scholarly journals 1245. In Vivo Efficacy of WCK 4282 (High Dose Cefepime [FEP]-Tazobactam [TZB]) Against β-Lactamase-Producing (BLP) Gram-Negative Bacteria in a Neutropenic Murine Pneumonia Model

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S641-S641
Author(s):  
Maxwell J Lasko ◽  
Kamilia Abdelraouf ◽  
David P Nicolau
Keyword(s):  
Systemic Exposure ◽  
Carbapenem Resistance ◽  
High Dose ◽  
Research Support ◽  
Gram Negative ◽  
Variable Activity ◽  
Model Treatment ◽  
Susceptibility Breakpoint

Abstract Background Carbapenems are often used for Extended-Spectrum β-lactamase (ESBL)- and cephalosporinase (AmpC or CMY)-producing infections. Their increased use resulted in the emergence of carbapenem resistance among Gram-negatives, promoting the need of an effective carbapenem-sparing option. WCK 4282 (FEP 2g-TZB 2g) maximizes systemic exposure of TZB and restores FEP activity against piperacillin-tazobactam (TZP) resistant isolates in vitro. Herein we describe the efficacy of WCK 4282 clinical exposures against BLP Enterobacterales (EB) and Pseudomonas aeruginosa (PA) in a murine pneumonia model. Methods Clinical isolates (14 EB and 2 PA) with in vitro resistance to FEP, ceftolozane-tazobactam, and TZP (EB isolates) were used. Isolates expressed ESBLs, AmpC/CMY, and/or serine carbapenemases (KPC, OXA-48-like). WCK 4282 MICs were 4-16 and 8-32 mg/L for non-carbapenemase and carbapenemase-producers, respectively. Human-simulated regimens (HSR) of FEP (mimicking human plasma exposure of 2g q8h as a 1.5 h infusion) alone and in combination with TZB (equivalent to 2g q8h as a 1.5 h infusion) were developed in a neutropenic pneumonia model. Treatment mice received FEP or FEP-TZB (WCK 4282) HSR. Control mice were vehicle-dosed. Efficacy was assessed as change in log10CFU/lung at 24 h compared with 0 h controls. Results Mean 0 h bacterial density across all isolates was 6.66 ± 0.29 log10CFU/lung and increased at 24 h by 2.48 ± 0.6 and 1.71 ± 1.13 among controls and FEP-treated groups, respectively. Potent WCK 4282 activity was observed against ESBL- and AmpC-harboring EB as well as ESBL- and AmpC-overexpressing PA with WCK 4282 MICs up to 16 mg/L (n=9); mean bacterial reductions were -2.70 ± 0.63 and -2.04 ± 0.18 log10CFU/lung, respectively. WCK 4282 showed variable activity against OXA-48-producing EB (n=3); log10CFU/lung change ranged from -1.2 to 0.28. Against KPC-producers (n=4), WCK 4282 groups grew to 0.53 ± 1.07 log10CFU/lung, ~1.2 log10CFU lower than FEP. Conclusion WCK 4282 produced potent in vivo activity against ESBL- and AmpC-harboring Gram-negative isolates and limited activity among serine carbapenamase-producers in a pneumonia model at clinically achievable exposures. Further studies are warranted to delineate WCK 4282’s spectrum of activity and susceptibility breakpoint. Disclosures David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)

scholarly journals 1244. Assessment of the In Vivo Activity of Human-Simulated Exposure of WCK 4282 (High Dose Cefepime [FEP]-Tazobactam [TZB]) against Enterobacterales (EB) and Pseudomonas aeruginosa (PA) in the Neutropenic Murine Thigh Infection Model

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S640-S641
Author(s):  
Christian M Gill ◽  
Kamilia Abdelraouf ◽  
David P Nicolau
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Carbapenem Resistance ◽  
Bacterial Suspension ◽  
Infection Model ◽  
High Dose ◽  
Comparative Efficacy ◽  
Research Support ◽  
Variable Activity

Abstract Background Carbapenems are often used for infections due to extended-spectrum-β-lactamase (ESBL) and cephalosporinase (CSase)-producers. As increased carbapenem utilization is associated with the development of carbapenem resistance, antimicrobial stewardship has targeted non-carbapenem options. WCK 4282 (FEP 2 g-TZB 2 g) offers pharmacodynamically optimized TZB exposure and demonstrated potent activity in vitro against ESBL-phenotype isolates. We describe the pharmacodynamics of a WCK 4282 human-simulated regimen (HSR) in the neutropenic murine thigh model. Methods 19 clinical strains harboring ESBLs or CSase (EB; n=8 and PA; n=4) or serine-carbapenemases (EB; KPC n=4 or OXA-48-like n=3) were tested in vivo. Per CLSI, 19, 18, and 17 isolates were cefepime, ceftolozane/tazobactam, and piperacillin/tazobactam (TZP) non-susceptible, respectively. Thighs of neutropenic, female, CD-1 mice (3 per group) were inoculated with ~107 CFU/mL of bacterial suspension 2 h prior to dosing. Mice received WCK 4282 HSR, FEP HSR, or saline (controls) for 24 h. WCK 4282 HSR and FEP HSR provided plasma exposures in mice that were similar in f%T > MIC and fAUC to FEP-TZB 2 g-2 g and FEP 2 g, respectively, as IV infusions over 1.5 h q8h in humans. Bacterial densities and their changes at 24 h relative to 0 h controls were determined to assess efficacy and reported as mean±SD log10 CFU/thigh. Results Bacterial burdens were 5.81±0.36 at 0 h and 9.29±0.88 at 24 h in untreated controls. WCK 4282 produced potent activity against ESBL/CSase producing EB and PA with WCK 4282 MIC ≤ 16 mg/L; mean change in log10 CFU from 0 h was -1.70±0.77, while growth was observed with FEP alone. WCK 4282 produced variable activity against OXA-48-like harboring EB. Against KPC-harboring EB, WCK 4282 produced stasis to growth. Mean Log10 CFU changes are reported in Table 1 and Figure 1. Table 1. Comparative efficacy of FEP HSR and WCK 4282 HSR by genotypic β-lactamase Figure 1. Mean Change in log10CFU/thigh for 24 h controls, FEP HSR, and WCK 4282 HSR across the tested MIC distribution. Conclusion WCK 4282, a novel TZB containing regimen, resulted in enhance in vitro potency against ESBL/CSase and OXA-48-like producers. Humanized exposures of WCK 4282 produced substantial kill in vivo against ESBL/CSase producers with MICs ≤ 16 mg/L including FEP resistant/TZP non-susceptible PA. These data support further evaluations of WCK 4282 as a carbapenem-sparing regimen for ESBL/cephalosporinase harboring strains. Disclosures David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)

scholarly journals In Vivo Activity of WCK 4282 (High-Dose Cefepime/Tazobactam) against Serine-β-lactamase-Producing Enterobacterales and Pseudomonas aeruginosa in the Neutropenic Murine Lung Infection Model

2021 ◽  
Author(s):  
Maxwell J. LASKO ◽  
Kamilia ABDELRAOUF ◽  
David P. NICOLAU
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Systemic Exposure ◽  
Lung Infection ◽  
Infection Model ◽  
High Dose ◽  
Bacterial Burden ◽  
Variable Activity ◽  
Potential Activity

Abstract (248/250) Introduction: WCK 4282 (cefepime 2g/tazobactam 2g) maximizes systemic exposure of tazobactam and restores cefepime activity against various extended-spectrum β-lactamase (ESBL)- and cephalosporinase-producing strains in vitro. We describe clinical WCK 4282 exposure efficacy against various serine β-lactamase-producing Enterobacterales and Pseudomonas aeruginosa in a murine pneumonia model. Clinical cefepime-resistant isolates (17 Enterobacterales and 2 P. aeruginosa) were utilized. Isolates expressed ESBLs, cephalosporinases, and/or serine carbapenemases (KPC, OXA-48-like). WCK 4282 MICs were 4-32 μg/mL. For in vivo experiments, lungs of neutropenic mice were inoculated using standard inoculum (107 log10 CFU/mL). Serine-carbapenemase-producing isolates were also assessed using a low inoculum (1:5 dilution). Treatment mice received HSR of cefepime, meropenem (control for serine carbapenemase expression with low inoculum experiments), or WCK 4282 human-simulated regimens. Efficacy was assessed as change in log10 CFU/lung at 24h compared with 0h controls. Results: At standard inoculum, mean 0h bacterial burden was 6.65±0.23 log10 CFU/lung and increased at 24h by 2.48 ± 0.60 log10 CFU/lung among untreated controls. Lower inoculums initial bacterial burdens ranged from 5.81±0.12-6.39±0.13 log10 CFU/lung. At standard and/or low inoculums, cefepime and meropenem provided minimal activity. WCK 4282 produced >1-log10 reduction against 9/9 ESBL/cephalosporinase-producing strains. WCK 4282 provided variable activity among mice infected with standard or lower inoculums of OXA-48-like-producers. WCK 4282 exposures provided 0.53±1.07 log10 CFU/lung growth against KPC-producers at standard versus bacteriostasis (-0.15±0.54 change in log10 CFU/lung) at low inoculum. Conclusion: WCK 4282 produced potent in vivo activity against ESBL- and cephalosporinase-producing Enterobacterales and P. aeruginosa, and potential activity against OXA-48-like-producing Enterobacterales in a neutropenic pneumonia model.

scholarly journals ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Ørjan Samuelsen ◽  
Ove Alexander Høgmoen Åstrand ◽  
Christopher Fröhlich ◽  
Adam Heikal ◽  
Susann Skagseth ◽  
...  
Keyword(s):  
Active Site ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Carbapenem Resistance ◽  
Functional Space ◽  
Bactericidal Effect ◽  
Gram Negative ◽  
Content Type

ABSTRACT Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n = 234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM, and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ∼30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound.

scholarly journals Cefiderocol: Discovery, Chemistry, and In Vivo Profiles of a Novel Siderophore Cephalosporin

2019 ◽  
Vol 69 (Supplement_7) ◽  
pp. S538-S543 ◽  
Author(s):  
Takafumi Sato ◽  
Kenji Yamawaki
Keyword(s):  
Structural Characteristics ◽  
Carbapenem Resistance ◽  
Public Health Issue ◽  
New Delhi ◽  
Gram Negative ◽  
Klebsiella Pneumoniae Carbapenemase ◽  
Significant Public Health ◽  
Healthcare Associated

Abstract The emergence of antimicrobial resistance is a significant public health issue worldwide, particularly for healthcare-associated infections caused by carbapenem-resistant gram-negative pathogens. Cefiderocol is a novel siderophore cephalosporin targeting gram-negative bacteria, including strains with carbapenem resistance. The structural characteristics of cefiderocol show similarity to both ceftazidime and cefepime, which enable cefiderocol to withstand hydrolysis by β-lactamases. The unique chemical component is the addition of a catechol moiety on the C-3 side chain, which chelates iron and mimics naturally occurring siderophore molecules. Following the chelation of iron, cefiderocol is actively transported across the outer membrane of the bacterial cell to the periplasmic space via specialized iron transporter channels. Furthermore, cefiderocol has demonstrated structural stability against hydrolysis by both serine- and metallo-β-lactamases, including clinically relevant carbapenemases such as Klebsiella pneumoniae carbapenemase, oxacillin carbapenemase-48, and New Delhi metallo-β-lactamase. Cefiderocol has demonstrated promising in vitro antibacterial and bactericidal activity, which correlates with its in vivo efficacy in several animal models. This article reviews the discovery and chemistry of cefiderocol, as well as some of the key microbiological and in vivo findings on cefiderocol from recently conducted investigations.

scholarly journals 1256. In Vivo Activity and Structural Characterization of a New Generation γ-Lactam Siderophore Antibiotic Against Multidrug-Resistant Gram-Negative Bacteria and Acinetobacter spp

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S645-S645
Author(s):  
Joel Goldberg ◽  
Christopher Bethel ◽  
Andrea M Hujer ◽  
Steven Marshall ◽  
Magdalena A Taracila ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Infection Model ◽  
Binding Studies ◽  
Research Support ◽  
Gram Negative ◽  
Preclinical Pharmacokinetics ◽  
Acinetobacter Spp ◽  
New Generation

Abstract Background Multidrug-resistant (MDR) A. baumannii presents a critical need for innovative antibacterial development. We have identified a new series of γ-lactam (oxopyrazole) antibiotics that target penicillin binding proteins (PBPs) and incorporate a siderophore moiety to facilitate periplasmic uptake. YU253911, an advanced iteration of this class shows potent in vitro activity against clinically relevant Gram-negative organisms including Acinetobacter spp. Methods Minimum inhibitory concentrations (MICs) for YU253911 were determined using broth microdilution against a 198-member panel of clinical isolates of Acinetobacter spp. Resistant strains were further evaluated for susceptibility to YU253911 in combination with sulbactam. The antibiotic’s target protein was evaluated by binding studies with Bocillin™, a fluorescent penicillin analogue, and modeled in the PBP active site. YU253911 was evaluated in vivo in a mouse soft tissue infection model. Results MIC testing for YU253911 revealed an MIC50 of 0.5 μg/mL and an MIC90 of 16 μg/mL, which compared favorably to all tested β-lactam antibiotics including penicillins, cephalosporins, monobactams and carbapenems (MIC50 = 2 to > 16 μg/mL). Combination with sulbactam augmented the activity of the agent. There was no apparent correlation between YU253911-resistance and the presence of specific β-lactamase genes, and incubation with representative β-lactamase proteins (KPC-2, OXA-23, OXA-24, PER-2, PDC-3, NDM-1, VIM-2, and IMP-1) showed negligible hydrolysis of the agent. YU253911 showed promising preclinical pharmacokinetics in mice with a 15 h half-life from intravenous administration and demonstrated a dose-dependent reduction in colony forming units from 50 and 100 mg/kg q6h dosing in a mouse thigh infection model using P. aeruginosa. Conclusion YU253911, a new generation γ-lactam antibiotic effective against MDR A. baumannii demonstrated promising in in vitro potency and favorable pharmacokinetics which correlated with in vivo efficacy. Disclosures Krisztina M. Papp-Wallce, PhD, Entasis (Grant/Research Support)Merck (Grant/Research Support)Venatorx (Grant/Research Support) Robert A. Bonomo, MD, Entasis, Merck, Venatorx (Research Grant or Support)

Significance of Platelet β-Adrenoceptors for Platelet Responses In Vivo and In Vitro

1992 ◽  
Vol 68 (06) ◽  
pp. 687-693 ◽  
Author(s):  
P T Larsson ◽  
N H Wallén ◽  
A Martinsson ◽  
N Egberg ◽  
P Hjemdahl
Keyword(s):  
Ex Vivo ◽  
High Dose ◽  
Platelet Aggregability ◽  
Adrenoceptor Agonist ◽  
Dose Infusion ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen

SummaryThe significance of platelet β-adrenoceptors for platelet responses to adrenergic stimuli in vivo and in vitro was studied in healthy volunteers. Low dose infusion of the β-adrenoceptor agonist isoprenaline decreased platelet aggregability in vivo as measured by ex vivo filtragometry. Infusion of adrenaline, a mixed α- and β-adrenoceptor agonist, increased platelet aggregability in vivo markedly, as measured by ex vivo filtragometry and plasma β-thromboglobulin levels. Adrenaline levels were 3–4 nM in venous plasma during infusion. Both adrenaline and high dose isoprenaline elevated plasma von Willebrand factor antigen levels β-Blockade by propranolol did not alter our measures of platelet aggregability at rest or during adrenaline infusions, but inhibited adrenaline-induced increases in vWf:ag. In a model using filtragometry to assess platelet aggregability in whole blood in vitro, propranolol enhanced the proaggregatory actions of 5 nM, but not of 10 nM adrenaline. The present data suggest that β-adrenoceptor stimulation can inhibit platelet function in vivo but that effects of adrenaline at high physiological concentrations are dominated by an α-adrenoceptor mediated proaggregatory action.

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

Methylprednisolone on circulating eicosanoids and vasomotor tone after endotoxin

1986 ◽  
Vol 61 (1) ◽  
pp. 185-191 ◽  
Author(s):  
C. A. Hales ◽  
R. D. Brandstetter ◽  
C. F. Neely ◽  
M. B. Peterson ◽  
D. Kong ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Resistance ◽  
Systemic Blood Pressure ◽  
Physiological Effect ◽  
High Dose ◽  
Systemic Blood ◽  
Eicosanoid Production ◽  
Circulating Levels

Acute pulmonary and systemic vasomotor changes induced by endotoxin in dogs have been related, at least in part, to the production of eicosanoids such as the vasoconstrictor thromboxane and the vasodilator prostacyclin. Steroids in high doses, in vitro, inhibit activation of phospholipase A2 and prevent fatty acid release from cell membranes to enter the arachidonic acid cascade. We, therefore, administered methylprednisolone (40 mg/kg) to dogs to see if eicosanoid production and the ensuing vasomotor changes could be prevented after administration of 150 micrograms/kg of endotoxin. The stable metabolites of thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were measured by radioimmunoassay. Methylprednisolone by itself did not alter circulating eicosanoids but when given 2.5 h before endotoxin not only failed to inhibit endotoxin-induced eicosanoid production but actually resulted in higher circulating levels of 6-keto-PGF1 alpha (P less than 0.05) compared with animals receiving endotoxin alone. Indomethacin prevented the steroid-enhanced concentrations of 6-keto-PGF1 alpha after endotoxin and prevented the greater fall (P less than 0.05) in systemic blood pressure and systemic vascular resistance with steroid plus endotoxin than occurred with endotoxin alone. Administration of methylprednisolone immediately before endotoxin resulted in enhanced levels (P less than 0.05) of both TxB2 and 6-keto-PGF1 alpha but with a fall in systemic blood pressure and vascular resistance similar to the animals pretreated by 2.5 h. In contrast to the early steroid group in which all of the hypotensive effect was due to eicosanoids, in the latter group steroids had an additional nonspecific effect. Thus, in vivo, high-dose steroids did not prevent endotoxin-induced increases in eicosanoids but actually increased circulating levels of TxB2 and 6-keto-PGF1 alpha with a physiological effect favoring vasodilation.

scholarly journals High-dose rifampicin kills persisters, shortens treatment duration, and reduces relapse rate in vitro and in vivo

2015 ◽  
Vol 6 ◽  
Author(s):  
Yanmin Hu ◽  
Alexander Liu ◽  
Fatima Ortega-Muro ◽  
Laura Alameda-Martin ◽  
Denis Mitchison ◽  
...  
Keyword(s):  
Relapse Rate ◽  
Treatment Duration ◽  
High Dose

scholarly journals Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 386
Author(s):  
Tung-Hu Tsai ◽  
Yu-Jen Chen ◽  
Li-Ying Wang ◽  
Chen-Hsi Hsieh
Keyword(s):  
Stereotactic Body Radiation Therapy ◽  
In Vivo Studies ◽  
Control Group ◽  
High Dose ◽  
Dependent Manner ◽  
Hep G2 ◽  
Time Curve ◽  
Dose Dependent

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).

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