequences. A total of 39 (92.9%) participants completed the study. Three participants (7.1%) were withdrawn from the study: one participant in period 1 in the amlodipine/S05590/S06593 sequence for AE (anal abscess), one participant in period 2 in the S05590/amlodipine/S06593 sequence for non-medical reasons (inability to continue the medication for personal reasons) and one participant at period 3 in the S05590/amlodipine/S06593 sequence for an AE (loss of consciousness).

All 42 participants received at least one investigational medicinal product and were included in the safety set. A total of 42 healthy participants were included in the amlodipine pharmacokinetic analysis after single oral administration of amlodipine. A total of 41 participants were included in the indapamide, perindopril and perindoprilat pharmacokinetic analysis after single oral administration of S05590. A total of 39 participants were included in the amlodipine, indapamide, perindopril and perindoprilat pharmacokinetic analysis after single oral administration of S06593. As planned in the protocol, all participants were Chinese men 20–40 years of age (mean ± SD, 29.0 ± 5.7 years). The healthy volunteers weighed 69.30 ± 7.75 kg on average (range: 54.5 to 83.4 kg) and were 170.8 ± 6.1 cm tall on average (range: 158 to 184 cm). The mean BMI was 23.74 ± 2.30 kg/m² (range: 19.4 to 27.9 kg/m²).

The main demographic data and baseline characteristics are summarized by treatment sequence in Table 1 . The demographic characteristics in each administration sequence were all balanced.

Table 1 |

Main baseline characteristics in the randomized set.

Item	S05590/amlodipine/S06593 (N=7)	S05590/S06593/amlodipine (N=7)	Amlodipine/S05590/S06593 (N=7)	Amlodipine/S06593/S05590 (N=7)	S06593/S05590/amlodipine (N=7)	S06593/amlodipine/S05590 (N=7)	All (N=42)
Age (years)
n	7	7	7	7	7	7	42
Mean ± SD	32.0 ± 7.8	27.3 ± 5.2	26.7 ± 2.6	31.3 ± 6.1	29.0 ± 6.2	27.7 ± 4.7	29.0 ± 5.7
Median	32.0	26.0	27.0	32.0	27.0	25.0	28.5
Minimum; maximum	20; 40	21; 35	23; 30	23; 40	22; 40	22; 35	20; 40
Weight (kg)
n	7	7	7	7	7	7	42
Mean ± SD	69.84 ± 10.18	68.71 ± 8.95	69.01 ± 8.77	69.91 ± 4.87	70.41 ± 6.90	67.89 ± 8.58	69.30 ± 7.75
Median	68.80	73.00	64.90	69.00	70.30	66.70	68.95
Minimum; maximum	55.9; 81.7	57.5; 78.3	58.0; 83.4	64.1; 76.8	61.3; 79.8	54.5; 81.0	54.5; 83.4
Height (cm)
n	7	7	7	7	7	7	42
Mean ± SD	171.1 ± 7.1	170.1 ± 3.1	173.0 ± 7.5	170.4 ± 2.7	173.6 ± 6.6	166.7 ± 7.2	170.8 ± 6.1
Median	171.0	170.0	176.0	171.0	174.0	165.0	171.0
Minimum; maximum	164; 183	165; 174	158; 180	167; 173	166; 184	159; 178	158; 184
BMI (kg/m2)
n	7	7	7	7	7	7	42
Mean ± SD	23.79 ± 2.68	23.71 ± 2.77	23.06 ± 2.45	24.10 ± 1.95	23.39 ± 2.24	24.39 ± 2.25	23.74 ± 2.30
Median	23.70	24.50	23.60	23.90	24.30	24.70	24.25
Minimum; maximum	20.4; 27.9	20.5; 27.1	19.4; 25.7	21.4; 27.5	19.6; 25.5	20.0; 27.3	19.4; 27.9

3.2. Pharmacokinetic evaluation

All pre-dose plasma concentrations of perindopril, perindoprilat, amlodipine and indapamide were below the limit of quantification. After administration of S06593 and S05590, maximum perindopril plasma concentrations were reached at a median of approximately 0.667 h and 0.707 h post-dose, respectively. Thereafter, the concentrations declined; the mean terminal half-lives were 0.689 h and 0.737 h for S06593 and S05590, respectively.

The maximum plasma concentrations of the active metabolite, perindoprilat, were attained at a median of 6.46 h and 7.15 h after administration of S06593 and S05590, respectively. After peaking, the perindoprilat concentrations then declined in a multi-phasic manner, with mean terminal half-lives of 70.0 h and 83.1 h for S06593 and S05590, respectively.

Furthermore, the maximum indapamide plasma concentrations were reached at a median of approximately 1.51 h and 1.90 h post-dose for S06593 and S05590, respectively. Thereafter, the concentrations declined in a multi-phasic manner, with mean terminal half-lives of approximately 15.3 h and 15.0 h for S06593 and S05590, respectively.

The maximum plasma concentrations of amlodipine were attained at 5.60 h and 5.46 h after administration of S06593 and amlodipine, respectively. After the peak concentration was reached, the amlodipine concentrations then declined in a multi-phasic manner, with mean terminal half-lives of 46.9 h and 45.3 h for S06593 and amlodipine, respectively.

Descriptive statistics for PK parameters is shown in Table 2 [37]. All results were obtained on the basis of the data of the 42 participants included for each analyte. The extrapolated part of the AUC_0-∞ calculated for perindoprilat accounted for more than 20% of the total AUC_0-∞ in 30 participants for S06593 treatment and 25 participants for S05590/amlodipine treatment.

Table 2 |

Pharmacokinetic parameters derived from plasma concentrations of perindopril, perindoprilat, indapamide and amlodipine after single oral administration of S06593 or S05590/amlodipine.

Parameters	Units	Amlodipine		Indapamide		Perindopril		Perindoprilat
		Amlodipine	S06593	S05590	S06593	S05590	S06593	S05590	S06593
AUC_%Extrap	%	3.63 ± 1.54	3.61 ± 1.52	3.61 ± 1.49	3.37 ± 1.50	1.67 ± 1.05	1.68 ± 1.03	22.5 ± 5.53	22.6 ± 7.19
AUC0-∞	h×ng/mL	168 ± 50.5	172 ± 45.2	296 ± 53.9	312 ± 65.5	48.0 ± 11.2	50.6 ± 10.9	190 ± 62.5	184 ± 76.1
AUC0-t	h×ng/mL	162 ± 47.2	166 ± 42.5	286 ± 52.3	302 ± 63.9	47.2 ± 11.3	49.7 ± 10.9	149 ± 45.0	153 ± 44.1
Cmax	ng/mL	3.06 ± 0.702	3.23 ± 0.691	16.6 ± 2.26	18.4 ± 3.88	40.3 ±13.1	43.2 ± 11.3	4.36 ± 1.78	4.91 ± 1.89
T1/2	h	45.3 ± 8.57	46.9 ±10.4	15.0 ± 2.11	15.3 ± 2.15	0.737 ± 0.151	0.689 ± 0.0921	83.1± 29.2	70.4 ± 41.3
Tmax	h	6.00 (1.50,8.00)	6.00 (1.50,8.00)	1.50 (0.750,4.00)	1.50 (0.750,3.00)	0.750 (0.500,1.50)	0.500 (0.500,1.00)	6.00 (3.00,14.0)	6.00 (4.00,12.0)
Tlag	h	0.0774 ± 0.129	0.128 ± 0.139	0.0854 ± 0.120	0.0577 ± 0.107	0.00610 ± 0.0390	0.00 ± 0.00	0.482 ± 0.246	0.397 ± 0.179

Note: Parameters (except T_max) are reported as mean ± SD. T_max is reported as median (minimum, maximum).

The results indicated that the mean plasma concentration-time profiles of perindopril, perindoprilat, indapamide and amlodipine were similar after administration of both S05590/amlodipine and S06593. Hence, the concentration-time profiles showed no evidence of any differences between these two formulations.

3.3. Statistical analysis

The test treatment in this statistical analysis was S06593, and S05590 and amlodipine served as references. Table 3 provides the summarized results of geometric mean ratios (GMRs) and the corresponding 90% confidence intervals obtained for the main PK parameters [37].

Table 3 |

Bioequivalence assessment of perindopril, perindoprilat, indapamide and amlodipine for main PK parameters.

Analysts	Treatment	Cmax			AUClast			AUCinf
		Point estimate	90% CI	Intra-CV	Point estimate	90% CI	Intra-CV	Point estimate	90% CI	Intra-CV
Perindopril	S06593/S05590	1.09	(1.01,1.18)	0.210	1.06	(1.03,1.09)	0.079	0.079	(1.03,1.09)	0.077
Perindoprilat	S06593/S05590	1.13	(1.06,1.21)	0.181	1.04	(1.00,1.09)	0.109	1.04	(1.00,1.09)	0.105
Indapamide	S06593/S05590	1.09	(1.04,1.15)	0.139	1.05	(1.00,1.10)	0.121	1.05	(1.00,1.10)	0.119
Amlodipine	S06593/Amlodipine	1.06	(1.02,1.10)	0.093	1.04	(1.00,1.09)	0.111	1.04	(1.00,1.09)	0.109

All S06593/S05590 or S06593/amlodipine GMRs for AUC_0-t or AUC_0-∞, and C_max ranged from 1.04 to 1.13 for perindopril, perindoprilat, indapamide and amlodipine. Furthermore, the 90% confidence intervals were fully within the limits of [80.00%–125.00%] for AUC_0-t, AUC_0-∞ and C_max. Thus, our findings indicated that both treatments were bioequivalent.

Table 4 provides the summarized results of the median and 90% confidence interval for the t_max difference in perindopril, perindoprilat, indapamide and amlodipine. In general, no appreciable difference was observed in the t_max for perindopril, perindoprilat, indapamide and amlodipine after administration of S06593 and S05590/amlodipine; the t_max differences were as follows: −0.00 h (−0.55 h, 0.46 h), 0.00 h (−3.35 h, 1.96 h), 0.00 h (−2.23 h, 1.45 h) and 0.00 h (−2.74 h, 2.85 h), respectively.

Table 4 |

Medians and 90% confidence intervals for the T_max difference of perindopril, perindoprilat, indapamide and amlodipine.

Parameters	Units	Amlodipine S06593-amlodipine	Indapamide S06593-S05590	Perindopril S06593-S05590	Perindoprilat S06593-S05590
Median	h	0.00	0.00	0.00	0.00
CI 90% lower	h	−2.74	−2.23	−0.55	−3.35
CI 90% upper	h	2.85	1.45	0.46	1.96

3.4. Safety evaluation

Safety data were collected for all participants who enrolled in the study. All reported AEs occurring after treatment were emergent AEs (EAEs), including serious AEs. In the safety set, 26 EAEs were reported with S06593, 14 EAEs were reported with S05590, and 15 EAEs were reported with amlodipine. The percentage of participants with at least one EAE was 30.8% with S06593, 26.8% with S05590 and 28.6% with amlodipine. The most frequently reported system organ class (SOC) for each treatment was cardiac disorders, for which ten participants (25.6%) were affected with S06593, five participants (12.2%) were affected with S05590, and six participants (14.3%) were affected with amlodipine, showing mainly tachycardia and bradycardia. Tachycardia was reported in seven participants (17.9%) with S06593, five participants (12.2%) with S05590 and four participants (9.5%) with amlodipine. Most cases of tachycardia were reported as transient conditions that occurred in standing position without associated signs or symptoms (without reported AE of orthostatic hypotension, except in one participant with S06593), and resolved on the same day. Bradycardia was reported in three participants (7.7%) with S06593 and two participants (4.8%) with amlodipine. Tachycardia was the most frequently reported treatment-associated EAE overall (nine participants, 21.4%). No EAEs had severe intensity during the study.

Only one serious emergent AE was reported during the study. Loss of consciousness of moderate intensity was reported in a participant in the S05590/amlodipine/S06593 sequence on P3D01 before S06593 administration (thus classified as receiving amlodipine) and was considered not to be associated with the study drug by the investigators but was upgraded to serious by the sponsor because the condition is present in the IME listing. All EAEs in all groups had resolved by the end of the study. Table 5 shows all treatment-associated EAEs reported throughout the study.

Table 5 |

Analysis of treatment-associated emergent adverse events by system organ class and preferred term in the safety set.

System organ class	S06593 (N=39)			S05590 (N=41)			Amlodipine (N=42)			ALL (N=42)
Preferred term	NEAE	n	%	NEAE	n	%	NEAE	n	%	NEAE	n	%
Cardiac disorders	8	7	17.9	5	5	12.2	5	4	9.5	18	10	23.8
Tachycardia	6	6	15.4	5	5	12.2	4	3	7.1	15	9	21.4
Bradycardia	1	1	2.6	-	-	-	1	1	2.4	2	2	4.8
Palpitations	1	1	2.6	-	-	-	-	-	-	1	1	2.4
Nervous system disorders	1	1	2.6	-	-	-	2	2	4.8	3	3	7.1
Dizziness	1	1	2.6	-	-	-	-	-	-	1	1	2.4
Dizziness postural	-	-	-	-	-	-	1	1	2.4	1	1	2.4
Headache	-	-	-	-	-	-	1	1	2.4	1	1	2.4
Gastrointestinal disorders	2	1	2.6	-	-	-	-	-	-	2	1	2.4
Abdominal discomfort	1	1	2.6	-	-	-	-	-	-	1	1	2.4
Nausea	1	1	2.6	-	-	-	-	-	-	1	1	2.4
General disorders and administration site conditions	1	1	2.6	-	-	-	-	-	-	1	1	2.4
Chest discomfort	1	1	2.6	-	-	-	-	-	-	1	1	2.4
Vascular disorders	1	1	2.6	-	-	-	-	-	-	1	1	2.4
Orthostatic hypotension	1	1	2.6	-	-	-	-	-	-	1	1	2.4
Investigations	-	-	-	3	2	4.9	-	-	-	3	2	4.8
Elevated alanine aminotransferase increased	-	-	-	1	1	2.4	-	-	-	1	1	2.4
Decreased blood pressure	-	-	-	1	1	2.4	-	-	-	1	1	2.4
Elevated gamma-glutamyl transferase	-	-	-	1	1	2.4	-	-	-	1	1	2.4
Respiratory, thoracic and mediastinal disorders		-	-	-	-	-	1	1	2.4	1	1	2.4
Nasal obstruction		-	-	-	-	-	1	1	2.4	1	1	2.4
All	13	7	17.9	8	6	14.6	8	6	14.3	29	12	28.6

Note: NEAE: Number of treatment-associated emergent adverse events.

N: number of participants under treatment.

n: number of participants affected.

%: n/N × 100.

3.5. Vital sign evaluation

The mean supine heart rate (HR) increased by 7 bpm between the study baseline and the last study visit, and the mean standing HR increased by 5.4 bpm. From the first hour post-dosing, the mean supine systolic blood pressure (SBP) and the mean supine diastolic blood pressure (DBP) decreased with the three treatments, this decrease persisted for at least 24 hours post-dosing (maximum mean decreases in supine SBP: −10.6, −11.0 and −9.7 mmHg at 8 hours post-dosing with S06593, S05590 and amlodipine, respectively; maximum mean decreases in supine DBP: −11.6 and −8.3 mmHg at 6 hours post-dosing with S06593 and amlodipine, respectively, and −10.2 mmHg at 8 hours post-dosing with S05590). The mean standing SBP and the mean standing DBP decreased from baseline to 24 h post-dosing with the three treatments (mean decreases in standing SBP: −7.8, −8.8 and −6.3 mmHg for S06593, S05590 and amlodipine, respectively; mean decreases in standing DBP: −5.8, −4.1 and −4.0 mmHg with S06593, S05590 and amlodipine, respectively). The mean standing pulse rate increased from baseline to 24 h post-dosing with the three treatments, with increases with S06593, S05590 and amlodipine of 7.4, 6.0 and 2.8 bpm, respectively.

Finally, the mean body temperature remained stable from baseline to day 11 with the three treatments. The changes in mean standing and supine SBP, DBP and pulse rate were not considered clinically relevant.

4. DISCUSSION

Combinations of different classes of antihypertensive therapies have been developed to take advantage of their complimentary action [2]. Moreover, FDCs of oral antihypertensive drugs show advantages in simplifying treatment regimens and improving adherence [44]. Several studies have demonstrated the antihypertensive effectiveness of the perindopril/indapamide/amlodipine combination, showing significant decreases in blood pressure and good treatment tolerance [12]. S06593 is a new formulation of the perindopril/indapamide/amlodipine combination in which the perindopril salt is changed (from tert-butylamine salt to arginine salt).

In the new FDC (S06593), perindopril is in the form of an L-arginine salt, which is 50% more stable than perindopril-tert-butylamine [27]. At equimolar doses, the pharmacokinetics, efficacy, safety and acceptability of the new salt is equivalent to that of perindopril-tert-butylamine.

Oral administration of S06593 (perindopril arginine salt 5 mg/indapamide 1.25 mg/amlodipine 5 mg) and S05590 (perindopril tert-butylamine salt 4 mg/indapamide 1.25 mg) or amlodipine 5 mg in healthy Chinese volunteers led to similar mean plasma concentration-time profiles for perindopril, perindoprilat, indapamide and amlodipine. Another bioequivalence study has also shown no drug-drug interactions among perindopril, indapamide and amlodipine in healthy participants administered a FDC of perindopril/indapamide/amlodipine [45].

For perindoprilat bioequivalence evaluation, some individual values obtained for AUC_0-∞ were considered unreliable, because the percentage of extrapolation of AUC (AUC__%extrap) was higher than 20%. This finding is explained by the plasma terminal phase for perindoprilat in plasma being driven by its dissociation from circulating ACE, in a non-linear and very slow process, thus resulting in low accuracy in the extrapolation of AUC_0-∞. This aspect of perindoprilat pharmacokinetics is a general characteristic of ACE inhibitors, whose pharmacokinetics fundamentally differs from those of conventional drugs [46]. However, the lack of AUC_0-∞ data does not prevent a conclusion of bioequivalence from being drawn, because AUC_0-t has been recognized as a more reliable parameter for assessing the bioequivalence of two oral formulations than AUC_0-∞ [47].

Because t_max did not conform to a normal or log-normal distribution, statistical comparison was performed with Koch’s stepwise nonparametric testing procedure. The Hodges-Lehmann estimate was calculated for the difference in t_max between treatments. No appreciable difference in the t_max of perindopril, perindoprilat, indapamide and amlodipine was observed.

5. CONCLUSION

The primary objective of this three-period, six-way cross-over, single dose study was to determine whether a PK interaction exists between perindopril tert-butylamine 4 mg (bioequivalent to perindopril arginine 5 mg)/indapamide 1.25 mg FDC and amlodipine 5 mg within the FDC perindopril arginine 5 mg/indapamide 1.25 mg/amlodipine 5 mg (S06593), after a single oral dose under fasting conditions, in 39 healthy male participants. All 90% confidence intervals of the GMR of C_max, AUC_0-t and AUC_0-∞ were within the range of [80.00%–125.00%] for perindopril, perindoprilat, indapamide and amlodipine. Therefore, we concluded that S06593 and S05590/amlodipine are bioequivalent, and no pharmacokinetic interactions exist between the three components of S06593. The safety after single oral administration of S06593 in healthy Chinese male participants is in line with the known safety profiles of each of its components.

ACKNOWLEDGEMENTS

The authors thanks all the staffs in Peking Union College Hospital, Institut de Recherches Internationales Servier (I.R.I.S.) and SERVIER (Beijing) Pharmaceutical Research & Development Co., Ltd who participated in the clinical trial.

CONFLICTS OF INTEREST

Stephanie Bricout-Hennel, Arnaud Lucien, Pauline Lauruol, Yaqin Wang and Xue Wang are the sponsors (I.R.I.S.) of the trial.

The authors of others declare that they have no known competing interests or personal relationships that could have appeared to influence the work reported in this paper.

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Graphical abstract

Highlights

• S06593 and S05590/amlodipine were bioequivalent, and no pharmacokinetic interactions exist between the three components (perindopril, indapamide and amlodipine) of S06593.

• The fixed combination of perindopril arginine 5 mg/indapamide 1.25 mg/amlodipine 5 mg (S06593) can help more hypertensive patients who cannot benefit from monotherapy, which showed great BP reduction and good safety.

In brief

S05590 is a fixed-dose combination of perindopril tert-butylamine 4 mg/indapamide 1.25 mg, and S06593 is a fixed-dose combination of perindopril arginine 5 mg/indapamide 1.25 mg/amlodipine 5 mg. The purpose of this study was to determine whether pharmacokinetic interactions exist among the components of S06593, compared with S05590 and amlodipine as reference drugs, in healthy Chinese male volunteers.

A total of 39 participants completed this study. The 90% confidence intervals of the geometric mean ratios of C_max, AUC_0-t and AUC_0-∞ for perindopril, perindoprilat, indapamide and amlodipine were all within 80.00–125.00%, thus indicating that S05590 plus amlodipine and S06593 were pharmacokinetically equivalent. During the study, only one serious emergent adverse event was reported, which was deemed not to be associated with the study drug. No serious treatment-associated adverse events were observed.