AIM: To investigate the metabolism and disposition characteristics of HSK7653 in healthy male Chinese participants. METHODS: A single oral dose of 80 µCi (25 mg) [14C]HSK7653 capsules was administered to six healthy participants, and blood, plasma, urine and faeces were collected. Quantitative and qualitative analysis was conducted to investigate the pharmacokinetics, blood-to-plasma ratio, mass balance and metabolism of HSK7653. RESULTS: The drug was well absorbed and reached a maximum concentration at 1.25 h. The drug-related components (HSK7653 and its metabolites) were eliminated slowly, with a half-life (t1/2) of 111 h. Unchanged HSK7653 contributed to more than 97% of the total radioactivity in all plasma samples. The blood-to-plasma ratio (0.573-0.845) indicated that HSK7653 did not tend to distribute into blood cells. At 504 h postdose, up to 95.9% of the dose was excreted, including 79.8% in urine and 16.1% in faeces. Most of the radioactivity (75.5% dose) in excreta was unchanged HSK7653. In addition, nine metabolites were detected in urine and faeces. The most abundant metabolite was M6-2, a dioxidation product of HSK7653, which accounted for 4.73% and 2.63% of the dose in urine and faeces, respectively. The main metabolic pathways of HSK7653 in vivo included oxidation, pyrrole ring opening and sulphonamide hydrolysation. CONCLUSION: HSK7653 was well absorbed, slightly metabolized and slowly excreted in humans. The high plasma exposure and long t1/2 of HSK7653 may contribute to its long-lasting efficacy as a long-acting dipeptidyl peptidase-4 inhibitor.
BACKGROUND: Iruplinalkib is a novel anaplastic lymphoma kinase (ALK) inhibitor for the treatment of ALK-positive crizotinib-resistant NSCLC. RESEARCH DESIGN AND METHODS: A single oral dose of 120 mg/3.7 MBq [14C]iruplinalkib was administered to healthy subjects. Blood, urine and fecal samples were collected and analyzed for iruplinalkib and its metabolites. The safety of iruplinalkib was also assessed. RESULTS: Iruplinalkib was absorbed quickly and eliminated slowly from plasma, with a Tmax of 1.5 h and t1/2 of 28.6 h. About 88.85% of iruplinalkib was excreted at 312 h, including 20.23% in urine and 68.63% in feces. Seventeen metabolites of iruplinalkib were identified, and M3b (demethylation), M7 (cysteine conjugation), M11 (oxidative dehydrogenation and cysteine conjugation of M3b) and M12 (oxidative dehydrogenation and cysteine conjugation) were considered the prominent metabolites in humans. Iruplinalkib-related compounds were found to be covalently bound to proteins, accounting for 7.70% in plasma and 17.96% in feces, which suggested chemically reactive metabolites were formed. There were no serious adverse events observed in the study. CONCLUSIONS: Iruplinalkib was widely metabolized and excreted mainly through feces in humans. Unchanged iruplinalkib, cysteine conjugates and covalent protein binding products were the main drug-related compounds in circulation. Iruplinalkib was well tolerated at the study dose. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (Identifier: Anonymized).
Cysteine , Protein Kinase Inhibitors , Humans , Administration, Oral , Cysteine/therapeutic use , Healthy Volunteers , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Receptor Protein-Tyrosine Kinases
Background: Acute graft-versus-host disease (aGVHD) is a major complication following hematopoietic stem cell transplantation (HSCT). Objective: This study aimed to explore the risk factors for the incidence of aGVHD in patients post-HSCT. Design: This was a retrospective study. Methods: A total of 407 patients were enrolled. The patients' data were recorded from the medical records. The exposure of cyclosporine was estimated based on a population pharmacokinetics model. The occurrence of aGVHD was clinically graded and staged in severity from grades I to IV. A proportional odds model that estimated the cumulative probabilities of aGVHD was used to analyze the data using a nonlinear mixed-effects model. Then, the model parameters and plausibility were evaluated by bootstrap and visual predictive checks. Results: The typical probabilities were 18.9% and 17.9% for grade II and grades III-IV, respectively. The incidence of grade II and grade III-IV aGVHD for human leukocyte antigen (HLA) haplo sibling donor patients was higher than that for HLA-matched donor patients. The incidence of grade II and grade III-IV aGVHD decreased with increasing early cyclosporine trough concentration; however, cyclosporine exposure was not associated with the incidence of aGVHD. Conclusion: HLA matching and early cyclosporine trough concentration were important factors for the occurrence of aGVHD.
BACKGROUND AND OBJECTIVES: Due to the high individual variability of anticoagulant warfarin, this study aimed to investigate the effects of vitamin K concentration and gut microbiota on individual variability of warfarin in 246 cardiac surgery patients. METHODS: The pharmacokinetics and pharmacodynamics (PKPD) model predicted international normalized ratio (INR) and warfarin concentration. Serum and fecal samples were collected to detect warfarin and vitamin K [VK1 and menaquinone-4 (MK4)] concentrations and gut microbiota diversity, respectively. In addition, the patient's medical records were reviewed for demographic characteristics, drug history, and CYP2C9, VKORC1, and CYP4F2 genotypes. RESULTS: The PKPD model predicted ideal values of 62.7% for S-warfarin, 70.4% for R-warfarin, and 76.4% for INR. The normal VK1 level was 1.34±1.12 nmol/ml (95% CI: 0.33-4.08 nmol/ml), and the normal MK4 level was 0.22±0.18 nmol/ml (95% CI: 0.07-0.63 nmol/ml). The MK4 to total vitamin K ratio was 16.5±9.8% (95% CI: 4.3-41.5%). The S-warfarin concentration of producing 50% of maximum anticoagulation and the half-life of prothrombin complex activity tended to increase with vitamin K. Further, Prevotella and Eubacterium of gut microbiota identified as the main bacteria associated with individual variability of warfarin. The results suggest that an increase in vitamin K concentration can decrease anticoagulation, and gut microbiota may influence warfarin anticoagulation through vitamin K2 synthesis. CONCLUSION: This study highlights the importance of considering vitamin K concentration and gut microbiota when prescribing warfarin. The findings may have significant implications for the personalized use of warfarin. Further research is needed to understand better the role of vitamin K and gut microbiota in warfarin anticoagulation.
Cardiac Surgical Procedures , Gastrointestinal Microbiome , Humans , Warfarin/pharmacology , Vitamin K , Cytochrome P450 Family 4/genetics , Vitamin K Epoxide Reductases/genetics , Anticoagulants/pharmacology , Anticoagulants/therapeutic use , Genotype
Rabbit anti-thymocyte globulin (rATG) has been widely used to prevent graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The therapeutic window of rATG is narrow, and it may increase the risk of relapse, viral reactivation, delayed immune reconstitution and GvHD when overexposed or underexposed. Therefore, a reliable method for detecting the rATG concentration in human serum by flow cytometry was established and fully validated for therapeutic drug monitoring. In this method, Jurkat T cells were used to capture active rATG in human serum, and PE-labeled donkey anti-rabbit IgG was used as a secondary antibody. The method showed good specificity, selectivity and excellent linearity at concentration of 0.00300-20.0â¯AU/mL. The intra- and interday precision values were all within 20% at four concentration levels for the analyte. The stock solutions of rATG showed no significant degradation after storage at ambient temperature for 8â¯h and at -â¯80⯰C for 481 days. No significant degradation of rATG in serum was observed at ambient temperature for 6â¯h, during six freezethaw cycles and at -â¯80⯰C for at least 373 days. This method was fully validated and successfully applied to monitor active rATG concentration in serum of patients with haploid-identical hematopoietic stem cell transplantation.
Antilymphocyte Serum , Graft vs Host Disease , Humans , Antilymphocyte Serum/therapeutic use , Drug Monitoring , Flow Cytometry , Graft vs Host Disease/drug therapy , Graft vs Host Disease/prevention & control , Jurkat Cells
Polymyxin B, which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections, became available in China in Dec. 2017. As dose adjustments are based solely on clinical experience of risk toxicity, treatment failure, and emergence of resistance, there is an urgent clinical need to perform therapeutic drug monitoring (TDM) to optimize the use of polymyxin B. It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use. We report a consensus on TDM guidelines for polymyxin B, as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society. The consensus panel was composed of clinicians, pharmacists, and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations, sample collection, reporting, and explanation of TDM results. The guidelines provide the first-ever consensus on conducting TDM of polymyxin B, and are intended to guide optimal clinical use.
Drug Monitoring , Polymyxin B , Humans , Anti-Bacterial Agents/therapeutic use , China , Drug Monitoring/methods , Practice Guidelines as Topic
BACKGROUND: Cyclosporin A is a calcineurin inhibitor which has a narrow therapeutic window and high interindividual variability. Various population pharmacokinetic models have been reported; however, professional software and technical personnel were needed and the variables of the models were limited. Therefore, the aim of this study was to establish a model based on machine learning to predict CsA trough concentrations in Chinese allo-HSCT patients. METHODS: A total of 7874 cases of CsA therapeutic drug monitoring data from 2069 allo-HSCT patients were retrospectively included. Sequential forward selection was used to select variable subsets, and eight different algorithms were applied to establish the prediction model. RESULTS: XGBoost exhibited the highest prediction ability. Except for the variables that were identified by previous studies, some rarely reported variables were found, such as norethindrone, WBC, PAB, and hCRP. The prediction accuracy within ±30% of the actual trough concentration was above 0.80, and the predictive ability of the models was demonstrated to be effective in external validation. CONCLUSION: In this study, models based on machine learning technology were established to predict CsA levels 3-4 days in advance during the early inpatient phase after HSCT. A new perspective for CsA clinical application is provided.
Cyclosporine , Hematopoietic Stem Cell Transplantation , Humans , Immunosuppressive Agents/adverse effects , Retrospective Studies , East Asian People , Transplantation, Homologous/adverse effects , Hematopoietic Stem Cell Transplantation/adverse effects , Machine Learning
Accurate therapeutic drug monitoring (TDM) of vancomycin, meropenem, linezolid and teicoplanin are conducive to developing optimal therapeutic regimes for patients. However, the measurement status of those drugs in different laboratories has not been reported. In this study, four samples including two frozen plasma samples and two lyophilized plasma samples were measured by over 35 laboratories across China. The inter- and intra-laboratory %CV, biases (%) of laboratories and intra- and inter-measurement-system %CV were calculated and analyzed. The short-term stability and homogeneity of those drugs in samples were studied. The results of frozen and lyophilized samples were also compared to determine whether there were significant differences in their matrix effects on various measurement systems. Results showed most laboratories' intra-laboratory %CVs were less than 9% for all drugs, and the mean inter-laboratory %CVs were 18.4%, 86.4%, 19.1% and 37.1% for vancomycin, meropenem, linezolid and teicoplanin measurements, respectively. For vancomycin, the intra-measurement %CV of commercial measurement systems was found to be smaller than that of other measurement systems. For meropenem, linezolid and teicoplanin, the agreement among laboratories using self-developed methods (Liquid chromatography-mass spectrometry [LC-MS] or high-performance liquid chromatography [HPLC]) was not satisfactory as most intra-measurement system CVs% were over 20%. Drugs in lyophilized samples were found to be more stable than in frozen samples, and no obvious differences in matrix effects were found for those two kinds of processed samples on most measurement systems. In conclusion, this study depicted the measurement status of those drugs in clinical laboratories, and found the lyophilized samples were more suitable EQA material for those drugs.
Anti-Bacterial Agents , Vancomycin , Humans , Anti-Bacterial Agents/therapeutic use , Linezolid , Meropenem , Teicoplanin , Drug Monitoring/methods
Nucleobase and nucleoside analogs (NAs) play important roles in cancer therapy. Although there are obvious individual differences in NA treatments, most NAs lack direct relationships between their plasma concentration and efficacy or adverse effects. Accumulating evidence suggests that the intracellular active metabolite levels of NAs predict patient outcomes. This article reviewed the relationships between NA intracellular active metabolite levels and their efficacy or adverse effects. The factors affecting the formation of intracellular active metabolites and combination regimens that elevate intracellular active metabolite levels were also reviewed. Given the mechanism of NA cytotoxicity, NA intracellular active metabolite levels may be predictive of clinical outcomes. Many clinical studies support this hypothesis. Therefore, the monitoring of intracellular active metabolite levels is beneficial for individualized NA treatment. However, to perform clinical monitoring in practice, well-designed studies are needed to explore the optimal threshold or range and the appropriate regimen adjustment strategies based on these parameters.
Nucleosides , Precision Medicine , Humans , Nucleosides/metabolism , Nucleosides/therapeutic use
Aims: The aims of the study were to 1) establish a population pharmacokinetic (Pop-PK) model for busulfan in Chinese pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) and then estimate busulfan exposure and 2) explore the association between busulfan exposure and clinical outcomes. Methods: A total of 128 patients with 467 busulfan concentrations were obtained for Pop-PK modeling using nonlinear mixed effect model (NONMEM) software. Sixty-three patients who received the 16-dose busulfan conditioning regimen were enrolled to explore the correlations between clinical outcomes and the busulfan area under the concentration-time curve (AUC) using the Cox proportional hazards regression model, Kaplan-Meier method and logistic regression. Results: The typical values for clearance (CL) and distribution volume (V) of busulfan were 7.71 L h-1 and 42.4 L, respectively. The allometric normal fat mass (NFM) and maturation function (Fmat) can be used to describe the variability in CL, and the fat-free mass (FFM) can be used to describe the variability in V. Patients with AUCs of 950-1,600 µM × min had 83.7% (95% CI: 73.3-95.5) event-free survival (EFS) compared with 55.0% (95% CI: 37.0-81.8) for patients with low or high exposure (p = 0.024). The logistic regression analysis results showed no association between transplant-related toxicities and the busulfan AUC (p > 0.05). Conclusions: The variability in busulfan CL was related to the NFM and Fmat, while busulfan V was related to the FFM. Preliminary analysis results suggested that a busulfan AUC of 950-1,600 µM × min was associated with better EFS in children receiving the 16-dose busulfan regimen.
PURPOSE: Positron emission tomography (PET) with specific diagnostic probes for quantifying CD8+ T cells has emerged as a powerful technique for monitoring the immune response. However, most CD8+ T cell radiotracers are based on antibodies or antibody fragments, which are slowly cleared from circulation. Herein, we aimed to develop and assess 68 Ga-NODAGA-SNA006 for instant PET (iPET) imaging of CD8+ T cells. METHODS: A novel nanobody without a hexahistidine (His6) tag, SNA006-GSC, was designed, site-specifically conjugated with NODAGA-maleimide and radiolabelled with 68 Ga. The PET imaging profiles of 68 Ga-NODAGA-SNA006 were evaluated in BALB/c MC38-CD8+/CD8- tumour models and cynomolgus monkeys. Three volunteers with lung cancer underwent whole-body PET/CT imaging after 68 Ga-NODAGA-SNA006 administration. The biodistribution, pharmacokinetics and dosimetry of patients were also investigated. In addition, combined with immunohistochemistry (IHC), the quantitative performance of the tracer for monitoring CD8 expression was evaluated in BALB/c MC38-CD8+/CD8- and human subjects. RESULTS: 68 Ga-NODAGA-SNA006 was prepared with RCP > 98% and SA > 100 GBq/µmol. 68 Ga-NODAGA-SNA006 exhibited specific uptake in MC38-CD8+ xenografts tumours, CD8-rich tissues (such as the spleen) in monkeys and CD8+ tumour lesions in patients within 1 h. Fast washout from circulation was observed in three volunteers (t1/2 < 20 min). A preliminary quantitative linear relationship (R2 = 0.9668, p < 0.0001 for xenografts and R2 = 0.7924, p = 0.0013 for lung patients) appeared between 68 Ga-NODAGA-SNA006 uptake and CD8 expression. 68 Ga-NODAGA-SNA006 was well tolerated by all patients. CONCLUSION: 68 Ga-NODAGA-SNA006 PET imaging can instantly quantify CD8 expression with an ideal safety profile and is expected to be important for dynamically tracking CD8+ T cells and monitoring immune responses for individualised cancer immunotherapy. TRIAL REGISTRATION: NCT05126927 (19 November 2021, retrospectively registered).
Neoplasms , Positron Emission Tomography Computed Tomography , Humans , Pilot Projects , Tissue Distribution , CD8-Positive T-Lymphocytes , Tomography, X-Ray Computed , Heterocyclic Compounds, 1-Ring , Positron-Emission Tomography/methods , Acetates , Maleimides , Immunoglobulin Fragments , Gallium Radioisotopes , Cell Line, Tumor
PURPOSE: Venetoclax (VEN), an anti-tumor drug that is a substrate of cytochrome P450 3A enzyme (CYP3A4), is used to treat leukemia. Voriconazole (VCZ) is an antifungal medication that inhibits CYP3A4. The goal of this study is to predict the effect of VCZ on VEN exposure. METHOD: Two physiological based pharmacokinetics (PBPK) models were developed for VCZ and VEN using the bottom-up and top-down method. VCZ model was also developed to describe the effect of CYP2C19 polymorphism on its pharmacokinetics (PK). The reversible inhibition constant (Ki) of VCZ for CYP3A4 was calibrated using drug-drug interaction (DDI) data of midazolam and VCZ. The clinical verified VCZ and VEN model were used to predict the DDI of VCZ and VEN at clinical dosing scenario. RESULT: VCZ model predicted VCZ exposure in the subjects of different CYP2C19 genotype and DDI related fold changes of sensitive CYP3A substrate with acceptable prediction error. VEN model can capture PK of VEN with acceptable prediction error. The DDI PBPK model predicted that VCZ increased the exposure of VEN by 4.5-9.6 fold. The increase in VEN exposure by VCZ was influenced by subject's CYP2C19 genotype. According to the therapeutic window, VEN dose should be reduced to 100 mg when co-administered with VCZ. CONCLUSION: The PBPK model developed here could support individual dose adjustment of VEN and DDI risk assessment. Predictions using the robust PBPK model confirmed that the 100 mg dose adjustment is still applicable in the presence of VCZ with high inter-individual viability.
Bridged Bicyclo Compounds, Heterocyclic , Cytochrome P-450 CYP3A , Models, Biological , Sulfonamides , Voriconazole , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Cytochrome P-450 CYP2C19/genetics , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Drug Interactions , Humans , Sulfonamides/pharmacokinetics , Voriconazole/pharmacokinetics
Enzyme-linked immunosorbent assay (ELISA) is one of the most common methods in biological studies, and enzyme-linked immunospot (ELISpot) is a method to measure specific cell numbers by detecting protein secretion at a single-cell level. However, these two current methods can only detect one signal at one time and the sensitivity is not high enough to test low-concentration samples, which are major shortcomings in systematically analyzing the samples of interest. Herein, we demonstrated fluorescence-based oligo-linked immunosorbent assay (FOLISA) and fluorescence-based oligo-linked immunospot (FOLISPOT), which utilized DNA-barcoded antibodies to provide a highly multiplexed method with signal amplification. Signal amplification and simultaneous multiple-target detection were achieved by DNA complementary pairing and modular orthogonal DNA concatemers. By comparing FOLISA with traditional ELISA and comparing FOLISPOT with traditional ELISPOT, we found that the detection sensitivities of FOLISA and FOLISPOT are much higher than those of traditional ELISA and ELISPOT. The detection limit of ELISA is around 3 pg/mL, and the detection limit of FOLISA is below 0.06 pg/mL. FOLISPOT can detect more spots than ELISPOT and can detect targets that are undetectable for ELISPOT. Furthermore, FOLISA and FOLISPOT allowed sequential detection of multiple targets by using a single dye or multiple dyes in one round and sequential detection in multiple rounds. Thus, FOLISA and FOLISPOT enabled simultaneous detection of a large number of targets, significantly improved the detection sensitivity, and overcame the shortcomings of ELISA and ELISPOT. Overall, FOLISA and FOLISPOT presented effective and general platforms for rapid and multiplexed detection of antigens or antibodies with high sensitivity, either in laboratory tests or potentially in clinic tests.
Antigens , Immunosorbents , Antibodies , Enzyme-Linked Immunosorbent Assay/methods , Enzyme-Linked Immunospot Assay/methods
In this study, a sensitive and rapid ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed for the simultaneous analysis of cytarabine (ara-C), cytarabine monophosphate (ara-CMP), cytarabine diphosphate (ara-CDP) and cytarabine triphosphate (ara-CTP) in the cytosol and nucleus. The separation of analytes and endogenous interferents was achieved in 8 min on a hypercarb column (2.1 mm × 100 mm, 3 µm) by using a gradient elution with 95% acetonitrile and aqueous 5 mM hexylamine with 0.4% (v/v) diethylamine adjusted to pH 10. The analytes were detected with both negative and positive electrospray ionization in multiple reaction monitoring (MRM) mode. The calibration curve demonstrated good linearity ranging from 5 to 750 nM for ara-C, 50-7500 nM for ara-CMP, 20-3000 nM for ara-CDP and 1-150 nM for ara-CTP in the cytosol. In the nucleus, good linearity was achieved over a concentration range of 1-100 nM for ara-C, 5-500 nM for ara-CMP, 2.5-250 nM for ara-CDP and 0.5-50 nM for ara-CTP. Intra- and interbatch accuracies and precisions met the standards of validation. The matrix effect, recovery and stability were also within acceptable ranges. After incubation with 10 µM ara-C for 3 h, the levels of ara-C, ara-CMP, ara-CDP and ara-CTP in the cytosol and nucleus of HL-60 cells and HL-60/ara-C cells were determined. Most of the metabolites were found within the quantitation range. The results showed that the nuclear ara-CTP level was significantly different than the intracellular ara-CTP level between HL-60 and HL-60/ara-C cells.
Arabinofuranosylcytosine Triphosphate , Cytarabine , Arabinofuranosylcytosine Triphosphate/analysis , Arabinofuranosylcytosine Triphosphate/metabolism , Chromatography, High Pressure Liquid/methods , Cytosol/metabolism , Diphosphates , Humans , Tandem Mass Spectrometry
AIM: This trial (NCT04013048) investigated the metabolite profiles, mass balance and pharmacokinetics of fuzuloparib, a novel poly (ADP-ribose) polymerase inhibitor, in subjects with advanced solid cancers. METHODS: A single dose of 150 mg [14 C]fuzuloparib was administered to five subjects with advanced solid cancers. Blood, urine and faecal samples were collected, analysed for radioactivity and unchanged fuzuloparib, and profiled for metabolites. The safety of the medicine was assessed during the study. RESULTS: The maximum concentrations (Cmax ) of the total radioactivity (TRA) and unchanged fuzuloparib in plasma were 5.39 µg eq./mL and 4.19 µg/mL, respectively, at approximately 4 hours post dose. The exposure (AUC0-t ) of fuzuloparib accounted for 70.7% of the TRA in plasma, and no single metabolite was observed accounting for more than 10% of the plasma TRA. The recovery of TRA in excreta was 103.3 ± 3.8% in 288 hours, including 59.1 ± 9.9% in urine and 44.2 ± 10.8% in faeces. Sixteen metabolites of fuzuloparib were identified, including mono-oxidation (M1), hydrogenation (M2), di-oxidation (M3), trioxidation (M4), glucuronidation (M5, M7, M8) and de-ethylation (M6) products, and there was no specific binding between these metabolites and blood cells. Aliphatic hydroxylated fuzuloparib (M1-1) was the primary metabolite in the excreta, accounting for more than 40% of the dose for subjects. There were no serious adverse events observed in the study. CONCLUSION: Fuzuloparib was widely metabolized and excreted completely through urine and faeces in subjects with advanced solid cancer. Unchanged fuzuloparib was indicated to be the primary drug-related compound in circulation. [14 C]fuzuloparib was well-tolerated at the study dose.
Antineoplastic Agents , Neoplasms , Adenosine Diphosphate/analysis , Administration, Oral , Antineoplastic Agents/adverse effects , Feces/chemistry , Humans , Neoplasms/drug therapy , Neoplasms/metabolism , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , Poly(ADP-ribose) Polymerase Inhibitors/analysis , Ribose/analysis
PURPOSE: The identification of optimal drug administration schedules to overcome the emergence of resistance that causes treatment failure is a major challenge in cancer research. We report the outcomes of a computational strategy to assess the dynamics of tumor progression as a function of time under different treatment regimens. METHODS: We developed an evolutionary game theory model that combined Lotka-Volterra equations and pharmacokinetic properties with 2 competing cancer species: nivolumab-response cells and Janus kinase (JAK1/2) mutation cells. We selected 3 therapeutic schemes that have been tested in the clinical trials: 3 mg/kg Q2w, 10 mg/kg Q2w, and 480 mg Q4w. The simulation was performed under the intervals of 75, 125, and 175 days, respectively, for each regimen. The data sources of the pharmacokinetic parameters used in this study were collected from previous published clinical trials. Other parameters in the evolutionary model come from the existing references. FINDINGS: Predictions under various dose schedules indicated a strong selection for nivolumab-independent cells. Under the 3 mg/kg dose strategy, the reproduction rate of JAK mutation cells was highest, with strongest tumor elimination ability at a 75-day interval between treatments. Prolonged drug intervals to 125 or 175 days delayed tumor evolution but accelerated tumor recurrence. Although 10 mg/kg Q2w had an obvious clinical effect in a short time, it further promotes the progress of resistant population compared with the 3 mg/kg dose. Our model suggests that 480 mg Q4w would be more valuable in terms of clinical efficacy, but complete resistant occurs earlier regardless the interval. IMPLICATIONS: The results of this study emphasize that increasing the dose or shortening the interval between doses accelerates the evolution of heterogeneous populations, although the short-term effect is significant. In practice, the therapeutic regimen should be balanced according to the evolutionary principle.
Neoplasms , Nivolumab , Computer Simulation , Drug Administration Schedule , Humans , Neoplasms/drug therapy , Nivolumab/therapeutic use , Treatment Outcome
BACKGROUND: It has been shown that eosinophils are decreased and monocytes are elevated in patients with acute ischemic stroke (AIS), but the impact of eosinophil-to-monocyte ratio (EMR) on clinical outcomes among AIS patients remains unclear. We aimed to determine the relationship between EMR on admission and 3-month poor functional outcome in AIS patients. METHODS: A total of 521 consecutive patients admitted to our hospital within 24 h after onset of AIS were prospectively enrolled and categorized in terms of quartiles of EMR on admission between August 2016 and September 2018. The endpoint was the poor outcome defined as modified Rankin Scale score of 3 to 6 at month 3 after admission. RESULTS: As EMR decreased, the risk of poor outcome increased (p < 0.001). Logistic regression analysis revealed that EMR was independently associated with poor outcome after adjusting potential confounders (odds ratio, 0.09; 95% CI 0.03-0.34; p = 0.0003), which is consistent with the result of EMR (quartile) as a categorical variable (odds ratio, 0.23; 95% CI 0.10-0.52; ptrend < 0.0001). A non-linear relationship was detected between EMR and poor outcome, whose point was 0.28. Subgroup analyses further confirmed these associations. The addition of EMR to conventional risk factors improved the predictive power for poor outcome (net reclassification improvement: 2.61%, p = 0.382; integrated discrimination improvement: 2.41%, p < 0.001). CONCLUSIONS: EMR on admission was independently correlated with poor outcome in AIS patients, suggesting that EMR may be a potential prognostic biomarker for AIS.
Biomarkers/blood , Eosinophils , Ischemic Stroke/blood , Monocytes , Recovery of Function , Aged , Female , Humans , Male , Middle Aged , Prognosis
AIMS: This trial (NCT03751956) investigated the mass balance, pharmacokinetics and pharmacodynamics of HSK3486, a novel anaesthetic, in healthy subjects. METHODS: A single dose of 0.4 mg/kg [14 C]HSK3486 was administered to six healthy subjects. Blood, urine and faecal samples were collected, analysed for radioactivity, unchanged HSK3486 and profiled for metabolites. The Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale and vital signs were closely monitored during the study. RESULTS: The mean recovery of total radioactivity in excreta was 87.3% in 240 h, including 84.6% in urine and 2.65% in faeces. The exposure (AUC0-t ) of total radioactivity was much higher than that of unchanged HSK3486 in plasma, indicating there were circulating metabolites in plasma. The glucuronide conjugate of HSK3486 (M4) was found as the only major circulating metabolite in plasma (79.3%), while unchanged HSK3486 accounted for only 3.97% of the total radiation exposure. M4 also resulted in a longer estimated elimination half-life (t1/2 ) of total radioactivity than that of unchanged HSK3486 in plasma. Fortunately, the metabolite was detected to be not specific to red blood cells and was suggested to be nonhypnotic and nontoxic. All the subjects were quickly anaesthetized (2 min) after drug administration and woke up smoothly after a short time (5.5-14.1 min) with few residual effects. The only adverse event in the study was mild (grade 1) and consisted of hypotension. CONCLUSION: HSK3486 is a promising anaesthetic candidate with rapid onset of action and clear absorption, distribution, metabolism, excretion (ADME) processes. HSK3486 showed favourable pharmacokinetic characteristics, pharmacodynamic responses and safety at the study dose.
Anesthetics , Administration, Intravenous , Administration, Oral , Feces , Healthy Volunteers , Humans , Metabolic Clearance Rate
CD47, an immune checkpoint receptor frequently unregulated in various blood and solid tumors, interacts with ligand SIPRα on innate immune cells, and conveys a "do not eat me" signal to inhibit macrophage-mediated tumor phagocytosis. This makes CD47 a valuable target for cancer immunotherapy. However, the therapeutic utility of CD47-SIRPα blockade monoclonal antibodies is largely compromised due to significant red blood cell (RBCs) toxicities and fast target-mediated clearance as a result of extensive expression of CD47 on normal cells. To overcome these limitations and further improve therapeutic efficacy, we designed IBI322, a CD47/PD-L1 bispecific antibody which attenuated CD47 activity in monovalent binding and blocked PD-L1 activity in bivalent binding. IBI322 selectively bound to CD47+PD-L1+ tumor cells, effectively inhibited CD47-SIRPα signal and triggered strong tumor cell phagocytosis in vitro, but only with minimal impact on CD47 single positive cells such as human RBCs. In addition, as a dual blocker of innate and adaptive immune checkpoints, IBI322 effectively accumulated in PD-L1-positive tumors and demonstrated synergistic activity in inducing complete tumor regression in vivo. Furthermore, IBI322 showed only marginal RBCs depletion and was well tolerated in non-human primates (NHP) after repeated weekly injections, suggesting a sufficient therapeutic window in future clinical development of IBI322 for cancer treatment.
Antibodies, Bispecific/therapeutic use , B7-H1 Antigen/therapeutic use , CD47 Antigen/antagonists & inhibitors , Immunotherapy/methods , Neoplasms/drug therapy , Animals , Antibodies, Bispecific/pharmacology , B7-H1 Antigen/pharmacology , Humans , Mice , Mice, Inbred NOD , Neoplasms/pathology
