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Background and Objective: There is an unmet need for a safer anticoagulant since bleeding remains a concern with currently approved anticoagulants. Coagulation factor XI (FXI) is an attractive anticoagulant drug target with limited a role in physiological hemostasis. The objective of this study was to evaluate the safety, pharmacokinetics, and pharmacodynamics of SHR2285, a novel small molecule FXIa inhibitor, in healthy Chinese volunteers. Methods: The study consisted of single ascending doses part (part 1: 25–600 mg) and multiple ascending doses part (part 2: 100, 200, 300, and 400 mg). In both parts, subjects were randomized in a 3:1 ratio to receive SHR2285 or placebo orally. Blood, urine and feces samples were collected to describe its pharmacokinetic and pharmacodynamic profile. Results: In total, 103 healthy volunteers completed the study. SHR2285 was well tolerated. SHR2285 was absorbed rapidly with median time to maximum plasma concentration (Tmax) of 1.50 to 3.00 h. The geometric median half-life (t1/2) of SHR2285 varied from 8.74 to 12.1 h across 25–600 mg single dose. Total systemic exposure of metabolite SHR164471 was approximately 1.77- to 3.61-fold that of the parent drug. The plasma concentration of SHR2285 and SHR164471 reached steady state by the morning of Day 7, with low accumulation ratio (0.956–1.20 and 1.18–1.56, respectively). The increase in pharmacokinetic exposure of SHR2285 and SHR164471 was less than dose proportional. Food has minimal effect on the pharmacokinetics of SHR2285 and SHR164471. SHR2285 produced an exposure-dependent prolongation of activated partial thromboplastin time (APTT) and a decrease in FXI activity. The maximum FXI activity inhibition rate (geometric mean) at steady state was 73.27%, 85.58%, 87.77% and 86.27% for 100–400 mg, respectively. Conclusions: SHR2285 was generally safe and well tolerated in healthy subjects across a wide range of doses. SHR2285 exhibited a predictable pharmacokinetic profile and an exposure-related pharmacodynamic profile. ClinicalTrials.gov Identifier NCT04472819; registered on July 15, 2020. [ABSTRACT FROM AUTHOR]

Background: Data available for pharmacokinetics (PK)/pharmacodynamics (PD) of ticagrelor and significant endogenous/exogenous factors or biomarkers related to bleeding events in both healthy and clinical patients are limited. Objective: Based on PK and PD data from multicenter healthy subjects and patients, we aimed to establish an integrated approach towards population PK (pop PK) and the PD model of ticagrelor. Methods: This study was conducted as a multicenter, prospective clinical registration study involving both healthy subjects and clinical patients. The integrated Pharmacokinetic/pharmacodynamic (PK/PD) models were characterized based on PK/PD [ticagrelor concentration, aggregation baseline (BASE), P2Y12 response unit (PRU) and inhibition rate (INHIBIT)] data from 175 healthy volunteers. The model was corrected by sparse PD (BASE, PRU and INHIBIT) data from 208 patients with acute coronary syndrome (ACS). The correlations between PD biomarkers and clinically relevant bleedings in 1 year were explored. Results: A one-compartment, linear model with first-order absorption was adopted as PK model. Food status (FOOD) and body weight (WT) significantly influenced clearance and improved the fitting degree of the PK model, while SEX was selected as the covariates of the PD model. For patients taking ticagrelor 90 mg, the peak value [mean (95% CI)] of PRU was 355.15 (344.24–366.06) and the trough value was 3.64 (3.14–4.15). The PRU mean parameters were basically within the expected range (80–200) of the literature suggestions. Conclusion: A fixed dose of ticagrelor, without adjusting the dosing regimen other than covariates of FOOD/WT/SEX, could be used in patients with acute coronary syndromes, and the standard regimen could be used in Chinese patients from the perspective of exposure. [ABSTRACT FROM AUTHOR]

Introduction: To identify the potential factors responsible for the individual variability of dabigatran, we investigated the genetic variations associated with clinical outcomes and pharmacodynamics (PD) in Chinese patients with nonvalvular atrial fibrillation (NVAF). Materials and methods: Chinese patients with NVAF taking dabigatran etexilate with therapeutic doses were enrolled. The primary (bleeding events) and secondary (thromboembolic and major adverse cardiac events) outcomes for a 2‐year follow‐up were evaluated. Peak and trough PD parameters (anti‐FIIa activity, activated partial thromboplastin time and prothrombin time) were detected. Whole‐exome sequencing, genome‐wide sequencing and candidate gene association analyses were performed. Results: There were 170 patients with NVAF treated with dabigatran (110 mg twice daily) who were finally included. Two single‐nucleotide polymorphisms (SNPs) were significantly related with bleeding, which include UBASH3B rs2276408 (odds ratio [OR] = 8.79, 95% confidence interval [CI]: 2.99–25.83, p = 7.77 × 10−5 at sixth month visit) and FBN2 rs3805625 (OR = 8.29, 95% CI: 2.87–23.89, p = 9.08 × 10−5 at 12th month visit), as well as with increased trends at other visits (p <.05). Furthermore, minor allele carriers of 16 new SNPs increased PD levels, and those of one new SNP decreased PD values (p < 1.0 × 10−5). Lastly, 33 new SNPs were found to be associated with bleeding and PD among 14 candidate genes. Unfortunately, the low number of secondary outcomes precluded further association analyses. Conclusions: Genetic variations indeed affected bleeding and PD in Chinese patients with NVAF treated with dabigatran. The functions of these suggestive genes and SNPs might further be explored and verified in more in vivo and in vitro investigations. [ABSTRACT FROM AUTHOR]

To assess bioequivalence of a generic dabigatran etexilate capsule in healthy Chinese subjects under fasting and fed conditions. This was an open‐label, single‐center, randomized four‐period crossover study with a 7‐day washout period. A single oral dose of 150 mg generic dabigatran etexilate capsule (test drug) or a commercial dabigatran etexilate capsule (Pradaxa®, reference drug) was given to healthy volunteers under the fasting and fed conditions. Plasma concentrations of total and free dabigatran were detected using a validated HPLC‐MS/MS method. A noncompartmental method was used for pharmacokinetic analysis and established coagulation assays were applied for pharmacodynamic analysis. The 90% CIs of the test/reference ratios of Cmax, AUC0‐t, and AUC0‐∞ for the total dabigatran concentration were 92.57%‐106.58%, 91.63%‐106.32%, and 92.54%‐106.17%, respectively, under fasting condition, and 99.30%‐110.74%, 98.58%‐105.37%, and 97.75%‐103.99%, respectively, under fed conditions. The 90% CIs of the ratios of the parameters for the free dabigatran were 93.18%‐106.98%, 92.13%‐107.10%, 92.89%‐106.48%, respectively, under fasting condition, and 100.05%‐110.89%, 99.37%‐106.23%, 97.59%‐103.98%, respectively, under the fed condition. Additionally, the upper limit of the 90% CIs for σWT/σWR was below 2.5. There were no significant differences in the coagulation parameters including thrombin clotting time, activated partial thromboplastin time, and anti‐IIa activity between the two preparations. The generic dabigatran etexilate capsule is bioequivalent to the brand‐named product in healthy Chinese volunteers under fasting and fed conditions. The two products have comparable pharmacodynamic parameters, with a good safety profile. In addition, food intake influences absorption of both products in a similar way. [ABSTRACT FROM AUTHOR]

Background and Objectives: Recombinant glucagon-like peptide-1 receptor agonist (rE-4) is a glucagon-like peptide-1 receptor agonist, which has the same amino acid sequence to exenatide, except for the C-terminal deamidated. This study assessed the pharmacokinetics and preliminary pharmacodynamics of rE-4, following single and multiple subcutaneous injections in Chinese patients with type 2 diabetes mellitus (T2DM). Design and methods: In the randomized, open-label study, Chinese patients with T2DM ( n = 36) were randomly assigned to three groups of rE-4 ( n = 12), rE-4 with metformin ( n = 12) and exenatide ( n = 12, as the control group) for 12 weeks. rE-4 and exenatide were administered by subcutaneous injection in the abdomen, and metformin was given by oral administration. Patients received rE-4 or exenatide 5 μg twice a day for the first 4 weeks and adjusted the dose of rE-4 or exenatide to 10 μg twice a day at day 29 for the following 8 weeks, if their glycated albumin (GA) values were still greater than 17%. We evaluated pharmacokinetic parameters of rE-4 and exenatide, fasting plasma glucose (FPG), 2-h postprandial blood glucose (PG2 h), glycosylated hemoglobin (HbA1c) and body weight at designated time points. Results: Thirty-six patients were enrolled, and 29 subjects finished the study. rE-4 was absorbed quickly with a median peak-reaching time ( t ) of 0.8-1.5 h and eliminated rapidly with a median terminal half-life ( t ) of 1.6-1.9 h. The exposure of rE-4 increased in an approximately dose-proportional method without accumulation. rE-4 10 μg twice a day could reduce FPG (~2.29 mmol/L), PG2 h (~6.00 mmol/L), HbA1c (~1.19%) and body weight (~0.48 kg) from baseline to 12 weeks, with no statistical significance compared with exenatide (FPG: ~1.88 mmol/L; PG2 h: ~6.66 mmol/L; HbA1c: ~1.13%; body weight: ~0.47 kg) and rE-4 with metformin (FPG: ~2.33 mmol/L; PG2 h: ~6.51 mmol/L; HbA1c: ~0.84%; body weight: ~1.16 kg) ( p > 0.05). Conclusions: rE-4 twice a day has a pharmacokinetic profile similar to exenatide and rE-4 with metformin after single and multiple doses in Chinese patients with T2DM. Also, rE-4 could improve glycemic control effectively. ClinicalTrials.gov identifier: NCT01342042. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study is to assess the efficacy and tolerability of canagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, added on to metformin in patients with type 2 diabetes mellitus (T2DM). Methods: Literatures were searched from major electronic databases, as well as the Chinese State Food and Drug Administration and for unpublished studies. Only randomized controlled trials (RCTs) comparing canagliflozin with placebo in combination with metformin were included. Two reviewers independently selected studies, evaluated the risk of bias, and extracted data. The included RCTs were analyzed by the software RevMan 5.3 provided by the Cochrane Collaboration. Results: Six RCTs were chosen for the meta-analysis. Compared to placebo, canagliflozin produced absolute reduction in glycated hemoglobin A1c (HbA1c) (−0.66 % [−0.72 %, −0.61 %]). The proportion of patients who achieved target HbA1c was significantly greater in the canagliflozin-treated group (1.86 [1.69, 2.03]). Canagliflozin led to greater fasting plasma glucose (FPG) reduction of 1.49 mmol/L (100 mg/day) and 1.80 mmol/L (300 mg/day). Significant body weight loss of 2.09 % (100 mg/day) and 2.66 % (300 mg/day) with canagliflozin was observed. Canagliflozin was found to improve β cell function in terms of homeostasis model assessment (HOMA2-%B) (15.59 % [12.84 %, 18.35 %]). Higher incidences of genital mycotic infection/female and pollakiuria (increased urine frequency) were noted with canagliflozin compared with placebo-controlled groups. Conclusions: Canagliflozin is a potential option as an add-on to metformin based on its improvement in HbA1c, FPG, body weight, and β cell function, but further studies are demanded to strengthen this evidence. Common adverse events (AEs) like genital mycotic infection/female and pollakiuria were identified. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Rivaroxaban is an oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. • In single- and multiple-dose Phase I studies in White subjects, rivaroxaban was safe and demonstrated predictable, dose-dependent pharmacokinetics and pharmacodynamics. WHAT THIS STUDY ADDS • The Phase III programme with rivaroxaban is being conducted worldwide. • Therefore, it is necessary to determine whether the pharmacokinetics, pharmacodynamics and tolerability of rivaroxaban are altered in patients of different ethnic origins. • Dose-escalation studies were conducted to determine the safety, pharmacokinetics and pharmacodynamics of single and multiple doses of rivaroxaban in healthy Chinese subjects. AIMS To investigate the safety, pharmacokinetics and pharmacodynamics of rivaroxaban, an oral, direct Factor Xa (FXa) inhibitor, in healthy, male Chinese subjects. METHODS Two randomized, single-blind, placebo-controlled, dose-escalation studies were conducted in healthy Chinese men aged 18–45 years. In the single-dose study, subjects received single, oral doses of rivaroxaban 2.5, 5, 10, 20 and 40 mg. In the multiple-dose study, oral rivaroxaban was administered in doses of 5, 10, 20 and 30 mg twice daily for 6 days. RESULTS Rivaroxaban, in single and multiple doses up to 60 mg, was well tolerated. Rapid absorption was observed in both studies (time to Cmax 1.25–2.5 h). In the multiple-dose study, rivaroxaban exposure increased dose-proportionally after the first dose and at steady state (for the 5–20-mg doses). The half-life of rivaroxaban was up to 7.9 h in the single-dose study. Maximal inhibition of FXa activity was achieved within 1–3 h of dosing in the single-dose study [at 20 mg FXa inhibition as a median percentage change from baseline, 45.92; 95% confidence interval (CI) 44.64, 50.70] and 2–3 h after administration at steady state in the multiple-dose study (at 20 mg median FXa inhibition as a median percentage change from baseline, 60.25; 95% CI 56.16, 63.05), in line with maximum rivaroxaban plasma concentrations. CONCLUSIONS Rivaroxaban demonstrated predictable pharmacokinetics and pharmacodynamics in healthy Chinese subjects, in line with findings observed previously in White subjects. This suggests that fixed doses of rivaroxaban may be administered to all patients, regardless of their ethnic origin. [ABSTRACT FROM AUTHOR]

Objective: Grapefruit juice (GFJ) inhibits cytochrome P450 (CYP) 3A4 in the gut wall and increases blood concentrations of CYP3A4 substrates by the enhancement of oral bioavailability. The effects of GFJ on two benzodiazepine hypnotics, triazolam (metabolized by CYP3A4) and quazepam (metabolized by CYP3A4 and CYP2C9), were determined in this study. Methods: Nine healthy subjects were administered 0.25 mg triazolam or 15 mg quazepam, with or without GFJ. Each trial was performed using an open, randomized, cross-over design with an interval of more than 2 weeks between trials. Blood samples were obtained during the 24-h period immediately following the administration of each dose. Pharmacodynamic effects were determined by the digit symbol substitution test (DSST) and utilizing a visual analog scale. Results: GFJ increased the plasma concentrations of both triazolam and quazepam and of the active metabolite of quazepam, 2-oxoquazepam. The area under the curve (AUC)(0–24) of triazolam significantly increased by 96% (p<0.05). The AUC(0–24) of quazepam (+38%) and 2-oxoquazepam (+28%) also increased; however, these increases were not significantly different from those of triazolam. GFJ deteriorated the performance of the subjects in the DSST after the triazolam dose (-11 digits at 2 h after the dose, p<0.05), but not after the quazepam dose. Triazolam and quazepam produced similar sedative-like effects, none of which were enhanced by GFJ. Conclusion: These results suggest that the effects of GFJ on the pharmacodynamics of triazolam are greater than those on quazepam. These GFJ-related different effects are partly explained by the fact that triazolam is presystemically metabolized by CYP3A4, while quazepam is presystemically metabolized by CYP3A4 and CYP2C9. [ABSTRACT FROM AUTHOR]