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.

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.

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.

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.

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.

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).

Influence of CYP2C19 loss-of-function variants on the antiplatelet effects and cardiovascular events in clopidogrel-treated Chinese patients undergoing percutaneous coronary intervention.

BACKGROUND AND OBJECTIVES: A large number of clinical studies have well demonstrated that the loss-of-function variant allele CYP2C19 2 is associated with attenuated response to clopidogrel and increased risk of developing stent thrombosis (ST) in white or black patients with stenting. However, similar association studies on the effect of the CYP2C19 2 and 3 variants on maximum platelet aggregation (MPA) and the risk of cardiovascular events are currently unavailable for the Chinese patients. This work was aimed at assessing the impact of the CYP2C19 2 and 3 variants on the antiplatelet effects and adverse cardiovascular events in clopidogrel-treated Chinese patients undergoing percutaneous coronary intervention (PCI). METHODS: The study population consisted of 617 patients undergoing PCI. Genotypes were determined using MALDI/TOF-MS. MPA was measured by light transmittance aggregometry. The clinical end-point was the 1-year incidence of adverse cardiovascular events, including ST. RESULTS: Carriers of CYP2C19 heterozygous (1/2, or 1/3; n = 278) and mutant homozygous (2/2, 2/3, or 3/3, n = 80) genotypes had significantly higher MPA values than noncarriers (1/1; n = 259; P = 0.036 and 0.007 respectively). Moreover, the presence of the CYP2C19 2 or 3 mutant allele was significantly associated with an increased risk of developing ST, with the higher risk of ST being seen in patients homozygous for the CYP2C19 2 or 3 variant allele than in noncarriers (OR, 13.58; 95% CI, 1.49-123.31; P = 0.012). Furthermore, multivariate analysis revealed an independent association of the presence of CYP2C19*2 and/or 3 variant alleles with greater MPA values (P = 0.001) and increased risk of ST (OR, 11.67; 95% CI, 1.21-78.83; P = 0.022). However, there was no significant influence of CYP2C19 2 and 3 on the risk of developing other adverse cardiovascular events. CONCLUSIONS: Carriage of the loss-of-function genetic variants CYP2C19 2 and 3 is significantly associated with attenuated platelet response to clopidogrel and an increased risk of ST in Chinese patients treated with stenting.

Efffect of the ABCC3 -211C/T polymorphism on clopidogrel responsiveness in patients with percutaneous coronary intervention.

Multidrug resistance protein 3 (MPR3), encoded by the ATP-binding cassette, subfamily C (CFTR/MRP), member 3 (ABCC3) gene, functions as an important drug efflux transporter. The ABCC3 -211C/T polymorphism is associated with decreased MRP3 mRNA expression, and low MRP3 mRNA expression is associated with increased clopidogrel response in patients. The aim of the present study was to determine whether the -211C/T polymorphism is associated with altered antiplatelet effects and clinical outcomes in clopidogrel-treated patients. 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 percutaneous coronary intervention and then categorized into three groups on the basis of their ABCC3 -211C/T genotype. Baseline data, clinical characteristics and DNA samples were collected for all patients. Light transmittance aggregometry was used to determine ADP-induced maximum platelet aggregation (MPA) in blood samples obtained from patients on Day 3 after starting daily clopidogrel maintenance doses. Genotyping of CYP2C19*2, *3 and *17 variants and the ABCC3 -211C/T polymorphism was performed using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. 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. There were no differences in MPA values according to ABCC3 -211C/T genotype. A multiple linear regression model revealed that the ABCC3 -211C/T polymorphism was not independently associated with ADP-induced MPA measurements; a multiple logistic regression model revealed that carrying the ABCC3 -211C allele was not associated with the risk of developing an ST event in clopidogrel-treated patients not harbouring CYP2C19*2, *3 and *17 variants. In conclusion, the ABCC3 -211C/T polymorphism seems not to be associated with altered antiplatelet effects and clinical outcomes in clopidogrel-treated patients.

CYP2C19 polymorphism and antiplatelet effects of clopidogrel in Chinese stroke patients.

Recently published data indicate that CYP2C19*2 allele is the major determinant of metabolic bioactivation of clopidogrel and thereby variability of antiplatelet effect of clopidogrel in white or black patients undergoing elective coronary stent placement. The conclusion may not be fully generalized or extrapolated to the Chinese people due to significantly higher frequencies of the CYP2C19*2 or *3 variant alleles. We sought to investigate whether the CYP2C19*2 or *3 alleles affects platelet reactivity of clopidogrel in Chinese stroke patients. The study included 183 consecutive Chinese stroke patients after loading with clopidogrel 300 mg. Platelet function was assessed by adenosine diphosphate-induced (ADP 20 micromol/L) platelet aggregation and by light transmittance aggregometry (LTA) after seven 75-mg maintenance doses of clopidogrel before discharge. CYP2C19*2 or *3 genotypes were determined by time-of-flight mass spectrometer (MALDI/TOF-MS). In those patients who were carriers of 1 mutant allele (mutant heterozygotes, CYP2C19*1/*2 or *1/*3), ADP-induced maximum platelet aggregation (MPA) were significantly different compared with wild-type homozygous patients [37.2% (IQR, 19.6 to 50.5%) versus 23.6% (IQR, 14.0 to 35.4%), respectively; P=0.002]. In addition, in the patients who were carriers of 2 mutant allele (mutant homozygotes, CYP2C19*2/*2, *2/*3 or *3/*3,), MPA were also significantly different compared with wildtype homozygous patients [35.7% (IQR, 21.0 to 78.1%) versus 23.6% (IQR, 14.0 to 35.4%, respectively; P = 0.039]. By multivariable linear regression, CYP2C19*2 or *3 loss-of-function alleles were independently associated with ADP-induced MPA measurements (partial R2 = 0.138, P = 0.001). CYP2C19*2 or *3 allele does link to increased MPA and clopidogrel response.

[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.

[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.

Paraoxonase-1 Q192R polymorphism is not associated with clopidogrel response in Chinese stroke patients.

It is well known that CYP2C19*2/*2 is associated with attenuated response to clopidogrel, but recent findings indicated that in white patients, paraoxonase-1 (PON1) 192Q/Q was a major determinant of clopidogrel efficacy. The objective of this research was to assess the impact of PON1 Q192R polymorphism on the maximum platelet aggregation (MPA) and the anti-platelet effect of clopidogrel in clopidogrel-treated Chinese stroke patients. The study recruited 183 eligible Chinese stroke patients treated with a loading dose of 300-mg clopidogrel and a 75-mg daily maintenance dose. CYP2C19*2 and PON1 Q192R were genotyped, a subcohort of 13 patients with CYP2C19 *2/*2 genotype was excluded. Finally 170 patients with CYP2C19*1/*1 (wild-type homozygotes, n = 87) or CYP2C19*1/*2 (mutant heterozygotes, n = 83) were enrolled in the study population. These patients were divided into three groups according to their PON1 Q192R genotype: wild-type homozygotes, PON1 192QQ, n = 17; mutant heterozygotes, PON1 192QR, n = 81; mutant homozygotes, PON1 192RR, n = 72. MPA was measured by light transmittance aggregometry (LTA) to assess platelet function after seven 75-mg maintenance doses of clopidogrel before discharge. In those patients who were carriers of 1 mutant allele (PON1 Q/R192), ADP-induced MPA were not significantly different compared with wild-type homozygous patients [30.5% (IQR, 17.5 to 49.1%) versus 25.0% (IQR, 10.0 to 52.5%), respectively; P = 0.910]. In addition, in the patients who were carriers of the 2 mutant allele (PON1 R/R192), MPA were also not significantly different from wild-type homozygous patients [29.2% (IQR, 15.0 to 43.4%) versus 25.0% (IQR, 10.0 to 52.5%), respectively; P = 0.717]. Results of a multivariable linear regression model demonstrated that PON1 192R allele carriage was not independently associated with ADP-induced MPA measurements (P = 0.408). PON1 Q192R polymorphism does not seem to exhibit any impact on MPA and clopidogrel response at all.

Pharmacokinetics of clopidogrel in healthy Chinese volunteers.

There are marked ethnic variabilities in the metabolism of clopidogrel. The pharmacokinetic (PK) characteristics of clopidogrel have been studied previously in whites or Korean volunteers, but these PK characteristics may not be fully extrapolated to the Chinese people. Little is known about the PK characteristics of clopidogrel in Chinese population. The aim of this study was to evaluate the pharmacokinetic profiles of clopidogrel in 20 healthy Chinese volunteers after administration of a single dose of clopidogrel 75 mg. The peak plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration versus time curve from time 0 h to 36 h (AUC(0-36)), elimination half-life (t1/2), clearance rate (CL/F) and apparent volume of distribution (Vd) were (1.804 +/- 1.706) ng/ml, (0.7 +/- 0.3) h, (2.465 +/- 1.693) ng x h/ml, (7.3 +/- 7.0) h, (53.09 +/- 34.65) x 10(3) L/h and (447.1 +/- 440.8) x 10(3) L, respectively.

CYP2C19 681G > A polymorphism and pharmacokinetics of clopidogrel in Chinese healthy volunteers.

The aim of this study was to investigate the contribution of the most frequent single nucleotide polymorphism of CYP2C19 681G>A to the pharmacokinetics of clopidogrel in 20 healthy Chinese volunteers after administration of a single dose of clopidogrel 75mg. The peak plasma concentration (Cmax) was higher in the 681GA+681AA group than that in the 681GG group (1.93 +/- 1.77 vs. 1.65 +/- 1.56ng/mL, P=0.613). The area under the curve to the last measurable concentration (AUC(0-36)) and area under the curve extrapolated to infinity (AUC(0-infinity)) of clopidogrel were lower in the 681GG group than that in the 681GA+ 681AA group (2.25 +/- 1.64 vs. 2.64 +/- 1.69 ng h/mL, P = 0.465; 2.26 +/- 1.65 vs. 2.67 +/- 1.71 ng h/mL, P = 0.455) respectively. The oral clearance (CI/F) was lower in the 681GA+681AA group than that in the 681GG group (51.96 +/- 36.13 vs. 54.47 +/- 35.21 x 10(3) L/h, P=0.829). The genetic polymorphism of CYP2C19 681G > A does not cause significant alterations in the pharmacokinetics of clopidogrel at a clinically relevant therapeutic dose in healthy Chinese volunteers.

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.

Quantification of pantoprazole in human plasma using LC-MS/MS for pharmacokinetics and bioequivalence study.

A highly sensitive and rapid method for the analysis of pantoprazole in human plasma using liquid chromatography coupled to tandem electrospray ionization mass spectrometry was developed. The procedure involves a simple protein precipitation method with methyl alcohol and separation by RP-HPLC. Detection was performed by positive ion electrospray ionization in multiple reaction monitoring mode, monitoring the transitions m/z 384.1→200.0 and m/z 346.1→198.0, for quantification of pantoprazole and IS, respectively. The standard calibration curves showed good linearity within the range of 5-5,000 ng mL(-1). The lower limit of quantitation (LLOQ) was about 5 ng mL(-1). The extractive recovery of pantoprazole from the biological matrix was more than 77.58% and the matrix effect was complied with relevant provision. The intra-day accuracy of the drug containing serum samples was more than 92.19% with a precision of 0.79-5.36%. The inter-day accuracy was 85.49% or more, with a precision of 0.91-12.67%. Intra and inter-day accuracy of the assay at four concentrations were 97.9-98.2% with a precision of 4.2-13.9%. This method offered good precision and accuracy and was successfully applied to the pharmacokinetic and bioequivalence studies of 40 mg of enteric-coated pantoprazole in 20 healthy Chinese volunteers.

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.

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.