Population pharmacokinetic study and application of ticagrelor and AR-C124910XX after percutaneous coronary intervention in Chinese patients with acute coronary syndrome.

OBJECTIVES: This study aimed to understand the pharmacokinetics of ticagrelor in Chinese patients with acute coronary syndrome (ACS), identify influencing factors, and inform ticagrelor treatment optimization. MATERIALS AND METHODS: Data from 195 ACS patients, including 491 plasma ticagrelor concentration timepoints and clinical information, were analyzed using NONMEN for pharmacokinetic (PK) parameter factors. The model underwent internal validation with bootstrap methodology. RESULTS: The PK curve of ticagrelor was well delineated using a one disposition compartment model with first-order absorption rate constant, 0.67/h. When the direct bilirubin levels and white plasma cell counts increased, female patients showed decreased glomerular filtration rate, decreased ticagrelor clearance rate, and increased exposure. When the direct bilirubin levels increased and body weight and hemoglobin decreased, rs6787801 was GG compared with AA and GA, the ticagrelor metabolite clearance rate decreased and exposure increased. CONCLUSION: The study offers key insights into ticagrelor's dose-exposure relationship post-percutaneous coronary intervention in ACS patients, highlighting factors critical for personalized treatment strategies.

Ticagrelor.

Ticagrelor is one of the most recent antiplatelet agents used to inhibit platelet aggregation via blocking the ADP receptors of the subtype P2Y12. It belongs to the non-thienopyridine class. The drug was first discovered by Astra Zeneca and approved for use in 2011 by the FDA. Ticagrelor is usually used for the prevention and treatment of thromboembolism in adult patients with acute coronary syndrome. This chapter include an overview on the physical properties, chemical properties, mode of action, pharmacokinetics and common uses of ticagrelor. In addition, the reported methods of ticagrelor assay will be discussed briefly in order to help analysts to find the most convenient method for its estimation in routine analysis. The methods of synthesis used for the preparation of ticagrelor will also be covered in this chapter. Moreover, the analytical and characterization techniques used to characterize ticagrelor row material are summarized herein.

Synthesis of Nucleoside-like Molecules from a Pyrolysis Product of Cellulose and Their Computational Prediction as Potential SARS-CoV-2 RNA-Dependent RNA Polymerase Inhibitors.

(1R,5S)-1-Hydroxy-3,6-dioxa-bicyclo[3.2.1]octan-2-one, available by an efficient catalytic pyrolysis of cellulose, has been applied as a chiral building block in the synthesis of seven new nucleoside analogues, with structural modifications on the nucleobase moiety and on the carboxyl- derived unit. The inverted configuration by Mitsunobu reaction used in their synthesis was verified by 2D-NOESY correlations, supported by the optimized structure employing the DFT methods. An in silico screening of these compounds as inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase has been carried out in comparison with both remdesivir, a mono-phosphoramidate prodrug recently approved for COVID-19 treatment, and its ribonucleoside metabolite GS-441524. Drug-likeness prediction and data by docking calculation indicated compound 6 [=(3S,5S)-methyl 5-(hydroxymethyl)-3-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)tetrahydrofuran-3-carboxylate] as the best candidate. Furthermore, molecular dynamics simulation showed a stable interaction of structure 6 in RNA-dependent RNA polymerase (RdRp) complex and a lower average atomic fluctuation than GS-441524, suggesting a well accommodation in the RdRp binding pocket.

Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for Its Effectiveness against COVID-19.

GS-441524 is an adenosine analog and the parent nucleoside of the prodrug remdesivir, which has received emergency approval for treatment of COVID-19. Recently, GS-441524 has been proposed to be effective in the treatment of COVID-19, perhaps even being superior to remdesivir for treatment of this disease. Evaluation of the clinical effectiveness of GS-441524 requires understanding of its uptake and intracellular conversion to GS-441524 triphosphate, the active antiviral substance. We here discuss the potential impact of these pharmacokinetic steps of GS-441524 on the formation of its active antiviral substance and effectiveness for treatment of COVID-19. Available protein expression data suggest that several adenosine transporters are expressed at only low levels in the epithelial cells lining the alveoli in the lungs, i.e., the alveolar cells or pneumocytes from healthy lungs. This may limit uptake of GS-441524. Importantly, cellular uptake of GS-441524 may be reduced during hypoxia and inflammation due to decreased expression of adenosine transporters. Similarly, hypoxia and inflammation may lead to reduced expression of adenosine kinase, which is believed to convert GS-441524 to GS-441524 monophosphate, the perceived rate-limiting step in the intracellular formation of GS-441524 triphosphate. Moreover, increases in extracellular and intracellular levels of adenosine, which may occur during critical illnesses, has the potential to competitively decrease cellular uptake and phosphorylation of GS-441524. Taken together, tissue hypoxia and severe inflammation in COVID-19 may lead to reduced uptake and phosphorylation of GS-441524 with lowered therapeutic effectiveness as a potential outcome. Hypoxia may be particularly critical to the ability of GS-441524 to eliminate SARS-CoV-2 from tissues with low basal expression of adenosine transporters, such as alveolar cells. This knowledge may also be relevant to treatments with other antiviral adenosine analogs and anticancer adenosine analogs as well.

Potency and pharmacokinetics of GS-441524 derivatives against SARS-CoV-2.

The nucleoside metabolite of remdesivir, GS-441524 displays potent anti-SARS-CoV-2 efficacy, and is being evaluated in clinical as an oral antiviral therapeutic for COVID-19. However, this nucleoside has a poor oral bioavailability in non-human primates, which may affect its therapeutic efficacy. Herein, we reported a variety of GS-441524 analogs with modifications on the base or the sugar moiety, as well as some prodrug forms, including five isobutyryl esters, two l-valine esters, and one carbamate. Among the new nucleosides, only the 7-fluoro analog 3c had moderate anti-SARS-CoV-2 activity, and its phosphoramidate prodrug 7 exhibited reduced activity in Vero E6 cells. As for the prodrugs, the 3'-isobutyryl ester 5a, the 5'-isobutyryl ester 5c, and the tri-isobutyryl ester 5g hydrobromide showed excellent oral bioavailabilities (F = 71.6%, 86.6% and 98.7%, respectively) in mice, which provided good insight into the pharmacokinetic optimization of GS-441524.

Quantitative HPLC-MS/MS determination of Nuc, the active metabolite of remdesivir, and its pharmacokinetics in rat.

Remdesivir is a nucleotide analog prodrug that has received much attention since the outbreak of the COVID-19 pandemic in December 2019. GS-441524 (Nuc) is the active metabolite of remdesivir and plays a pivotal role in the clinical treatment of COVID-19. Here, a robust HPLC-MS/MS method was developed to determine Nuc concentrations in rat plasma samples after a one-step protein precipitation process. Chromatographic separation was accomplished on Waters XBrige C18 column (50 × 2.1 mm, 3.5 µm) under gradient elution conditions. Multiple reaction monitoring transitions in electrospray positive ion mode were m/z 292.2 → 163.2 for Nuc and 237.1 → 194.1 for the internal standard (carbamazepine). The quantitative analysis method was fully validated in line with the United States Food and Drug Administration guidelines. The linearity, accuracy and precision, matrix effect, recovery, and stability results met the requirements of the guidelines. Uncertainty of measurement and incurred sample reanalysis were analyzed to further ensure the robustness and reproducibility of the method. This optimized method was successfully applied in a rat pharmacokinetics study of remdesivir (intravenously administration, 5 mg kg-1). The method can act as a basis for further pharmacokinetic and clinical efficacy investigations in patients with COVID-19. Graphical abstract.

Adenosine-imprinted magnetic core-shell polyvinylbutyral microbeads for quantification of adenosine in plasma.

Adenosine is an important molecule in the human body because it participates various biochemical processes, signalling in the physiological processes, and neurological disorders. In the current study, the surface imprinting method was used to prepare adenosine-imprinted magnetic core-shell polyvinylbutyral microbeads. These microbeads were utilized for quantification of adenosine in aqueous solution and control plasma in the range of 1-200 µM. The limit of detection was found to be 1.9 nM, which is quite sensitive compared with to some earlier studies. Fourier transform infrared spectroscopy, scanning electron microscopy, and a Zetasizer (particle size analyzer) were used for characterization of the prepared imprinted microbeads. To determine the efficiency of this method, selectivity experiments were conducted with adenosine-imprinted and non-imprinted magnetic core-shell polyvinylbutyral microbeads and with the competitive nucleosides cytidine, uridine, guanosine, and thymidine. Thermodynamic and kinetic studies were performed to assess adsorption of adenosine onto the adenosine-imprinted magnetic core-shell polyvinylbutyral microbeads from adenosine solution. The efficiency was linked to the specific surface reactivity, polarity and porosity of the imprinted microbeads.

Structure-Guided Drug Design of 6-Substituted Adenosine Analogues as Potent Inhibitors of Mycobacterium tuberculosis Adenosine Kinase.

Mycobacterium tuberculosis adenosine kinase (MtbAdoK) is an essential enzyme of Mtb and forms part of the purine salvage pathway within mycobacteria. Evidence suggests that the purine salvage pathway might play a crucial role in Mtb survival and persistence during its latent phase of infection. In these studies, we adopted a structural approach to the discovery, structure-guided design, and synthesis of a series of adenosine analogues that displayed inhibition constants ranging from 5 to 120 nM against the enzyme. Two of these compounds exhibited low micromolar activity against Mtb with half maximal effective inhibitory concentrations of 1.7 and 4.0 µM. Our selectivity and preliminary pharmacokinetic studies showed that the compounds possess a higher degree of specificity against MtbAdoK when compared with the human counterpart and are well tolerated in rodents, respectively. Finally, crystallographic studies showed the molecular basis of inhibition, potency, and selectivity and revealed the presence of a potentially therapeutically relevant cavity unique to the MtbAdoK homodimer.

Validated liquid chromatography-tandem mass spectrometry method for quantification of ticagrelor and its active metabolite in human plasma.

A rapid, simple and sensitive LC-MS/MS method was established and validated for simultaneous quantification of ticagrelor and its active metabolite AR-C124910XX in human plasma. After plasma samples were deproteinized with acetonitrile, the post-treatment samples were chromatographed on a Dikma C18 column interfaced with a triple quadrupole tandem mass spectrometer. Electrospray negative ionization mode and multiple reaction monitoring were adopted to assay ticagrelor and AR-C124910XX. Acetonitrile and 5 mΜ ammonium acetate was used as the mobile phase with a gradient elution at a flow rate of 0.5 mL/min. The method was linear in the range of 0.781-800 ng/mL for both ticagrelor and AR-C124910XX with a correlation coefficient ≥0.994. The intra- and inter-day precisions were within 12.61% in terms of relative standard deviation and the accuracy was within ±7.88% in terms of relative error. The LC-MS/MS method was fully validated for its sensitivity, selectivity, stability, matrix effect and recovery. This convenient and specific LC-MS/MS method was successfully applied to the pharmacokinetic study of ticagrelor and AR-C124910XX in healthy volunteers after an oral dose of 90 mg ticagrelor.

Two-phase delivery using a horse oil and adenosine-loaded dissolving microneedle patch for skin barrier restoration, moisturization, and wrinkle improvement.

BACKGROUND: Dissolving microneedles (DMNs) have been used for skin restoration and wrinkle improvement. Although lipophilic compounds, for example, natural oils or ceramides, enrich the skin barrier, their delivery via DMNs is challenging because of DMN fabrication difficulties. OBJECTIVES: In the present study, we combined a topical formulation and a DMN patch to perform two-phase delivery comprising a lipophilic formulation and hydrophilic compound-loaded DMNs to improve skin barrier status and the efficacy of drug delivery. METHODS: Horse oil-spread and adenosine-loaded DMN arrays were developed in a single patch (HOS-Ad-DMN patch). In vitro analysis was conducted to confirm the successful delivery of the compositions. Clinical assessments were conducted on the lateral canthus of 20 women to compare the efficacy of HOS-Ad-DMN patches with that of adenosine-loaded DMN patches (Ad-DMN patches). RESULTS: Adenosine was delivered via the DMNs after skin penetration and horse oil was delivered successfully into the skin through the microchannels created by the Ad-DMNs. Compared with Ad-DMN patches, HOS-Ad-DMN patches significantly improved skin elasticity, hydration, dermal density, and wrinkles. No adverse events were observed. CONCLUSION: HOS-Ad-DMN patches are a safe and efficient system for skin restoration and wrinkle improvement.

Preclinical pharmacokinetic study of a novel lipid-lowering agent, IMM-H007.

OBJECTIVE: To investigate the pharmacokinetic characteristics of absorption, distribution, metabolism, and excretion in vivo after oral administration and sublingual venous injection of the small molecule IMM-H007 in hamsters. MATERIALS AND  METHODS: Pharmacokinetic characteristics, including absorption, distribution, metabolism, and excretion, were studied in vivo by LC-MS/MS after oral administration and sublingual venous injection of IMM-H007 in hamsters. Furthermore, IMM-H007 stability in artificial gastric juices, artificial intestinal juices, and Tris-HCl buffer was also analyzed. RESULTS: There was no significant matrix or impurity interference in golden hamster whole blood as shown using MS/MS analysis to detect the existence of these substances. IMM-H007, Ml, and MP exhibited good linearity in the range of 1-500 ng/mL, 2-1000 ng/mL, and 10-5000 ng/mL, respectively. The matrix effect was 71.93-105.49%, and IMM-H007, M1, and MP were stable during the process of sample disposal. These results illustrate that the HPLC MS/MS analytic method is simple, reliable, and sensitive and exhibits high specificity and which meets the clinical pharmacokinetic requirements of IMM-H007. IMM-H007 is rapidly absorbed through the oral route in hamsters. The Cmax and AUC(0-t) of the Ml and MP metabolites in male and female hamsters were increased with increasing dosage and were proportional to the dose. In addition, T1/2 and MRT(0-t) were significantly prolonged with increasing dosage, exhibiting linear dynamic characteristics and no significant gender differences. Bioavailability in male and female golden hamsters after oral administration of IMM-H007 was calculated using the sum of Ml and MP, resulting in 6.97% and 8.95%, respectively. IMM-H007 and its metabolites were stable in Tris-HCl buffer, artificial gastric juices, and artificial intestinal juices. CONCLUSIONS: We provide an experimental basis for elucidating the material pharmacodynamics actions of IMM-H007 and predicting its potential drug interactions.

Pharmacokinetic and tissue distributions study of adenosine, 4-hydroxybenzyl alcohol and Parishin C from Gastrodia elata extract in rats.

The plant Gastrodia elata is a type of the orchid plant Gastrodia elata Bl. which contains glycosides, phenols, polysaccharides, sterols, and organic acids and a variety of active ingredients are proved to have certain pharmacological activities. To understand the process in the body of Gastridua elata, we used HPLC to study pharmacokinetics and tissue distributions of adenosine, 4-hydroxybenzyl alcohol and Parishin C in rats. The results showed that the three ingredients could be detected in plasma and different organizations at various time points. There was no significant difference in systemic clearance at three ingredients and it may be show that the three ingredients distributed (0.475±0.025, 0.518±0.033, 0.699±0.051) quickly and eliminated (5.37±0.87, 4.54±0.69, 5.34±0.82) slowly in plasma. There was the highest content of adenosine in spleen, followed by liver and lung. The highest content of 4-hydroxybenzylacohol in liver, and was higher in spleen. Parishin C was highest in heart, followed by liver and spleen. It is obvious that the contents of three ingredients are all higher in liver. The trends of the three ingredients' contents in G. rhizome extract were consistent with the contents in the plasma after intravenous administration.

METoclopramide Administration as a Strategy to Overcome MORPHine-ticagrelOr Interaction in PatientS with Unstable Angina PectorIS-The METAMORPHOSIS Trial.

Extensive search for methods of overcoming morphine-related delay of the absorption and onset of action of oral P2Y12 inhibitors in patients presenting with acute coronary syndrome is on-going. The aim of the trial was to investigate whether metoclopramide co-administration could reduce this delay and improve the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ticagrelor and its active metabolite AR-C124900XX. Plasma concentration of both compounds and platelet reactivity were evaluated in nine pre-defined time points within 6 hours after administration of ticagrelor loading dose. The results of our study show that mean platelet activity within the first hour was noticeably higher in metoclopramide-naive patients. Moreover, ticagrelor mean plasma concentration was significantly higher within the initial four time points (15, 30, 45, 60 minutes) in patients receiving metoclopramide (p = 0.039; p = 0.009; p = 0.005; p = 0.008, respectively). To conclude, the co-administration of metoclopramide in patients presenting with unstable angina and treated with morphine, has a beneficial effect on the PK/PD profile of ticagrelor and its metabolite; however, its impact on ST-elevation myocardial infarction patients requires further investigation.

Pharmacokinetics and pharmacodynamics of ticagrelor in subjects on hemodialysis and subjects with normal renal function.

PURPOSE: This single-dose, randomized, open-label, parallel-group, and crossover study assessed pharmacokinetics (PK), pharmacodynamics (PD), and safety of ticagrelor in subjects on hemodialysis versus healthy subjects. METHODS: Hemodialysis subjects were randomized, receiving a single ticagrelor 90-mg dose 1 day post-hemodialysis or just before hemodialysis, with an intervening washout of ≥ 7 days. Healthy subjects (creatinine clearance ≥ 90 mL/min) received a single ticagrelor 90-mg dose. PK, PD (P2Y12 reaction units [PRU], inhibition of platelet aggregation [IPA]), and safety were evaluated. RESULTS: Twenty-seven subjects (14 hemodialysis, 13 healthy) received ticagrelor. The mean maximum plasma concentration (Cmax) and area under the plasma concentration curve from time zero to infinity (AUC0-∞) of ticagrelor were 598.4 ng/mL and 3256.1 ng·h/mL, respectively, in pre-hemodialysis subjects; 560.3 ng/mL and 3015.1 ng·h/mL, respectively, in post-hemodialysis subjects; and 370.8 ng/mL and 2188.8 ng·h/mL, respectively, in healthy subjects. Cmax and AUC0-∞ of AR-C124910XX, the active metabolite, were 152.3 ng/mL and 1144.2 ng·h/mL, respectively, in pre-hemodialysis subjects; 130.8 ng/mL and 1127.8 ng·h/mL, respectively, in post-hemodialysis subjects; and 111.7 ng/mL and 1000.4 ng·h/mL, respectively, in healthy subjects. Mean IPA time curves over 24 h post-dose were almost indistinguishable for all three treatments. The greatest reduction in mean PRU occurred approximately 2 h post-dose for all three treatments. No safety or tolerability issues were identified. CONCLUSION: Hemodialysis resulted in modestly higher exposure to ticagrelor and AR-C124910XX, with no clinically significant effect on PD or tolerability. Accordingly, no dose adjustment is required for hemodialysis patients. Timing of hemodialysis has little impact on ticagrelor PK, or the effect of ticagrelor on IPA.

Ticagrelor for the prevention of ischemic events in patients with prior myocardial infarction and peripheral artery disease.

INTRODUCTION: Cardiovascular disease (CVD) is the main cause of death in the world. Coronary artery disease (CAD) is the most common form of CVD presentation, but the prevalence of peripheral artery disease (PAD) is increasing. Patients with polyvascular disease comprise a very high-risk population that has been infrequently studied. Areas covered: The authors review the current evidence of the efficacy and safety of ticagrelor in the setting of acute coronary syndrome and stable patients post-MI with and without PAD and summarize its pharmacokinetics, pharmacodynamics, and regulatory issues. Expert opinion: Randomized studies showed that ticagrelor is superior to clopidogrel in patients with acute coronary syndromes, and is superior to placebo in the chronic phase (>1 year) post-myocardial infarction. Sub-analyses of these studies suggest that patients with myocardial infarction and PAD, compared to patients without these characteristics, may have greater benefit with ticagrelor. Nonetheless, the global evidence about the role of ticagrelor in patients with myocardial infarction and PAD remains relatively sparse, and a prospective randomized trial testing this hypothesis would be necessary to provide more definite data regarding the efficacy and safety of ticagrelor in this very high-risk population.

Effects of food and gender on pharmacokinetics of ticagrelor and its main active metabolite AR-C124910XX in healthy Chinese subjects
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OBJECTIVES: The manuscript was mainly aimed to evaluate effects of food and gender on the pharmacokinetics of ticagrelor and its main active metabolite AR-C124910XX in healthy Chinese subjects observed in the bioequivalence studies of the two formulations of ticagrelor tablets. MATERIALS AND METHODS: The single-dose, two-sequence, two-period and crossover studies were respectively conducted under fasting and fed conditions. Plasma samples were analyzed by an HPLC-MS/MS method. Log-transformed pharmacokinetic parameters of ticagrelor and AR-C124910XX obtained from the trials were compared by the mean of two one-sided t-test. RESULTS: Pharmacokinetic parameters of the two formulations were evaluated. The mean ticagrelor tmax value was delayed by 0.28 - 0.53 hours owing to meals. A 21.6 - 24.0% (p < 0.05) increase in the mean ticagrelor AUC* (body weight-normalized AUC) value was measured (fed vs. fasting). For AR-C124910XX, the mean T1/2 value was delayed by 0.84 - 1.33 hours (p < 0.05) due to meals. A 52.0 - 55.8% (p < 0.05) decrease in the mean Cmax* (body weight-normalized Cmax) value and a 15.6 - 16.9% (p < 0.05) decrease in the mean AUC* value were observed (fed vs. fasting). The female subjects exhibited higher exposures to ticagrelor and AR-C124910XX than the male subjects. Compared with other populations, the Chinese subjects in this study experienced a greater decrease in Cmax of AR-C124910XX due to meals. 21 adverse events of mild intensity occurred over the study periods. CONCLUSION: The studies showed food effects on the absorption of ticagrelor and the formation of AR-C124910XX, and gender effects on exposures to the drug after single oral-dose administration.
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Population pharmacokinetics and pharmacodynamics of ticagrelor and AR-C124910XX in Chinese healthy male subjects.

BACKGROUND: Ticagrelor, the first reversible P2Y12 receptor antagonist, exhibits faster onset and offset of antiplatelet effects and more consistent platelet inhibition than clopidogrel in both healthy subjects and patients with stable coronary artery disease. OBJECTIVE: The objectives of this study were to establish a population pharmacokinetics (PK) and pharmacodynamics (PD) model of ticagrelor and to provide a theoretical basis for the optimization of ticagrelor treatment in clinic. METHODS: A single oral dose of 180 mg ticagrelor was administered to 14 healthy male subjects in a randomized study. Common single-nucleotide polymorphisms (SNPs) in biotransformation enzymes CYP3A4 and CYP3A5 (CYP3A4*1G and CYP3A5*3) were genotyped by PCR-direct sequencing. Blood samples were collected to measure plasma concentrations of ticagrelor and its active metabolite AR-C124910XX and maximal platelet inhibition. Various models were evaluated to characterize the pharmacokinetics of ticagrelor and AR-C124910XX as well as their PK-PD relationship. Covariates that may potentially affect PK or PD of ticagrelor and AR-C124910XX were included and assessed. Simulation for dosage regimen was performed based on the final PK-PD model. RESULTS: Ticagrelor and AR-C124910XX PK were best described by a two-compartment model with first-order transit absorption model. CYP3A4*1G increased clearance for AR-C124910XX, but had no significant effect on ticagrelor clearance. The relationship between concentration and platelet response of ticagrelor was best described by a turnover model. Simulation results indicated that a lower dosage regimen of 30 mg maintenance dose (MD) could produce an anticipated anti-platelet response in comparison to the routine clinical dosage regimen (180 mg loading dose (LD), 90 mg MD). CONCLUSION: Our study developed a population PK-PD model for ticagrelor and further simulation for dosage regimen was performed based on the final model. Compared to the current recommended dosage regimen (180 mg LD, 90 mg MD), our simulation result of a relatively lower dose (30 mg MD) could also obtain an acceptable anti-platelet response, which may provide a reference for further dosage regimen design in Chinese population.

Long-term pharmacodynamic effects of Ticagrelor versus Clopidogrel in fibrinolytic-treated STEMI patients undergoing early PCI.

The long-term pharmacodynamic effects of Ticagrelor versus Clopidogrel in patients undergoing early percutaneous coronary intervention (PCI) after fibrinolytic therapy is unknown. From May 2014 to August 2016, 212 patients undergoing PCI within 24 h of Tenecteplase (TNK), Aspirin, and Clopidogrel for ST-elevated myocardial infarction (STEMI) were randomized at four Canadian sites to receive additional Clopidogrel or Ticagrelor initiated prior to PCI. The platelet reactivity units (PRU) were measured with the VerifyNow Assay before study drug administration (baseline), at 4 and 24 h post PCI, and follow-up appointment. A mixed-model analysis with time as the repeated measure and drug as the between-subjects factor was calculated using 2 separate 1 × 4 ANOVAs, with students t-tests used to compare drugs within each time point. Complete clinical follow-up data (median 115.0 days; IQR 80.3-168.8) was available in 50 patients (23.6%) randomized to either Clopidogrel (n = 23) or Ticagrelor (n = 27). Analyses revealed significant decreases in PRU from baseline to 4 h (261.4 vs. 71.7; Mdiff = - 189.7; p < 0.001) to 24 h (71.7 vs. 27.7; Mdiff = - 44.0; p < 0.001) to end of follow-up (27.7 vs.17.9; Mdiff = - 9.9. p = 0.016) for those randomized to Ticagrelor and significant decreases in PRU only from baseline to 4 h (271.3 vs. 200.8; Mdiff = - 70.5, p = < 0.001) in patients receiving Clopidogrel, and a significantly greater proportion of patients with adequate platelet inhibition (PRU < 208) on long-term follow-up (Clopidogrel, 82.6% vs. Ticagrelor, 100.0%; p = 0.038). Our results demonstrate that in patients undergoing PCI within 24 h of fibrinolysis for STEMI, Ticagrelor provides prolonged platelet inhibition compared with Clopidogrel.

Temporal cytokine and lymphoid responses to an inhaled TLR7 antedrug agonist in the cynomolgus monkey demonstrates potential safety and tolerability of this approach.

AZD8848 is a TLR7 agonist antedrug developed for administration by inhalation dosing for the treatment of allergic diseases, such as asthma. Allergic asthma is associated with increased levels of Th2 cytokines which are suppressed for extended periods by TLR7 agonists in a number of preclinical models of allergic airway inflammation. However, TLRs form a central part of innate immunity and their activation often results in proinflammatory responses. Whilst AZD8848's antedrug mechanism is designed to restrict its pharmacological action beyond the lung, the effect of chronic, supramaximal dosing to the target tissue has yet to be defined. To support clinical development of this potentially disease modifying approach the nonclinical safety and pharmacodynamics of AZD8848 were evaluated in cynomolgus monkeys in studies examining single or multiple weekly inhaled doses. Here we show that following a single dose nearly all responses returned to baseline within a week. During multiple dosing serum biomarkers were quantified over the dosing period and indicated a limited systemic response. The dose at which maximal interferon responses were seen was dependent on dose. Thorough histopathological examination revealed a dose related increase of size and cells of lymphoid tissues in the lung and nose. Local lymphoid responses were recovered after the treatment free period. These studies are the first to evaluate safety of an inhaled TLR7 agonist and demonstrate AZD8848 is safe with a no observed adverse effect level at 26µg/kg allowing progression to man with weekly inhalation dosing.