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This study was aimed to investigate differences in antioxidant and anti-inflammatory effects of propofol at two commonly used dosing schedules on morbidly obese patients. Twenty-two morbidly obese patients were randomly divided into two groups, namely, TBW (dosing based on total body weight) and LBW (dosing based on lean body weight) groups. Three biomarkers, i.e. superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) were measured as indicators of the level of oxidation stress reaction. Pro-inflammatory cytokines including Interleukin-6 (IL-6) and Interleukin-8 (IL-8) were used to describe the degree of inflammation. Plasma levels of SOD, MDA and NO were increased and reached a peak value 0.5h after anesthesia induction, but the increase was smaller in the LBW group compared with the TBW group. Besides, plasma concentrations of IL-6 and IL-8 were also increased and attained a peak level 0.5h after anesthesia induction, but the increase was higher in the TBW group compared with the LBW group. The LBW-based dosing of propofol had more potent antioxidant and anti-inflammatory effects than the TBW-based dosing during anesthesia induction period on morbidly obese patients. This study provided a dosing recommendation of propofol for morbidly obese patients.

Objective: This study is aimed to establish a proper clinical commissioning procedure for the Halcyon 1.0 linear accelerator (linac) with pre-configured reference beam data (RBD) set and to ensure the commissioning results meet the clinical treatment requirements. Methods: Four parts were carried out during the commissioning work on the first Halcyon linac in China, which were according to the characteristics of this linac, the experience of the acceptance tests and commissioning procedure of our existing linacs and treatment planning systems (TPS), reports of AAPM & IAEA and relevant publications with the choice of appropriate quality assurance (QA) tools and procedures. These four aspects were as follows: 1. Commissioning of the Halcyon linac; 2. commissioning of the Eclipse TPS; 3. QA and quality control (QA & QC) of the Halcyon linac; 4. QA & QC of the Eclipse TPS and developing the corresponding procedures. Results: The 3D radius of the isocenter of gantry and collimator rotation from Winston-Lutz test was 0.64mm, the coincidence of the virtual isocenter and the treatment isocenter was quite well, and the maximum travel position deviation was 0.7mm. Percentage Depth Doses (PDDs) was 63.3% at 10cm at the reference setup and the tolerance was within 1%. The Machine Performance Check (MPC) results were within the relevant tolerance, and the gantry isocenter size measured from MPC test was 0.67mm. The pre-configured beam model data was in agreement with the measured data. In the process of rotation, the speed of gantry rotation and multi-leaf collimator (MLC) movement and the control of dose rate were all accurate with all deviations were controlled below 2%. The CT values of Surface and Interior of the carbon fiber treatment couch were -750HU and -950HU, respectively. All MPPG 5.a recommended regular field gamma compare tests met the requirements. The task group 119 test was also performed on Halcyon, the point dose difference for intensity-modulated radiation therapy (IMRT) and RapidArc techniques were -0.003 ± 0.011 and - 0.012 ± 0.006, respectively, with confidence limits of 0.025 and 0.024. Conclusion: The measured data of the Halcyon linac are in good consistency with the pre-configured beam model data in Eclipse TPS. The commissioning results of the IMRT technique and the RapicArc technique are all within the tolerance ranges recommended by AAPM and relevant publications, which could meet the needs of clinical requirements. The pre-configured data can facilitate the commissioning work and the validation and replace fully collecting beam data, which will be the trend of the commissioning of linac in the future.

This study aims to determine the pharmacodynamics (PD) effect (measured by cardiovascular depression) of propofol during anesthesia induction period on morbidly obese (MO) patients. Four hemodynamics indexes [i.e., three indexes about blood pressure and cardiac output (CO)] representing cardiovascular function were measured. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was performed by population analysis to obtain PD parameters. Two propofol dosing scalars, namely, dosing based on total body weight (TBW) or lean body weight (LBW), were used for MO subjects. The PD data were well described by a PK/PD model. Blood pressure and CO were rapidly decreased within one minute after intravenous injection of propofol (2 mg/kg). TBW group showed significantly lower blood pressure and CO values at and 1 min after propofol administration compared with the control group, whereas the control and LBW groups had similar PD profiles. In addition, the propofol EC50 value was significantly decreased in MO patients, whereas all other PD parameters were similar between control and MO subjects. This change indicated that propofol potency and/or sensitivity was increased in MO subjects. For MO patients, dosing of propofol based on LBW rather than TBW would be a safer choice due to a less cardiovascular depression effect.

There is a relationship between circadian rhythm and metabolic disorders. The active agent, SR8278, could competitively bind to and inhibit the nuclear receptor, Rev-erb (a major modulator of mammalian circadian clock system), to regulate the metabolism in organisms. However, we had limited knowledge of the pharmacokinetic (PK) characteristics of SR8278. Here, we describe a sensitive and reproducible ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to quantify SR8278 in vivo. The linearity range and the limit of quantification (LOQ) for SR8278 were 30-3000 ng/mL and 6 ng/mL, respectively. The inter-day and intra-day variability were within 10%. This UPLC-MS/MS method was successfully used to characterize the PK behaviors of SR8278 in normal and diabetic rats after intravenous (i.v.) injection at a dosage of 2mg/kg. No significant differences were observed in the PK parameters of SR8278 in normal and diabetic rats. Specifically, the values of areas under plasma concentration time curves (AUC), initial plasma concentrations (C0), elimination half-lives (t1/2), and clearances (CL) were 608.33 ± 295.25 vs. 598.59 ± 276.92 ng·h/mL, 2410.25 ± 202.36 vs. 3742.11 ± 1300.21 ng/mL, 0.17 ± 0.08 vs. 0.11 ± 0.04 h, 3330.83 ± 1609.48 vs. 3364.81 ± 1111.38 mL/kg·h for SR8278 in normal rats vs. diabetic rats, respectively. In conclusion, a UPLC-MS/MS method was successfully developed and validated for the first time, with a wide linearity range, low LOQ, small sample volume (10 μL), rapid analysis (4 min) and excellent recoveries (>80%). It was also used to clarify the PK characteristics of SR8378 in rats. The same PK behaviors of SR8278 in normal and diabetic rats showed that diabetes may have little or no effect on the disposition, metabolism and/or elimination in vivo, which may be of great importance for future clinical studies.

e16025 Background: JMT101 is a fully human monoclonal IgG1 antibody targeting epidermal growth factor receptor (EGFR). This study aimed to evaluate the safety and tolerability of JMT101 alone or in combination with chemotherapy in ACC. Methods: This is an open label, dose-escalating, phase I clinical trial. The pts with ACC and naïve to systemic EGFR-targeted therapy were assigned to receive JMT101 monotherapy (JMT101 group, pts with wild-type RAS ACC and had experienced failure of at least one standard regimen) or JMT101 in combination with mFOLFOX6/FOLFIRI (combination group, pts with wild-type RAS/non-BRAF V600E mutant ACC). JMT101 was infused intravenously by accelerated titration and traditional "3+3" dose-escalation scheme. The initial dose of JMT101 monotherapy was 0.5 mg/kg (q1w), and sequentially escalated to 2.0, 4.0, 6.0, 8.0, and 10.0 mg/kg (q2w). Until the dose of JMT101 group was escalated to the higher dose and sufficient safety data were obtained, the dose of the combination group would be escalated sequentially from 6.0, 8.0, to 10.0 mg/kg (q2w). The primary endpoints were safety and tolerability. The secondary endpoints were clinical efficacy and pharmacokinetic parameters. Results: From April 2017 to December 2019, 16 enrolled pts in JMT101 group (13 males, 3 females, median age 59.5 [27-64] years) and 7 in combination group (4 males, 3 females, median age 49 [39-68] years) were evaluable. The dose of JMT101 was escalated to 10.0, 8.0, 6.0 mg/kg in JMT101 group, mFOLFOX6 group and FOLFIRI group, respectively. Dose-limiting toxicity was not observed, maximum tolerated dose was not reached, and treatment-related SAE was not reported so far. JMT101 monotherapy and combination therapy were associated with grade 1 (15 and 7 cases), grade 2 (10 and 7 cases), and grade 3 (5 and 5 cases) AEs. In all groups, the most common AEs were skin rash (81.3% [13/16] in JMT101 group, 100% [7/7] in combination group), proteinuria (62.5% [10/16] in JMT101 group, 28.6% [2/7] in combination group) and oral mucositis (86.0% [6/7] in combination group). JMT101 monotherapy and combination therapy resulted in partial response (2 and 4 pts), objective response rate (12.5% and 57.1%), disease control rate (56.2% and 100%), and disease control > 24 weeks (4 and 3 pts). Conclusions: JMT101 shows good safety, tolerability, and antitumor activity in pts with ACC. Clinical trial information: 20160904 .

3638 Background: Bone is one of the most common metastatic sites of malignancies. The metastatic tumor cells activate osteoclast activity and promote bone resorption via RANKL/RANK signaling pathway, and lead to osteolytic destruction. JMT103 is an innovative fully human IgG4 monoclonal antibody targeting RANKL. It can block RANKL/RANK signaling pathway, inhibit bone resorption, and protect bones from tumor metastasis. This study aimed to evaluate the safety and tolerability of JMT103 in patients with bone metastasis. Methods: This is a multi-center, open label, dose escalation, phase I clinical trial. The patients (ECOG score: 0-1) with bone metastasis from solid tumor who had not received bisphosphonates within 6 weeks before enrollment and were naïve to denosumab were enrolled. The initial dose was 0.5 mg/kg, sequentially escalated to 1.0, 2.0, and 3.0 mg/kg. JMT103 was injected subcutaneously by accelerated titration in 0.5 and 1.0 mg/kg dose groups, but via traditional "3+3" dose-escalation design in 2.0 and 3.0 mg/kg dose groups. Expansion study was conducted for subjects in 1.0, 2.0, and 3.0 mg/kg dose groups. Specifically, 3 additional doses (q4w) were injected after the end of 12-week single-dose study. The primary endpoints were maximum tolerated dose and safety. The secondary outcome measures included PK profile, preliminary efficacy biomarkers, immunogenicity, and bone mineral density (BMD). Results: From May 2018 to January 2020, 56 patients (13 males, 43 females, mean (SD) age: 55.57 (11.42) years) were enrolled, including bone metastasis from breast cancer (n = 36), gastric cancer (n = 5), lung cancer (n = 4), rectal cancer (n = 3), colorectal cancer (n = 2), or other solid tumors (n = 6). Nineteen patients participated in the dose-escalating study and 37 patients participated in the expansion study. JMT103 showed overall good safety. There were 74 drug-related AEs in all, including grade 3 (DLT hypocalcemia, n = 1; hypophosphatemia, n = 3), grade 2 (n = 15), and grade 1 (n = 55) AEs. The most common drug-related AEs were hypophosphatemia (n = 15), hypocalcemia (n = 12), and hypermagnesemia (n = 6). Median uNTx/Cr decrease from baseline was 76.6% (n = 20). Conclusions: JMT103 shows good safety and tolerability in patients with bone metastasis. Clinical trial information: NCT03550508 .

The neuromuscular blocking agent cisatracurium is frequently used adjunctively in anesthesia to facilitate endotracheal intubation and to provide muscle relaxation during surgery. We aimed to determine the pharmacokinetics (PK)/pharmacodynamics (PD) of cisatracurium in patients with congenital heart defects (CHDs), such as ventricular septal defects and atrial septal defects, and to assess the effects of CHDs on the PK/PD profiles of cisatracurium. A modified two-compartment model with drug clearance from both compartments was best fitted to the PK data to determine the PK parameters. The model suggested that septal defects significantly lowered the rate of cisatracurium distribution from the central to peripheral compartment. The intercompartment rate constants k12 and k21 were significantly reduced (35%-60%, P < 0.05) in patients with ventricular septal defects and in patients with atrial septal defects compared with control patients. Consistently, septal defects caused a marked increase (160%-175%, P < 0.001) in the distribution half-life. Furthermore, significantly delayed pharmacodynamic responses to cisatracurium were observed in patients with septal defects. The onset time (i.e., the time to maximal neuromuscular block) was prolonged from 2.2 minutes to 5.0 minutes. PK/PD modeling suggested that reduced concentrations of cisatracurium in the effect compartment due to poorer distribution were the main cause of lagged pharmacodynamic responses. In conclusion, cisatracurium PK/PD were significantly altered in patients with septal defects. Our study should be of use in clinical practice for the administration of cisatracurium to patients with CHDs.

1.UDP-glucuronosyltransferase1A3 (UGT1A3) catalyzes glucuronidation of numerous xenobiotics/drugs. Here, we aimed to establish substrate selectivity models for UGT1A3 using the pharmacophore and VolSurf approaches. 2.Fifty structurally diverse substrates of UGT1A3 were collated from the literature. These substrates were divided into training (n=34) and test sets (n=16). The pharmacophore model was developed using the Discovery Studio 2.5 software. A user-defined feature (i.e. the glucuronidation site) was included in the program for model generation. The VolSurf model was derived using the VolSurf program implemented in SYBYL 8.0 software. 3.The pharmacophore model consisted of three features (i.e. one glucuronidation site and two hydrogen-bond acceptors). The activities of 81% of test set substrates were adequately predicted (deviated by less than one-log unit) by the model, suggestive of a satisfactory predictive power. The refined VolSurf model based on 22 molecular descriptors was statistically significant (r(2)=0.793, q(2)=0.606). It also processed a good predictability as the activities of 14 test set compounds were well predicted. The VolSurf model highlighted the chemical features (including large molecule size, hydrophilic regions and hydrogen-bonding groups) contributing to favored glucuronidation by UGT1A3. 4.In conclusion, two predictive 3D-QSAR models (i.e. the pharmacophore and VolSurf models) for UGT1A3 were successfully established. These models contributed to an improved understanding of the substrate preference of UGT1A3 and a more comprehensive prediction of UGT-mediated metabolism.

Objectives To determine the reaction kinetics for regioselective glucuronidation of gingerols (i.e. 6-, 8- and 10-gingerol) by human liver microsomes and expressed UDP-glucuronosyltransferase (UGT) enzymes, and to identify the main UGT enzymes involved in regioselective glucuronidation of gingerols. Methods The rates of glucuronidation were determined by incubating the gingerols with uridine diphosphoglucuronic acid-supplemented microsomes. Kinetic parameters were derived by fitting an appropriate model to the data. Activity correlation analyses were performed to identify the main UGT enzymes contributing to hepatic metabolism of gingerols. Key findings Glucuronidation at the 4′-OH group was much more favoured than that at 5-OH. The degree of position preference was compound-dependent; the catalytic efficiency ratios of 4′-O- to 5-O-glucuronidation were 9.1, 19.7 and 2.9 for 6-, 8- and 10-gingerol, respectively. UGT1A8 (an intestinal enzyme), UGT1A9 and UGT2B7 were the enzymes showing the highest activity towards gingerols. Formation of 5-O-glucuronide was mainly catalysed by UGT1A9. UGT2B7 was the only enzyme that generated glucuronides at both 4′-OH and 5-OH sites, although a strong position preference was observed with 4′-OH (≥80.2%). Further, activity correlation analyses indicated that UGT2B7 and UGT1A9 were primarily responsible for 4′-O-glucuronidation and 5-O-glucuronidation of gingerols in the liver, respectively. Conclusions Gingerols were metabolized by multiple hepatic and gastrointestinal UGT enzymes. Also, UGT1A9 and 2B7 were the main contributors to regioselective glucuronidation of gingerols in the liver.

Macelignan is a natural phenolic compound that possesses many types of health benefits such as antiinflammation. This study aimed to characterize the metabolism of macelignan via the glucuronidation pathway and to identify the main UGT enzymes involved in macelignan glucuronidation. The rates of glucuronidation were determined by incubating macelignan with UDPGA-supplemented microsomes. Kinetic parameters were derived by fitting an appropriate model to the data. Reaction phenotyping, the relative activity factor (RAF) approach and activity correlation analysis were employed to identify the main UGT enzymes contributing to the hepatic metabolism of macelignan. Glucuronidation of macelignan in pooled human liver microsomes (pHLM) was rather efficient with a high CLint (the intrinsic clearance) value of 13.90 ml/min/mg. All UGT enzymes, except UGT1A4, 1A6 and 2B10, showed metabolic activities toward macelignan. UGT1A1 and 2B7 were the enzymes with the highest activities; the CLint values were 4.92 and 2.13 ml/min/mg, respectively. Further, macelignan glucuronidation was significantly correlated with 3-O-glucuronidation of β-estradiol (r = 0.69; p < 0.01) and glucuronidation of zidovudine (r = 0.60; p < 0.05) in a bank of individual HLMs (n = 14). Based on the RAF approach, UGT1A1 and 2B7, respectively, contributed 55.40% and 32.20% of macelignan glucuronidation in pHLM. In conclusion, macelignan was efficiently metabolized via the glucuronidation pathway. It was also shown that UGT1A1 and 2B7 were probably the main contributors to the hepatic glucuronidation of macelignan.

Macelignan is a natural phenolic compound that possesses many types of health benefits such as antiinflammation. This study aimed to characterize the metabolism of macelignan via the glucuronidation pathway and to identify the main UGT enzymes involved in macelignan glucuronidation. The rates of glucuronidation were determined by incubating macelignan with UDPGA-supplemented microsomes. Kinetic parameters were derived by fitting an appropriate model to the data. Reaction phenotyping, the relative activity factor (RAF) approach and activity correlation analysis were employed to identify the main UGT enzymes contributing to the hepatic metabolism of macelignan. Glucuronidation of macelignan in pooled human liver microsomes (pHLM) was rather efficient with a high CLint (the intrinsic clearance) value of 13.90 ml/min/mg. All UGT enzymes, except UGT1A4, 1A6 and 2B10, showed metabolic activities toward macelignan. UGT1A1 and 2B7 were the enzymes with the highest activities; the CLint values were 4.92 and 2.13 ml/min/mg, respectively. Further, macelignan glucuronidation was significantly correlated with 3-O-glucuronidation of β-estradiol (r = 0.69; p0.01) and glucuronidation of zidovudine (r = 0.60; p0.05) in a bank of individual HLMs (n = 14). Based on the RAF approach, UGT1A1 and 2B7, respectively, contributed 55.40% and 32.20% of macelignan glucuronidation in pHLM. In conclusion, macelignan was efficiently metabolized via the glucuronidation pathway. It was also shown that UGT1A1 and 2B7 were probably the main contributors to the hepatic glucuronidation of macelignan.

1. The promising anticancer agent SNX-2112 (a novel Hsp90 inhibitor) is poorly bioavailable after oral administration. Here, we aim to determine the role of P-glycoprotein (P-gp) in the intestinal absorption of SNX-2112. 2. We found that SNX-2112 significantly stimulated P-gp ATPase activity in in vitro ATPase assay with a small EC50 (the half-maximal effective concentration) value of 0.32 µM. 3. In the single-pass perfused rat intestine model, absorption of SNX-2112 was not favored in the small intestine with a [Formula: see text] (the wall permeability) value of 0.38-0.64. By contrast, the compound was well absorbed in the colon with a [Formula: see text] value of 1.19. The P-gp inhibitors cyclosporine and elacridar (i.e. GF120918A) markedly enhanced SNX-2112 absorption in all four intestinal segments (i.e. duodenum, jejunum, ileum and colon) and the fold change ranged from 3.1 to 14.1. Pharmacokinetic study revealed that cyclosporine increased the systemic exposure of SNX-2112 by a 2.5-fold after oral administration. 4. This is the first report that P-gp-mediated efflux is a limiting factor for intestinal absorption of SNX-2112 in rats.