Acute coronary syndromes (ACS) are a set of progressive medical syndromes precipitated primarily by thrombus formation as a consequence of coronary plaque instability and rupture, resulting in myocardial ischemia, hypoxia and even myocardial necrosis.1 ACS stays to be a threatening well being downside related to excessive danger of morbidity and mortality, which ends up in greater than 1,045,000 hospitalizations yearly in the USA.2 Twin antiplatelet remedy (DAPT) has been advisable by the American Faculty of Cardiology Basis/American Coronary heart Affiliation (ACCF/AHA) within the administration of ACS,3 together with acute remedy and early secondary prevention.4 In earlier research, using DAPT with aspirin plus P2Y12 inhibitors (clopidogrel, prasugrel or ticagrelor) has been proven to be related to the lowered danger of recurrence of cardiovascular occasions and demise.5 Nevertheless, there are some limitations in using clopidogrel, one of many accessible P2Y12 inhibitors. As an example, it’s an inactive prodrug requiring metabolic activation by hepatic cytochrome P450 enzymes (CYP450), corresponding to CYP2C19 with gene polymorphisms, which ends up in a delayed onset of impact and important particular person variations,6 in addition to excessive platelet reactivity in medical settings.7 Due to this fact, there are growing pursuits in new P2Y12 inhibitors, corresponding to ticagrelor.
Ticagrelor is a brand new cyclopentyl-triazolo-pyrimidine antiplatelet agent, which is the primary reversely-binding and noncompetitive P2Y12 inhibitor accredited for stopping thrombotic occasions in ACS by European Medical Fee and United States Meals and Drug Administration (FDA) in 2010 and 2011, respectively.8 It isn’t a prodrug and thus doesn’t require metabolic activation, which exhibits speedy antiplatelet exercise and little particular person variations.9 As the key metabolite of ticagrelor metabolized by CYP3A4/5, AR-C124910XX additionally exhibits the same efficiency to ticagrelor in platelet inhibition.10 They’re each excreted primarily by bile and partly by the kidney.11 It’s due to this fact apparent that ticagrelor could be utilized to sufferers with kidney dysfunction. Apart from, in contrast with clopidogrel, ticagrelor exhibits a faster and better inhibition of platelet aggregation (IPA), which isn’t affected by the gene polymorphisms of CYP2C19, and likewise behaves effectively in sufferers with excessive platelet reactivity to clopidogrel.12 In earlier medical trials,13–15 it has been proven that ticagrelor displays the next discount charge within the incidence of vascular demise, myocardial infarction and stroke than clopidogrel, with a suitable danger of bleeding. Due to this fact, many pointers have advisable ticagrelor because the first-line remedy in DAPT for ACS sufferers with excessive platelet reactivity, power kidney illness, complicated coronary artery illness and so forth.16–18
Though the branded drug of ticagrelor19 has been available on the market for a few years, it’s not inexpensive to be prescribed for sufferers with ACS in creating nations, particularly when associated to the lengthy secondary prevention. Due to this fact, we performed bioequivalence analysis of a generic model of ticagrelor to assist the advertising software. The approval of the generic product will cut back value and thus enhance entry to the drugs. Based on the bioequivalence examine pointers,20,21 the bioequivalence analysis for an orally administered, immediate-release pill, corresponding to ticagrelor pill, ought to be performed beneath each fasting and fed situations, besides when labeled to be taken solely on an empty abdomen. As well as, due to the roughly comparable efficiency to ticagrelor in platelet inhabitation, which contributes considerably to efficacy and security, the metabolite AR-C124910XX information are additionally required to offer supportive proof of a comparable therapeutic final result.20 Due to this fact, this examine was designed to guage the pharmacokinetics, bioequivalence and security of the take a look at drug and reference drug of ticagrelor in wholesome Chinese language topics beneath each fasting and fed situations.
Supplies and Strategies
The take a look at drug (T) of ticagrelor of 90 mg/pill (batch quantity: 170503; manufacturing date: Might 2017; expiration date: April 2019) was produced by Jiangsu FEIMA Pharmaceutical Co., Ltd. (Jiangsu, China). The reference drug (R) of ticagrelor of 90 mg/pill (batch quantity: RAMX, batch packaging report: 1705151; manufacturing date: March 2017; expiration date: February 2019) was bought from AstraZeneca Pharmaceutical Co., Ltd. (London, UK).
Eligible wholesome topics have been a minimum of 18 years of age, with a minimal weight of 45 kg for girls or 50 kg for males and a physique mass index (BMI) within the vary of 19.0–26.0 kg/m2. All topics have been assessed to be wholesome primarily based on very important indicators, bodily examinations, medical laboratory checks and electrocardiogram (ECG) and agreed to follow contraception all through the examine interval and inside 3 months after the tip of the examine. No different medicines have been taken inside 14 days earlier than the trial.
Topics have been excluded if any of the next situations have been current: 1) unqualified for the bodily examination judged by physicians; 2) being pregnant, lactation or menstruation (together with the anticipated menstrual interval falling in 0–9 days earlier than the examine); 3) historical past and/or presence of intracranial hemorrhage, hemophilia, coagulation problems, atrioventricular block, sinus bradycardia, sinus tachycardia or different situations growing the propensity for bleeding; 4) donation of blood prior to now 30 days; 5) historical past and/or presence of gastrointestinal, renal, hepatic, cardiovascular, hematological, respiratory, nervous or psychological illness; 6) allergy to any part of the take a look at or reference medication; 7) heavy cigarette smoking (>5 cigarettes per day), alcohol or drug abuse at present or inside 1 yr earlier than examine; 8) ingestion of medicine and meals affecting CYP3A4/5 prior to now 30 days; 9) participation in one other medical trial inside 3 months earlier than the examine.
The bioequivalence examine has registered with the Chinese language Scientific Trial Registry (http://www.chictr.org.cn, ChiCTR1800015091) in 2018 and been accredited by the Impartial Ethics Committee (IEC) of Folks’s Liberation Military (PLA) Basic Hospital (C2017-061-03). The examine was performed in accordance with the Declaration of Helsinki (1989), the Tips of Good Scientific Follow (GCP) and native relevant legal guidelines and laws. All topics have offered written knowledgeable consent varieties (ICF) previous to their participation within the examine.
This was a randomized, open-label, single-dose, two-period, two-sequence, and two-treatment crossover bioequivalence examine, aimed to guage the bioequivalence of two ticagrelor tablets in each fasting and fed situations. All topics have been randomly assigned to the Check-Reference (T-R) drug group and Reference-Check (R-T) drug group. They have been admitted to the hospital and checked at some point earlier than the beginning of deliberate drug administration and left the middle 72 h later (on day 4, 3 days after the drug administration) with associated assessments accomplished. The examine move chart is introduced in Figure 1.
Determine 1 The examine move chart beneath fasting and fed situations.
Fasting Bioequivalence Research
Following the screening, eligible wholesome topics have been randomized to receiving a single oral dose of 90 mg take a look at or reference tablets with 240 mL heat water following fasting for a minimum of 10 h in a single day. The drug was cross-administrated after a 7-day washout interval.
Fed Bioequivalence Research
The procedures have been the identical because the fasting bioequivalence examine besides that each one topics had an ordinary high-fat, high-calorie breakfast inside half an hour earlier than taking the designed drug.
Venous blood samples (4 mL) have been collected at 1 h predosing and 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 6, 8, 10, 12, 16, 24, 36 and 48 h postdosing right into a vacuum anticoagulation tube containing Heparin lithium. The blood samples have been centrifuged (1500 g, 10 min) at 4 °C to separate the plasma which was divided into two elements (drug monitoring and backup). All samples have been saved at −20 °C inside 1 h and transferred to −80 °C in 96 h for storage till evaluation.
Plasma concentrations of ticagrelor and its essential energetic metabolite AR-C124910XX have been measured by a longtime and validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique. The accuracy, intra-day and inter-day precision, and pattern stability beneath totally different situations have been ample for the tactic, which have been introduced in Supplement Tables S1 and S2. The usual curves of each ticagrelor and AR-C124910XX have been linear over the vary of 1.00 ng/mL to 600 ng/mL. The bottom restrict of quantitation (LLOQ) was 1.00 ng/mL (N=6). High quality management (QC) samples have been consisted of low-quality management (LQC), geometric mean-quality management (GMQC), middle-quality management (MQC), and high-quality management (HQC) samples.
The pharmacokinetics (PK) parameters have been calculated with non-compartmental mannequin utilizing Phoenix WinNonlin model 6.3. The first PK endpoints together with peak focus (Cmax), space beneath the curve (AUC) from zero to t time level (AUC0-t), and AUC from zero to infinity (AUC0-∞). The secondary PK endpoints have been charge fixed of obvious terminal elimination (λz), terminal elimination half-life (t1/2), time to Cmax (Tmax) and relative bioavailability (F). The Cmax and Tmax have been immediately obtained from the plasma focus information. The AUC0-t was calculated by the linear/log trapezoidal technique and AUC0-∞ was calculated because the sum of AUC0-t and Ct/λz, by which the λz was obtained by the linear regression in the course of the terminal log-linear section of the focus–time curve. The t1/2 was calculated as 0.693/λz, whereas the F was calculated as follows: F = AUC0-t (take a look at drug)/AUC0-t (reference drug) × 100%.
Security endpoints have been evaluated by very important indicators (physique temperature, blood strain, pulse, and respiratory charge), bodily examinations, medical laboratory checks (routine blood, serum biochemistry, routine urine, routine stool, and so on.), 12-lead electrocardiogram, antagonistic occasions (AEs) and drug-related AEs.
AEs have been coded by the Medical Dictionary for Regulatory Actions (MedDRA, model 20.0) and categorized by System Organ Class (SOC) and Most well-liked Time period (PT). The severities of AEs have been graded by Widespread Terminology Standards for Adversarial Occasions (CTCAE, model 4.03).
- Full Evaluation Set (FAS): All randomized topics have been included in FAS to investigate compliance and demographic traits.
- Security Set (SS): All FAS topics receiving a minimum of one examine drug have been included in SS.
- Pharmacokinetic Evaluation Focus Set (PKCS): All SS topics with a minimum of one accessible focus information worth have been included in PKCS to explain the designed drug focus information.
- Pharmacokinetic Evaluation Parameter Set (PKPS): All SS topics with a minimum of one accessible PK parameter have been included in PKPS for PK evaluation.
- Bioequivalence Evaluation Set (BES): Topics who have been eligible to guage PK parameters in a minimum of one cycle have been included in BES for bioequivalence evaluation.
Statistical evaluation was performed with the statistical software program bundle SAS Enterprise Information 9.4 (SAS Institute Inc., USA). All demographic traits, together with age, intercourse, ethnicity, peak (cm), weight (kg) and BMI (kg/m2), have been assessed by descriptive evaluation. Scholar’s t-test and Fisher’s actual take a look at have been used to calculate P values between teams of steady variables and categorical variables, respectively. PK endpoints have been calculated with non-compartmental mannequin primarily based on PKPS and likewise summarized by descriptive evaluation. The descriptive statistics included imply, customary deviation, geometric imply, coefficient of variation (%CV), median, minimal and most. Scholar’s t-test was utilized to calculate P values of Cmax, AUC and λz between gender teams, with Wilcoxon rank-sum take a look at for t1/2 and tmax. Bioequivalence was evaluated by the Evaluation of Variance (ANOVA) for calculating the 90% confidence intervals (CIs) of the geometric imply ratios (Cmax, AUC0-t, and AUC0-∞), with assessing the consequences of sequence, interval, formulations. When the 90% CIs of the geometric imply ratio (GMR) of the take a look at/reference drug have been inside the predefined vary of 80%-125%, the 2 medication have been thought of bioequivalent. Non-parametric evaluation (Wilcoxon signed-rank take a look at) was carried out to calculate the median and 90% CIs for non-transformed values of Tmax.
As proven in Figure 1, 99 wholesome Chinese language topics have been screened and 40 of them (12 males and 28 females) have been enrolled for the examine beneath fasting situation. In the end, 39 topics accomplished the examine, however one withdrew after the take a look at drug administration for private cause in T-R drug group. For the examine beneath fed situation, a complete of 112 wholesome Chinese language topics have been screened and 40 of them (12 males and 28 females) have been enrolled. Lastly, 39 topics accomplished the examine, with 1 withdrawing after the take a look at drug administration as a consequence of superior menstruation in T-R drug group. The T-R and R-T drug teams have been effectively matched primarily based on demographic traits, together with age, gender, ethnicity, peak and BMI (Table 1).
Desk 1 Baseline Demographic Traits – FAS
All PK parameters have been analyzed primarily based on PKCS and PKPS. Within the examine beneath fasting situation, one topic was excluded from PKCS and PKPS as a result of the drug plasma focus was decrease than the LLOQ (1.00 ng/mL) within the take a look at drug group, and one other one was excluded due to withdrawing throughout reference drug administration. Within the examine beneath fed situation, all 40 randomized topics have been included for PKCS and PKPS within the take a look at drug group, whereas 39 topics have been included within the reference drug group as a consequence of one withdrawing for superior menstruation. The imply plasma focus–time curves of take a look at versus reference ticagrelor medication have been superimposable beneath each fasting and fed situations (Figures 2 and 3), in addition to that of AR-C124910XX (Figures S1 and S2). Main and secondary PK parameters of ticagrelor tablets beneath each fasting and fed situations are proven in Table 2. The information confirmed that no important variations have been discovered between the teams receiving the take a look at and reference drug of ticagrelor.
Desk 2 Pharmacokinetic Parameters of Ticagrelor Underneath Fasting and Fed Circumstances – PKPS
Determine 2 Imply plasma focus–time curves of ticagrelor beneath fasting situation – Pharmacokinetic Evaluation Focus Set (PKCS).
Determine 3 Imply plasma focus–time curves of ticagrelor beneath fed situation – Pharmacokinetic Evaluation Focus Set (PKCS).
The PK parameters of ticagrelor and AR-C124910XX by gender classification after administrating a single dose of the take a look at and reference drug beneath fasting and fed situations are introduced in Table 3. As proven, the impact of gender on the PK parameters was nearly similar among the many group receiving take a look at drug (Supplement Table S3), the group receiving reference drug (Supplement Table S4) and the mixed group. From the pooled outcomes beneath fasting situation, the AUC0-t, AUC0-∞ and Cmax of ticagrelor have been elevated by 16.9% (P=0.084), 16.9% (P=0.095) and 43.8% (P<0.05), respectively, within the feminine topics evaluating with the male topics. In the meantime, the AUC0-t, AUC0-∞ and Cmax of AR-C124910XX have been additionally statistically increased in females than in males by 49.6%, 49.3% and 45.2%, respectively (P<0.05). Within the pooled evaluation beneath fed situation, a 21.2% improve in AUC0-t and a 22.7% improve in AUC0-∞ of AR-C124910XX (P<0.05) have been noticed within the feminine topics evaluating with the male topics, with solely numerically increased AUC0-t (13.4%) and AUC0-∞ (14.3%) discovered for ticagrelor within the feminine topics (P>0.05).
Desk 3 Abstract of PK Parameters of Ticagrelor and AR-C124910XX within the Male and Feminine Topics After Administration of T and R Underneath Fasting and Fed Circumstances – PKPS
All 40 topics have been enrolled within the BES beneath fasting or fed situation. As proven in Table 4, relating to the AUC0-t, AUC0-∞ and Cmax for ticagrelor and its essential energetic metabolite AR-C124910XX, the 90% CIs for the GMRs ranged from 95.09% to 111.67% and have been inside the predefined vary of 80% to 125% beneath each fasting and fed situations. The information indicated that the take a look at drug of ticagrelor was bioequivalent to the reference drug no matter meals consumption or not. Based mostly on the ANOVA outcomes, a big interval impact was noticed within the AUC of ticagrelor beneath each fasting and fed situations (P<0.05), in addition to within the AUC0-∞ of its metabolite beneath fed situation. Nevertheless, it may be negligible for a totally ample 7-day washout interval. As for bioequivalence evaluation of Tmax for ticagrelor and AR-C124910XX, there was additionally no statistically important distinction between take a look at and reference drug primarily based on Wilcoxon signed-rank take a look at beneath each situations (P>0.05) (Table 5).
Desk 4 Bioequivalence Statistics for PK Parameters of Ticagrelor and AR-C124910XX Underneath Fasting and Fed Circumstances – BES
Desk 5 The Rank of Tmax of Ticagrelor and AR-C124910XX Underneath Fasting and Fed Circumstances Based mostly on Wilcoxon Signed-Rank Check – BES
The overview of AEs is summarized in Table 6. No critical AEs have been reported. Within the examine beneath fasting situation, a complete of 12 AEs (T=6, R=6) have been recorded in 9 topics (9/79, 11.4%), and 6 AEs recorded in 6 topics have been regarded as drug-related (6/79, 7.6%). The drug-related AEs have been irregular T wave (5% vs 2.5%), elevated uric acid (0% vs 2.5%), elevated serum ALT (0% vs 2.5%), and dizziness (2.5% vs 0%). Within the examine beneath fed situation, a complete of 10 AEs (T=5, R=5) have been reported in 8 topics (8/79, 10.1%), and three AEs occurring in 3 topics have been regarded as drug-related (3/79, 3.8%). The drug-related AEs have been irregular T wave (2.5% vs 2.5%) and elevated uric acid (2.5% vs 0%). All of the AEs have been delicate and individuals spontaneously recovered with out particular intervention no matter meals, besides one case of elevated uric acid beneath the fasting situation, the end result of which was unknown. The take a look at drug of ticagrelor confirmed good tolerance in all topics, in addition to the reference drug.
Desk 6 Abstract of AE Underneath Fasting and Fed Circumstances – SS
The current bioequivalence examine was performed to check the PK, bioequivalence and security profiles between the take a look at generic ticagrelor and the branded reference drug in wholesome Chinese language topics, with enrolling forty topics beneath fasting situation and one other forty beneath fed situation. The outcomes demonstrated that the PK profiles, together with Cmax, AUC0-t, AUC0-∞, Tmax, t1/2 and λz, and security profiles have been comparable within the two formulations of ticagrelor. Certainly, bioequivalence was effectively established primarily based on the AUC (AUC0-t and AUC0-∞) and Cmax beneath fasting situation in addition to beneath fed situation, suggesting the generic ticagrelor can be utilized as a substitute of the reference drug to enhance entry and cut back the drug-related value.
Based on the rules20,21 on investigation of bioequivalence, AUC0-t and AUC0-∞, the overall drug publicity built-in over time, replicate the extent of absorption, whereas Cmax and Tmax point out the speed of absorption, all of that are major and necessary parameters within the concept of pharmacokinetics. These PK parameters have been calculated by the non-compartmental mannequin to discover the PK traits of ticagrelor and its metabolites. When involved with bioequivalence research, non-compartmental mannequin would get extra constant PK parameters than compartmental fashions.
Our outcomes confirmed that the feminine topics have been extra prone to have increased values in AUC and Cmax of ticagrelor and AR-C124910XX than male topics beneath fasting and fed situations. There are solely two reported research investigating the impact of gender on ticagrelor.22,23 Teng et al22 observe that the AUC0-∞ and Cmax of ticagrelor beneath fasting situation are elevated by 37% and 52% in females vs. males, with 55% and 56% improve in AUC0-∞ and Cmax of AR-C124910XX, respectively. One other examine23 additionally stories 20.2% – 33.8% improve in AUC0-∞ and 30.2–32.7% improve in Cmax of ticagrelor and AR-C124910XX in females. Our outcomes have been in step with that reported by these earlier research. The explanation might be attributed to the gender-related bodily distinction, decrease hepatic exercise of p-gp (the protein of excretion) and so forth.24 Nevertheless, whether or not the gender distinction in PK parameters has medical significance stays to be explored. As well as, it might be extra convincing if the male-to-female ratio reached 1:1, the place males accounted for 70% in our examine.
Some research have investigated the PK profiles of a single 90-mg dose of the reference drug ticagrelor in wholesome volunteers beneath fasting situation.23,25,26 In contrast with the examine26 (N=36) cited by the label of patented ticagrelor (AstraZeneca), the Cmax, Tmax and t1/2 of each formulations of ticagrelor and AR-C124910XX in our examine have been roughly in step with that in the USA, exhibiting speedy absorption and elimination. Nevertheless, the AUC0-t and AUC0-∞ within the current examine have been barely increased, indicating increased publicity and bioavailability. One cause for the delicate distinction could also be accounted by the ethnic disparity. All topics in our examine have been Chinese language, whereas most topics enrolled within the in contrast examine26 have been Caucasians. There exist some physiological variations between ethnics, corresponding to smaller physique dimension and decrease portions of CYP3A enzymes in Chinese language in comparison with Caucasians, which suggests increased publicity of ticagrelor.27 Apart from, pharmacogenetic variations additionally contribute to the ethnic disparity, the place the purposeful variants of CYP enzymes are widespread. For instance, CYP3A4, the primary metabolic enzyme of ticagrelor, has a loss-of-function variant CYP3A4*20, which has a distinct prevalence in differing ethnics: Chinese language (22%), Caucasians (6%).28 It has been reported that Asians present increased bioavailability of ticagrelor, as mirrored by AUC, than Caucasians in lots of research.29–31 In the meantime, the AUC values have been in settlement with a examine23 (N=25) performed in Chinese language topics beneath fasting situation. Another excuse for the upper AUC noticed in our examine could also be as a result of affect of gender. It has been demonstrated that females have increased AUC of ticagrelor and AR-C124910XX than males within the current and former examine,22,24 with 30% females in our examine in contrast with 22.2% in Teng’s examine.26
From the outcomes beneath fed situation, Tmax of ticagrelor and AR-C124910XX was delayed as a consequence of an ordinary high-fat, high-calorie meal in each take a look at and reference drug, in contrast with the present outcomes beneath fasting situation. In the meantime, meals consumption elevated the AUC however decreased the Cmax of ticagrelor, whereas the AUC and Cmax of AR-C124910XX all decreased, whatever the take a look at or reference drug. It indicated that meals may improve the absorption of ticagrelor, mirrored by elevated AUC, however decelerate the speed of absorption mirrored by decreased Tmax and Cmax, which thus influenced the formation of the primary metabolite (AR-C124910XX). Nevertheless, our discovering was barely totally different from the earlier examine cited by the label of patented ticagrelor (AstraZeneca).25,32 Within the cited examine,32 wholesome Hispanics (N=19), Blacks (N=5) and Caucasians (N=2) topics have been enrolled and administrated with 3*90 mg ticagrelor tablets to analyze the meals–drug interactions. It has been discovered that meals ends in a 21% improve in AUC of ticagrelor and a 22% lower in Cmax of AR-C124910XX, with no impact on Cmax of ticagrelor and AUC of AR-C124910XX. Inter-ethnic distinction perhaps may account for the variability, with totally different ranges of metabolizing enzymes and transporters, influencing the drug absorption and metabolism.27 Furthermore, totally different examine design may also be one of many causes. The cited examine32 is performed with the identical topics, minimizing the variation between teams beneath each fasting and fed situations. Nevertheless, with the primary goal to estimate the bioequivalence fairly than meals–drug interactions, we performed the current examine in two totally different teams of topics, inflicting an imprecise affect of meals on PK profiles of ticagrelor. In conclusion, there existed some delicate deviations in AUC and Cmax in contrast with the earlier examine, nevertheless it made no distinction to the bioequivalence between the take a look at drug and the reference drug.
Security analysis indicated all of the AEs have been delicate and the affected individuals recovered with out particular intervention, besides one participant with AE misplaced contact throughout follow-up. The AEs reported within the our examine have been irregular T wave, constructive urine albumin and RBC, elevated occult blood, uric acid, serum ALT, WBC and neutrophils share, dizziness, hemorrhage and hyperchlorhydria, which had been reported in earlier research.25 There was no important distinction within the charge of AEs between the take a look at and reference drug teams beneath fasting in addition to fed situation. The commonest AEs reported within the label of ticagrelor are bleeding (11.6%), elevated uric acid (22%) and dyspnea (13.8%), which have additionally occurred within the current examine other than dyspnea. Briefly, each formulations of ticagrelor confirmed good tolerance no matter quick or fed situation in wholesome Chinese language topics.
The obtained major PK parameters (Cmax, AUC0-t, AUC0-∞) in wholesome Chinese language topics demonstrated that the take a look at drug of ticagrelor was bioequivalent to the reference drug regardless beneath fasting or fed situation. The 2 formulations have been pharmacokinetically comparable and effectively tolerated. These findings indicated that the take a look at generic ticagrelor can be utilized instead medication to the branded reference drug in China.
PK, pharmacokinetics; Cmax, peak focus; AUC, space beneath the curve; AUC0–t, AUC from zero to final quantifiable focus; AUC0–∞, AUC from zero to infinity; CIs, confidence intervals; GMR, geometric imply ratio; AEs, antagonistic occasions; ACS, acute coronary syndromes; DAPT, twin antiplatelet remedy; ACCF/AHA, American Faculty of Cardiology Basis/American Coronary heart Affiliation; CYP450, cytochrome P450 enzymes; FDA, United States Meals and Drug Administration; IPA, inhibition of platelet aggregation; T, take a look at drug; R, reference drug; BMI, physique mass index; ECG, electrocardiogram; IEC, Impartial Ethics Committee; PLA, Folks’s Liberation Military; GCP, the Tips of Good Scientific Follow; ICF, knowledgeable consent varieties; T-R, Check-Reference; R-T, Reference-Check; LC-MS/MS, liquid chromatography-tandem mass spectrometry; QC, qc; LQC, low-quality management; GMQC, geometric mean-quality management; MQC, middle-quality management; HQC, high-quality management; λz, charge fixed of obvious terminal elimination; t1/2, terminal elimination half-life; Tmax, time to Cmax; F, relative bioavailability; SOC, System Organ Class; PT, Most well-liked Time period; CTCAE, Widespread Terminology Standards for Adversarial Occasions; FAS, full evaluation set; SS, security set; PKCS, pharmacokinetic evaluation focus set; PKPS, pharmacokinetic evaluation parameter set; BES, bioequivalence evaluation set; %CV, coefficient of variation; ANOVA, evaluation of variance.
The information that assist the findings of this examine can be found from the corresponding creator upon affordable request.
Ethics Approval and Knowledgeable Consent
The medical trial was accredited by the Impartial Ethics Committee of Folks’s Liberation Military Basic Hospital (C2017-061-03). The examine was performed in accordance with the Declaration of Helsinki (1989), the Tips of Good Scientific Follow and native relevant legal guidelines and laws. All topics have offered written knowledgeable consent varieties previous to their participation within the examine.
Consent for Publication
All named authors take accountability for the integrity of the work as an entire and have given their approval for this model to be revealed.
All authors sincerely acknowledge the themes who have been enrolled for his or her contributions to the medical trial.
This analysis didn’t obtain any particular grant from funding businesses within the public, industrial, or not-for-profit sectors.
The authors declare that there aren’t any conflicts of curiosity.
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