Combined angiogenesis and PD-1 inhibition for immunomodulatory TNBC: concept exploration and biomarker analysis in the FUTURE-C-Plus trial.

BACKGROUND: Immune checkpoint inhibitors had a great effect in triple-negative breast cancer (TNBC); however, they benefited only a subset of patients, underscoring the need to co-target alternative pathways and select optimal patients. Herein, we investigated patient subpopulations more likely to benefit from immunotherapy and inform more effective combination regimens for TNBC patients. METHODS: We conducted exploratory analyses in the FUSCC cohort to characterize a novel patient selection method and actionable targets for TNBC immunotherapy. We investigated this in vivo and launched a phase 2 trial to assess the clinical value of such criteria and combination regimen. Furthermore, we collected clinicopathological and next-generation sequencing data to illustrate biomarkers for patient outcomes. RESULTS: CD8-positivity could identify an immunomodulatory subpopulation of TNBCs with higher possibilities to benefit from immunotherapy, and angiogenesis was an actionable target to facilitate checkpoint blockade. We conducted the phase II FUTURE-C-Plus trial to assess the feasibility of combining famitinib (an angiogenesis inhibitor), camrelizumab (a PD-1 monoclonal antibody) and chemotherapy in advanced immunomodulatory TNBC patients. Within 48 enrolled patients, the objective response rate was 81.3% (95% CI, 70.2-92.3), and the median progression-free survival was 13.6 months (95% CI, 8.4-18.8). No treatment-related deaths were reported. Patients with CD8- and/or PD-L1- positive tumors benefit more from this regimen. PKD1 somatic mutation indicates worse progression-free and overall survival. CONCLUSION: This study confirms the efficacy and safety of the triplet regimen in immunomodulatory TNBC and reveals the potential of combining CD8, PD-L1 and somatic mutations to guide clinical decision-making and treatments. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04129996 . Registered 11 October 2019.

Famitinib with Camrelizumab and Nab-Paclitaxel for Advanced Immunomodulatory Triple-Negative Breast Cancer (FUTURE-C-Plus): An Open-Label, Single-Arm, Phase II Trial.

PURPOSE: Camrelizumab, an mAb against programmed cell death protein 1 (PD-1), plus nab-paclitaxel exhibited promising antitumor activity in refractory metastatic immunomodulatory triple-negative breast cancer (TNBC). Famitinib is a tyrosine kinase inhibitor targeting VEGFR2, PDGFR, and c-kit. We aimed to assess the efficacy and safety of a novel combination of famitinib, camrelizumab, and nab-paclitaxel in advanced immunomodulatory TNBC. PATIENTS AND METHODS: This open-label, single-arm, phase II study enrolled patients with previously untreated, advanced, immunomodulatory TNBC (CD8 IHC staining ≥10%). Eligible patients received 20 mg of oral famitinib on days 1 to 28, 200 mg of i.v. camrelizumab on days 1 and 15, and i.v. nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 in 4-week cycles. The primary endpoint was objective response rate (ORR), as assessed by investigators per RECIST v1.1. Key secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR), safety, and exploratory biomarkers. RESULTS: Forty-eight patients were enrolled and treated. Median follow-up was 17.0 months (range, 8.7-24.3). Confirmed ORR was 81.3% [95% confidence interval (CI), 70.2-92.3], with five complete and 34 partial responses. Median PFS was 13.6 months (95% CI, 8.4-18.8), and median DOR was 14.9 months [95% CI, not estimable (NE)-NE]. Median OS was not reached. No treatment-related deaths were reported. Among 30 patients with IHC, 13 (43.3%) were programmed death-ligand 1 (PD-L1)-negative, and PD-L1 was associated with favorable response. PKD1 and KAT6A somatic mutations were associated with therapy response. CONCLUSIONS: The triplet regimen was efficacious and well tolerated in previously untreated, advanced, immunomodulatory TNBC. The randomized controlled FUTURE-SUPER trial is under way to validate our findings. See related commentary by Salgado and Loi, p. 2728.

Assessment of anti-PD-(L)1 for patients with coexisting malignant tumor and tuberculosis classified by active, latent, and obsolete stage.

BACKGROUND: It is not a rare clinical scenario to have patients presenting with coexisting malignant tumor and tuberculosis. Whether it is feasible to conduct programmed death-(ligand) 1 [PD-(L)1] inhibitors to these patients, especially those with active tuberculosis treated with concurrent anti-tuberculosis, is still unknown. METHODS: This study enrolled patients with coexisting malignancy and tuberculosis and treated with anti-PD-(L)1 from Jan 2018 to July 2021 in 2 institutions. The progression-free survival (PFS), objective response rate (ORR), and safety of anti-PD-(L)1 therapy, as well as response to anti-tuberculosis treatment, were evaluated. RESULTS: A total of 98 patients were screened from this cohort study, with 45 (45.9%), 21 (21.4%), and 32 (32.7%) patients diagnosed with active, latent, and obsolete tuberculosis, respectively. The overall ORR was 36.0% for anti-PD-(L)1 therapy, with 34.2%, 35.5%, and 41.2% for each subgroup. Median PFS was 8.0 vs 6.0 vs 6.0 months (P=0.685) for each subgroup at the time of this analysis. For patients with active tuberculosis treated with concurrent anti-tuberculosis, median duration of anti-tuberculosis therapy was 10.0 (95% CI, 8.01-11.99) months. There were 83.3% (20/24) and 93.3% (42/45) patients showing sputum conversion and radiographic response, respectively, after anti-tuberculosis therapy, and two patients experienced tuberculosis relapse. Notably, none of the patients in latent and only one patient in obsolete subgroups showed tuberculosis induction or relapse after anti-PD-(L)1 therapy. Treatment-related adverse events (TRAEs) occurred in 33 patients (73.3%) when treated with concurrent anti-PD-(L)1 and anti-tuberculosis. Grade 3 or higher TRAEs were hematotoxicity (n = 5, 11.1%), and one patient suffered grade 3 pneumonitis leading to the discontinuation of immunotherapy. CONCLUSIONS: This study demonstrated that patients with coexisting malignant tumor and tuberculosis benefited equally from anti-PD-(L)1 therapy, and anti-tuberculosis response was unimpaired for those with active tuberculosis. Notably, the combination of anti-PD-(L)1 and anti-tuberculosis therapy was well-tolerated without significant unexpected toxic effects.

Effects of Food on the Pharmacokinetic Properties and Mass Balance of Henagliflozin in Healthy Male Volunteers.

PURPOSE: Henagliflozin is a highly selective and effective sodium glucose co-transporter (SGLT)-2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate the effects of meal intake on the pharmacokinetic properties of henagliflozin, and to understand the excretion pathways of henagliflozin in humans. METHODS: In this Phase I, randomized, open-label, single-dose, two-period crossover study, 12 healthy male Chinese volunteers were randomized to receive either henagliflozin 10 mg in the fasted condition followed by henagliflozin 10 mg in the fed condition, or the reverse schedule, with the two administrations separated by a washout period of at least 7 days. Samples of blood, urine, and feces were collected and analyzed for the investigation of the pharmacokinetic profile and excretion pathways in the fasted and fed conditions. Any adverse events that occurred throughout the study were recorded for tolerability assessment. FINDINGS: After the administration of a single oral dose of henagliflozin, mean (SD) plasma AUC0-∞ and Cmax were 1200 (274) h · ng/mL and 179 (48.8) ng/mL, respectively, in the fasted state and were decreased to 971 (245) h · ng/mL and 115 (34.2) ng/mL in the fed state. The fed/fasted ratios (90% CIs) of the geometric mean values of Cmax, AUC0-t, and AUC0-∞ were 64% (54%-76%), 80% (76%-85%), and 80% (76%-85%), respectively. The median (range) Tmax was prolonged from 1.5 (1-3) hours in the fasted condition to 2 (1.5-6) hours in the fed condition. Mass-balance testing revealed that henagliflozin was eliminated primarily as the parent drug in feces and as glucuronide metabolites in urine. In the fasted state, the cumulative excretion percentages of the parent drug and its metabolites to dose in feces and urine were 40.6% and 33.9%, respectively. The values in the fed condition were changed to 50.4% and 25.5%, respectively. These findings suggest that postprandial administration decreases the absorption rate and the extent of henagliflozin exposure in humans, but has no effect on the metabolism or elimination of the drug. IMPLICATIONS: In the present study, the consumption of a high-fat meal prior to henagliflozin administration was associated with reductions in AUC0-∞ and Cmax of 19.4% and 36.4%, respectively. However, based on the analysis of the pharmacokinetic/pharmacodynamic findings on henagliflozin, this slight change may not have clinical significance. Mass balance of henagliflozin in humans was achieved with ∼75% of the administered dose recovered in excretions within 4 days after administration whether in the fasted or fed state. These findings suggest that henagliflozin tablets can be administered with or without food.

Tolerability, Pharmacokinetic, and Pharmacodynamic Profiles of Henagliflozin, a Novel Selective Inhibitor of Sodium-Glucose Cotransporter 2, in Healthy Subjects Following Single- and Multiple-dose Administration.

BACKGROUND: Henagliflozin, a novel selective inhibitor of sodium-glucose cotransporter 2, is under development as a treatment for type 2 diabetes mellitus. PURPOSE: To evaluate the tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of henagliflozin in healthy Chinese volunteers. METHODS: Two clinical studies were conducted. One was a single ascending dose (SAD) study (2.5-200 mg) involving 80 healthy subjects, and the other was a multiple ascending dose (MAD) study (1.25-100 mg for 10 days) involving 48 healthy subjects. The tolerability, PK profiles of henagliflozin and its main metabolites, and the urinary glucose excretion over 24 h were characterized in these 2 studies. FINDINGS: No serious adverse events were observed in the healthy subjects after single- and multiple-dose oral administration of henagliflozin, suggesting that this drug was well tolerated. Henagliflozin was rapidly absorbed, with a Tmax of 1.5-3 h, and then eliminated from plasma with a half-life of 11-15 h. It was not accumulated following once-daily oral administration. Plasma exposure of henagliflozin exhibited dose-proportional PK properties over the dose ranges of 2.5-200 mg (SAD) and 1.25-100 mg (MAD). The excretion of henagliflozin in urine was found to be very low, with 3.00%-5.13% of the dose. The glucuronide metabolites M5-1, M5-2 and M5-3 were the main metabolites detected in plasma samples, which accounted for up to 54.3%, 19.8%, and 27.5%, respectively, of the parent drug at steady state. Both the SAD and MAD studies demonstrated that the urinary glucose excretion over 24 h was dose-dependently increased and displayed saturation kinetics at >25 mg. No significant changes in the levels of serum glucose and urine electrolytes were found following a single or multiple doses of henagliflozin administration. IMPLICATIONS: Henagliflozin was well tolerated and showed predictable PK/PD profiles in these healthy subjects. Henagliflozin did not affect blood glucose level or urinary electrolyte excretion. It is best characterized for once-daily administration with a maximum dose of 25 mg. ChinaDrugTrials.org.cn identifiers: CTR20131986 and CTR20140132.

A NAC nomogram to predict the probability of three-month unfavorable outcome in Chinese acute ischemic stroke patients treated with mechanical thrombectomy.

BACKGROUND AND PURPOSE: Mechanical thrombectomy (MT) is a standard care for most acute ischemic stroke (AIS) patients. For AIS patients underwent MT, predicting the patients at high risk of unfavorable outcome and adjusting therapeutic strategies accordingly can greatly improve patient outcomes. We aimed to develop and validate a nomogram for individualized prediction of Chinese AIS patients underwent MT. METHODS: We conducted a multicenter prospective study including 238 AIS patients who underwent MT from January 2014 to December 2018. The main outcome measure was three-month unfavorable outcome (modified Rankin Scale 3-6). A nomogram was generated based on multivariate logistic model. We assessed the discriminative performance by using the area under the receiver-operating characteristic curve and calibration of risk prediction model by using the Hosmer-Lemeshow test. RESULTS: In NAC nomogram, NIHSS (National Institutes of Health Stroke Scale) score on admission (OR: 1.193, p < 0.0001), Age (OR: 1.025, p = 0.037) and Creatinine (OR: 1.028, p < 0.0001) remained independent predictors of 3-month unfavorable outcome in Chinese AIS patients treated with MT. The NAC nomogram exhibited an area under the curve of 0.816 for predicting functional impairment. Calibration was good (p = 0.560 for the Hosmer-Lemeshow test). CONCLUSIONS: The NAC nomogram is the first nomogram developed and validated in Chinese AIS patients treated with MT and it may be used to predict 3 months unfavorable outcome for these patients.

Population pharmacokinetics, safety and dosing optimization of voriconazole in patients with liver dysfunction: A prospective observational study.

AIMS: Voriconazole is a broad-spectrum antifungal agent for the treatment of invasive fungal infections. There is limited information about the pharmacokinetics and appropriate dosage of voriconazole in patients with liver dysfunction. This study aimed to explore the relationship between voriconazole trough concentration (Ctrough ) and toxicity, identify the factors significantly associated with voriconazole pharmacokinetic parameters and propose an optimised voriconazole dosing regimen for patients with liver dysfunction. METHODS: The study prospectively enrolled 51 patients with 272 voriconazole concentrations. Receiver operating characteristic curves were used to explore the relationship between voriconazole Ctrough and toxicity. The pharmacokinetic data was analysed with nonlinear mixed-effects method. Dosing simulations stratified by total bilirubin (TBIL, TBIL-1: TBIL < 51 µmol/L; TBIL-2: 51 µmol/L ≤ TBIL < 171 µmol/L; TBIL-3: TBIL ≥ 171 µmol/L) were performed. RESULTS: Receiver operating characteristic curve analysis revealed that voriconazole Ctrough of ≤ 5.1 mg/L were associated with significantly lower the incidence of adverse events. A 1-compartment pharmacokinetic model with first-order absorption and elimination was used to describe the data. Population pharmacokinetic parameters of clearance, volume of distribution and oral bioavailability were 0.88 L/h, 148.8 L and 88.4%, respectively. Voriconazole clearance was significantly associated with TBIL and platelet count. The volume of distribution increased with body weight. Patients with TBIL-1 could be treated with a loading dose of 400 mg every 12 hours (q12h) for first day, followed by a maintenance dose of 100 mg q12h administered orally or intravenously. TBIL-2 and TBIL-3 patients could be treated with a loading dose of 200 mg q12h and maintenance doses of 50 mg q12h or 100 mg once daily and 50 mg once daily orally or intravenously, respectively. CONCLUSIONS: Lower doses and longer dosing intervals should be considered for patients with liver dysfunction. TBIL-based dosing regimens provide a practical strategy for achieving voriconazole therapeutic range and therefore maximizing treatment outcomes.

Efficacy and safety of concurrent anti-tuberculosis treatment and chemotherapy in lung cancer patients with co-existent tuberculosis.

BACKGROUND: This retrospective study evaluated the safety and efficacy of concurrent anti-tuberculosis (TB) and chemotherapy treatment in patients with advanced lung cancer and active TB. METHODS: We retrospectively analyzed patients who were first diagnosed with advanced lung cancer and received first-line chemotherapy in Guangzhou Chest Hospital from 2015 to 2017. Patients were categorized into two groups (2:1): lung cancer patients without active TB (Group A), and lung cancer patients with active TB (Group B). Primary endpoints included adverse events (AEs), objective response rate (ORR), time to treatment failure, and overall survival (OS). RESULTS: A total of 99 patients were eligible (Group A, n=66; Group B, n=33). Grade ≥3 treatment-related AEs, primarily hematologic toxicity, occurred in 39.4% and 51.5% of patients in Groups A and B, respectively. The hypohepatia in both groups was generally at grade 1 or 2, with similar incidences (26% and 27%, respectively). After two cycles of chemotherapy, the ORR was 42.4% and 33.3% in Group A and B, respectively (P=0.383). The median time to treatment failure (TTF) was 7.0 and 5.6 months for Groups A and B, respectively (P=0.175). The median OS was 17.0 and 14.0 months for Groups A and B, respectively (P=0.312). After 3 months of anti-TB treatment, all patients achieved sputum acid-fast bacilli (AFB) smear conversion and absorption on imaging, and the end of follow-up observed no recurrence. CONCLUSIONS: Concurrent anti-TB and chemotherapy treatment did not increase hematological toxicity or hypohepatia in lung cancer patients with pulmonary TB.

Physiologically-Based Pharmacokinetic-Pharmacodynamics Model Characterizing CYP2C19 Polymorphisms to Predict Clopidogrel Pharmacokinetics and Its Anti-Platelet Aggregation Effect Following Oral Administration to Coronary Artery Disease Patients With or Without Diabetes.

Background and Objective: Clopidogrel (CLOP) is commonly used in coronary artery disease (CAD) patients with or without diabetes (DM), but these patients often suffer CLOP resistance, especially those with diabetes. This study was aimed to develop a physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) model to describe the pharmacokinetics and pharmacodynamics of clopidogrel active metabolite (CLOP-AM) in CAD patients with or without DM. Methods: The PBPK-PD model was first established and validated in healthy subjects and then in CAD patients with or without DM. The influences of CYP2C19, CYP2C9, CYP3A4, carboxylesterase 1 (CES1), gastrointestinal transit rates (K t,i) and platelets response to CLOP-AM (k irre) on predicted pharmacokinetics and pharmacodynamics were investigated, followed with their individual and integrated effects on CLOP-AM pharmacokinetics due to changes in DM status. Results: Most predictions fell within 0.5-2.0 folds of observations, indicating successful predictions. Sensitivity analysis showed that contributions of interested factors to pharmacodynamics were CES1> k irre> K t,i> CYP2C19 > CYP3A4> CYP2C9. Mimicked analysis showed that the decreased exposure of CLOP-AM by DM was mainly attributed to increased CES1 activity, followed by decreased CYP2C19 activity. Conclusion: The pharmacokinetics and pharmacodynamics of CLOP-AM were successfully predicted using the developed PBPK-PD model. Clopidogrel resistance by DM was the integrated effects of altered K t,i, CYP2C19, CYP3A4, CES1 and k irre.

Tumor Mutational Burden and Genomic Alterations in Chinese Small Cell Lung Cancer Measured by Whole-Exome Sequencing.

PURPOSE: Studies on genetic alterations of the heterogenous small cell lung cancer (SCLC) are rare. We carried out the present study to clarify the genomic alterations and TMB levels of Chinese SCLC patients by whole-exome sequencing. MATERIALS AND METHODS: Whole-exome sequencing by next-generation sequencing technique was implemented on twenty SCLC samples. Significant somatic mutations and copy number variations were screened, followed by comparison with the data extracted from COSMIC. Besides, altered signaling pathways were examined in order to figure out actionable targets. RESULTS: A total of 8,062 nonsynonymous mutations were defined. The number of mutations for each case ranged from 98 to 864. As for base substitutions, a total of 15,817 substitutions were detected with C > A conversion which was correlated to smoking occupying 25.57%. The TMB values ranged from 2.51/Mb to 22.1/Mb with a median value of 9.95/Mb. RB1 was the most frequently mutated gene altered in 18 (90%) cases, followed by TP53 altered in 17 (85%) cases. Other commonly changed genes were PTEN, and RBL1, with frequencies of 55% and 50%, respectively. SOX2 significantly amplified in 6 (30%) cases and MYCN amplified in 1 (5%) patient. Notch signaling pathway and PI3K/AKT/mTOR signaling pathway were universally and significantly changed. Major genomic alterations were in consistency with data from COSMIC, but frequencies of less common mutations were different. CONCLUSION: TP53 and RB1 inactivations were universally detected in SCLC. The Notch and PI3K/AKT/mTOR signaling pathways were both significantly altered, implying potential actionable targets.

Identifying factors affecting the pharmacokinetics of voriconazole in patients with liver dysfunction: A population pharmacokinetic approach.

Voriconazole is a broad-spectrum antifungal agent commonly used to treat invasive fungal infections. Voriconazole has significant intraindividual and interindividual pharmacokinetics variability in different patient populations. Pharmacokinetic data of voriconazole in patients with liver dysfunction were limited. The aims of this study were to evaluate the population pharmacokinetics of voriconazole in patients with liver dysfunction and to identify the factors that affect voriconazole pharmacokinetics. A total of 166 samples taken from 57 patients with liver dysfunction were included in the study. A one-compartment pharmacokinetic model with first-order absorption and elimination was used to describe the data. Voriconazole clearance (CL) was 0.58 L/h, the volume of distribution (Vd ) was 134 L, and oral bioavailability (F) was 80.8%. This study showed that platelet count was significantly associated with voriconazole pharmacokinetic parameters. CYP2C19 polymorphisms had no effect on voriconazole pharmacokinetic parameters. Voriconazole CL was significantly decreased in patients with liver dysfunction. This study provides useful pharmacokinetics information for patients with liver dysfunction while highlighting the value of therapeutic drug monitoring in adjusting doses.

Effect of antiplatelet pretreatment on safety and efficacy outcomes in acute ischemic stroke patients after intravenous thrombolysis: a systematic review and meta-analysis.

BACKGROUND: About 40% of acute ischemic stroke patients are under antiplatelet pretreatment. Previous studies have shown conflicting results on the effect of prior antiplatelet agents on post thrombolytic clinical outcomes. METHODS: A systematic search using PubMed and EMBASE databases for eligible studies. Prior antiplatelet safety was measured by symptomatic intracerebral hemorrhage (sICH) and mortality. Efficacy was measured by functional independence and favorable functional outcome. RESULTS: Crude analysis indicated that antiplatelet pretreatment was associated with sICH and mortality. In adjusted analysis, the results confirmed a nonsignificant association between antiplatelet pretreatment and a higher risk of sICH and mortality, but demonstrated that antiplatelet pretreatment tended to improve functional independence and favorable functional outcome. Subgroup analysis detected a racial disparity in prior antiplatelet effect on sICH and the association between antiplatelet pretreatment and sICH was dependent on different antiplatelet regiments. CONCLUSION: There was no significant difference in sICH and mortality between patients with and without antiplatelet pretreatment. Besides, antiplatelet pretreatment did not adversely affect the efficacy outcomes. The prevalence of sICH among Asians receiving antiplatelet pretreatment was relatively high. Additionally, it needs to be noticed that the effect of preexisting antiplatelet on clinical outcomes may be dependent on post thrombolytic antiplatelet regiments.

Effects of CYP2C19 Genetic Polymorphisms on the Pharmacokinetic and Pharmacodynamic Properties of Clopidogrel and Its Active Metabolite in Healthy Chinese Subjects.

PURPOSE: Some studies in the white population have shown that carriers of at least 1 loss-of-function allele in the gene that encodes the cytochrome P-450 2C19 isozyme (CYP2C19) have lower levels of the clopidogrel active metabolite (CAM) and a reduced antiplatelet effect of clopidogrel. However, data are limited regarding the association between CYP2C19 genetic variants and exposure to CAM and on the pharmacodynamic properties of CAM in the Chinese population. Data from the white population cannot be extrapolated to the Chinese population because of the marked interethnic differences in CYP2C19 variants. This study was aimed to investigate the influence of CYP2C19 genetic polymorphisms on the pharmacokinetic properties of CAM and the antiplatelet effect of clopidogrel in healthy Chinese volunteers, and to provide evidence for the role of a CYP2C19 genotyping test in predicting the antiplatelet effect of clopidogrel in the Chinese population. METHODS: Twenty healthy subjects received a single 300-mg dose of clopidogrel and were assigned to 1 of 3 groups according to CYP2C19 genotype: CYP2C19 *1/*1 (normal metabolizers [NM]; n = 8), CYP2C19 *1/*2 or *3 (intermediate metabolizers [IM]; n = 10) and CYP2C19 *2/*2 or *3 and *3/*3 (poor metabolizers [PM]; n = 2). Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after administration. The plasma concentrations of clopidogrel and CAM were analyzed by LC-MS/MS, and adenosine diphosphate-induced platelet aggregation was measured by light-transmittance aggregometry. FINDINGS: There were no significant differences in Cmax and AUC0-t of clopidogrel prodrug in the NM group compared with the IM and PM groups. The mean CAM Cmax value was significantly higher in the NM group than in IM and PM groups (45.39 [12.57] vs 29.15 [7.92] ng/mL [P = 0.003] and 19.55 [2.19] ng/mL [P = 0.004], respectively). The mean CAM AUC0-t value was significantly higher in the NM group than in the IM and PM groups (61.05 [21.63] vs 37.67 [11.01] ng · h/mL [P = 0.007] and 27.08 [2.72] ng · h/mL [P = 0.016]). The NM group exhibited a significantly higher percentage of inhibition of platelet aggregation than did the IM or PM group (P = 0.001). The correlations between the pharmacokinetic properties (Cmax, AUC0-t) of CAM and the pharmacodynamic data (maximal and inhibition of platelet aggregation) were significant (both, Pearson r > 0.5 and P < 0.01). IMPLICATION: In these healthy Chinese subjects, carriers of CYP2C19 loss-of-function allele(s) had significantly reduced exposure of CAM and decreased levels of inhibition of platelet aggregation with clopidogrel; these genotypes therefore might be a determinant for the formation of CAM and its antiplatelet effects. Study identifier: ChiCTR-OCH-14004382.

ABCB1 hypomethylation is associated with decreased antiplatelet effects of clopidogrel in Chinese ischemic stroke patients.

Current predictive models including the CYP2C19 polymorphism and clinical factors still explain only about 12% of variability of clopidogrel responsiveness. Up until recently, the precise mechanism of clopidogrel resistance remains unclear. P-glycoprotein (P-gp) encoded by ABCB1, a transmembrane calcium-dependent efflux pump for clopidogrel, implicated a role in clopidogrel resistance. In this present study, we investigated the methylation status of ABCB1 gene promoter in relation to ABCB1 mRNA expressions and the antiplatelet effects of clopidogrel. This study was a prospective cohort analysis of eligible stroke patients (n = 183, aged 18-75 years) who received clopidogrel (75 mg/day) for at least 5 days before discharge. A final subcohort of 87 patients with CYP2C19*1/*1 genotype were enrolled in the study population. Patients were grouped in quartiles of maximum platelet aggregation (MPA values (Q1, Q2, Q3 and Q4, MPA(Q1) < 14.1%, MPA(Q4) > 35.4%). The methylation status of the ABCB1 promoter was 1.8 times in the Q1 MPA group (10.1 ± 2.4%) than in the Q4 MPA group (5.5 ± 2.1%) (P < 0.001). ABCB1 methylation correlated inversely with MPA (R = - 0.764, P < 0.001) and mRNA expression (R = - 0.839, P < 0.001). Results of a multivariate linear regression model demonstrated that ABCB1 methylation was independently associated with MPA (ß(coef ficient) = - 4.71, P < 0.001). ABCB1 expression was 0.62 times in the Q1 MPA group (5.3 ± 1.4 per thousand) than in the Q4 MPA (8.5 ± 2.5%o), and the expression of ABCB1 correlated positively with ADP-induced MPA (R = 0.791, P < 0.001). ABCB1 promoter methylation status in whole blood appears to be inversely associated with ABCB1 mRNA expressions and MPA. In conclusions, hypomethylation of ABCB1 promoter is associated with a decreased response to clopidogrel in ischemic stroke patients via increased ABCB1 mRNA expression.

CES1A -816C as a genetic marker to predict greater platelet clopidogrel response in patients with percutaneous coronary intervention.

This study was designed to determine whether CES1A -816A/C polymorphism could be associated with altered clopidogrel response. Recruited patients were pretreated with 300 mg clopidogrel loading dose before undergoing percutaneous coronary intervention for stenting and genotyped with CYP2C19 *2, *3, or *17, and CES1A -816A/C, respectively. Adenosine diphosphate-induced maximum platelet aggregation (MPA) was determined on day 3 after initiation of daily clopidogrel maintenance doses. The clinical primary end point was the 1-year incidence of definite stent thrombosis (ST). Multivariable linear regression revealed that the CES1A -816A/C polymorphism was independently associated with MPA measures with an absolute ß value of 6.76. Of 617 patients, a subcohort of 249 patients not carrying CYP2C19 *2, *3, or *17 were categorized into 3 groups based on the -816A/C genotype. The median MPA value was lower in 125 carriers of the -816C variant than in 124 noncarriers (21.5% vs. 31.7%, P = 0.001). The 1-year definite ST occurred in 7 patients in that subcohort, and only 1 ST case was one of carriers of the -816 A/A that was associated with higher MPA values. The CES1A -816C would be used to predict greater platelet response to clopidogrel than the CES1A -816A in percutaneous coronary intervention-treated patients not carrying CYP2C19 variants.

Increased risk for developing major adverse cardiovascular events in stented Chinese patients treated with dual antiplatelet therapy after concomitant use of the proton pump inhibitor.

BACKGROUND: Some clinical studies have demonstrated that the proton pump inhibitor (PPI) could decrease clopidogrel platelet response and increase major adverse cardiovascular events (MACE) in white or black subjects. However, that remains to be determined in Chinese patients. In this study, we sought to determine whether there could be an increased risk for developing MACE after concomitant use of dual antiplatelet therapy (DAT) and a PPI in Chinese patients treated with percutaneous coronary intervention (PCI) and stenting. METHODS: This study was a 5-year, single-center, retrospective cohort analysis of eligible patients (n = 6188) who received DAT and a PPI concomitantly (defined as PPI users) before discharge and/or 12-month follow-up after discharge as compared with those who received DAT alone (also defined as non-PPI users, n = 1465). The incidence of recurrent MACE, such as myocardial infarction (MI), definite stent thromboses (ST), or cardiovascular death, was compared between the PPI users and non-users. RESULTS: PPI users had a significantly higher incidence of the MACE than non-users (13.9% vs. 10.6%; adjusted HR: 1.33; 95% CI: 1.12 - 1.57, P = 0.007). Stratified analysis revealed that concurrent use of DAT and a PPI was associated with a significantly increased risk for developing ST compared with DAT alone (1% vs. 0.4%; adjusted HR: 2.66, 95% CI: 1.16 - 5.87, P = 0.012). However, there were no significant differences in the risk of MI, cardiovascular death and other adverse events, regardless of combination of clopidogrel and a PPI. CONCLUSIONS: The study further suggests that concomitant use of DAT and a PPI may be associated with an increased risk for developing MACE, in particular definite ST, in Chinese PCI patients after discharge as compared with use of DAT alone.

The association of ABCC3 promoter methylation with clopidogrel response in Chinese ischemic stroke patients.

Multidrug resistance protein 3 (MRP3), encoded by ABCC3, is an ATP-dependent efflux pump mediating the transport of many drugs, implicated in clopidogrel resistance. This study enrolled 87 ischemic stroke patients with CYP2C1 9*1/*1 genotype, who received clopidogrel (75 mg/day) for at least 5 days before discharge. The maximum platelet aggregation (MPA) was measured by light transmittance aggregometry (LTA) to assess platelet function. Whole blood samples were obtained to evaluate the ABCC3 promoter methylation and mRNA expression of ABCC3. Pyrosequencing was carried out to investigate ABCC3 methylation and ABCC3 mRNA expression was evaluated by qPCR. The ABCC3 methylation was neither significantly different among the four MPA quartile groups (P = 0.275) nor independently associated with MPA values (R = 0.100, P = 0.358). However, the ABCC3 promoter methylation status in 87 clinical samples from patients correlated inversely with the expression of ABCC3 (R = - 0.854, P < 0.001). In addition, the ABCC3 expression was neither significantly different among the four quartile groups (P = 0.499) nor independently associated with MPA values (R = 0.060, P = 0.582). ABCC3 promoter methylation does not seem to exhibit any impact on MPA and clopidogrel response at all.

Association of the use of amlodipine with clopidogrel response in Chinese patients undergoing percutaneous coronary intervention.

Until recently, the precise mechanism of clopidogrel resistance remains unclear. Some clinical studies have demonstrated that calcium channel blockers (CCBs) could reduce the antiplatelet effect of clopidogrel in white or black subjects, implicating in clopidogrel resistance. However, that remains to be determined in Chinese patients. In this study, we sought to determine whether there could be a decreased antiplatelet effect of clopidogrel and an increased risk for developing adverse cardiovascular events after concomitant use of different CCBs and clopidogrel in Chinese patients treated with percutaneous coronary intervention (PCI). A subcohort of 249 patients not carrying the CYP2C19 *2, *3 or *17 variant was identified from a total of 617 consecutive clopidogrel-treated patients undergoing PCI and then categorized into three groups according to various CCB treatments. Baseline data, clinical characteristics and blood samples were collected for all patients. The maximum platelet aggregation (MPA) was measured by light transmittance aggregometry (LTA) to assess the platelet function in blood samples obtained from patients on day 3 after starting daily clopidogrel maintenance doses. The primary clinical end-point was a definite stent thrombosis (ST) episode, whereas secondary end-points were other major adverse cardiovascular events within 12 months after stenting. Of the 249 patients not carrying CYP2C19 *2, *3 and *17 variants, the ADP-induced MPA differed significantly among the three groups (P < 0.001). The MPA values were 1.76 times in the amlodipine group (41.6 ± 23.0%) than in the No CCB group (23.7 ± 14.1%) (P < 0.001). Moreover, in a linear regression model, the use of amlodipine was independently associated with MPA values (R = 0.375, P < 0.001), suggesting that the use of amlodipine might link to the increased MPA. However, the incidence of 1-year ST was not significantly higher in the amlodipine group than the No CCB group (OR, 4.80; 95% CI, 0.87 to 26.52; P = 0.068), and none of the risks for other adverse cardiovascular events were significantly different across the three groups (P = 0.11).

[Determination pharmacokinetics parameters of raw and different processed epimediums by pharmacology effect method].

OBJECTIVE: To determine the pharmacokinetics parameters of raw and different processed epimediums with pharmacology effect method. METHODS: The kidney-yang deficiency model mice induced with hydrocortisone was used and oxidative stress level was taken as index to estimate main pharmacokinetics parameters of raw and different processed epimediums. RESULTS: After raw and different processed epimediums po. in mice, the main pharmacokinetics parameters were: raw epimedium AUC(0-t) = 184.77 (g/kg) x h, AUC(0-infinity) = 342.30 (g/kg) x h, MRT(0-t) = 5.95 h, MRT (0-infinity) = 28.58 h,Tmax, = 0.75 h, Cmax = 57.67 g/kg; Fried epimedium AUC(0-t) = 208.08 (g/kg) x h, AUC(0-infinity) = 523.95 (g/kg) x h, MRT(0-t) = 5.86 h, MRT(0-infinity) = 22.55h, Tmax = 1 h, Cmax = 62.53 g/kg; Fat-fried epimedium AUC (0-t) = 232.17 (g/kg) x h, AUC(0-infinity) = 629.96 (g/kg) x h, MRT(0-t) = 5.28 h, MRT(0-infinity) = 19.62 h, Tmax = 1.5 h, Cmax = 81.84 g/kg. CONCLUSION: The differences of Cmax and AUC between processed products and raw products are significant, and the sequence is as follows: fat-fried products > fried products > raw products.

[Comparative study on effect of crude and different processed products of epimedium on pharmacokinetics characteristics in mice].

To study different impacts of crude epimedium and extracts from different processed epimedium on pharmacokinetic characteristic parameters in mice. To explore the rationality of its processed products, mice were orally administered with crude epimedium and extracting solutions from heated epimedium and processed epimedium. With increased SOD value as an indicator, the relationship between time and equivalent body dose was obtained by using the pharmacological effect method. DAS 2.0 software was adopted to compare their pharmacokinetic parameters. The results showed significant differences in such pharmacokinetic parameters as Cmax and AUC of processed epimedium, heated epimedium and crude epimedium, namely processed epimedium > heated epimedium > crude epimedium. We could come to the conclusion that heated epimedium showed increased bioavailability, while epimedium processed with sheep oil could further promote in vivo absorption.