scholarly journals Pharmacodynamics of Anidulafungin against Clinical Aspergillus fumigatus Isolates in a Nonneutropenic Murine Model of Disseminated Aspergillosis

2012 ◽  
Vol 57 (1) ◽  
pp. 303-308 ◽  
Author(s):  
Seyedmojtaba Seyedmousavi ◽  
Roger J. M. Brüggemann ◽  
Willem J. G. Melchers ◽  
Paul E. Verweij ◽  
Johan W. Mouton
Keyword(s):  
Aspergillus Fumigatus ◽  
Murine Model ◽  
Resistance Mechanism ◽  
Maximal Response ◽  
Dependent Manner ◽  
Time Curve ◽  
Content Type ◽  
Disseminated Aspergillosis ◽  
The Hill

ABSTRACTAzole resistance is an emerging increasing problem inAspergillus fumigatusthat results in treatment failure. Alternative treatments may improve the therapeutic outcome in patients with azole-resistant invasive aspergillosis (IA). Little is known about thein vivoefficacy of the echinocandin anidulafungin (AFG) in IA. Thein vivoefficacy of 2.5, 5, 10, and 20 mg/kg of body weight AFG was assessed against two clinicalAspergillus fumigatusisolates with identical AFG minimum effective concentrations (MECs; 0.03 mg/liter) in a murine model of IA: a wild-type voriconazole (VCZ)-susceptible (VCZs)A. fumigatusisolate (AZN 8196) and a VCZ-resistant (VCZr)A. fumigatusisolate (V52-35) harboring the TR34/L98H resistance mechanism (substitution at codon L98 in combination with a 34-bp tandem repeat in the promoter region of theCYP51Agene). The pharmacokinetics of AFG were also assessed for each dose. Increasing doses increased survival for both isolates in a manner dependent on the AFG dose level (R2= 0.99 and 0.95, respectively) up to a maximum of 72.7% and 45.45% for the VCZsand VCZrisolates, respectively. The area under the concentration-time curve (AUC) correlated significantly with the dose in a linear fashion over the entire dosing range (R2= 0.86). The Hill equation with a variable slope fitted the relationship between the 24-h AUC/MEC ratio and 14-day survival well (R2= 0.87;P< 0.05). The 50% effective AUC/MEC for total AFG was 126.5 (95% confidence interval, 79.09 to 202.03). AFG treatment improved the survival of mice in a dose-dependent manner; however, a maximal response was not achieved with either isolate even in those treated with the highest AFG dose.

scholarly journals Efficacy of Posaconazole against Three Clinical Aspergillus fumigatus Isolates with Mutations in the cyp51A Gene

2009 ◽  
Vol 54 (2) ◽  
pp. 860-865 ◽  
Author(s):  
Eleftheria Mavridou ◽  
Roger J. M. Brüggemann ◽  
Willem J. G. Melchers ◽  
Johan W. Mouton ◽  
Paul E. Verweij
Keyword(s):  
Aspergillus Fumigatus ◽  
Resistance Mechanism ◽  
Gene Promoter ◽  
Resistance Mechanisms ◽  
Time Curve ◽  
Wild Type Phenotype ◽  
Disseminated Aspergillosis ◽  
The Hill ◽  
The Relationship

ABSTRACT The in vivo efficacy of posaconazole against 4 clinical Aspergillus fumigatus isolates with posaconazole MICs ranging from 0.03 to 16 mg/liter, as determined by CLSI method M38A, was assessed in a nonneutropenic murine model of disseminated aspergillosis. The underlying resistance mechanisms of the isolates included substitutions in the cyp51A gene at codon 220 (M220I), codon 54 (G54W), and codon 98 (L98H). The latter was combined with a 34-bp tandem repeat in the gene promoter region (TR L98H). The control isolate exhibited a wild-type phenotype without any known resistance mechanism. Oral posaconazole therapy was started 24 h after infection and was given once daily for 14 consecutive days. Mice were treated with four different doses (1 to 64 mg/kg of body weight), and survival was used as the end point. Survival was dependent both on the dose and on the MIC. The Hill equation with a variable slope fitted the relationship between the dose/MIC ratio and 14-day survival well (R 2, 0.92), with a 50% effective dose (ED50) of 29.0 mg/kg (95% confidence interval [CI], 15.6 to 53.6 mg/kg). This also applied to the relationship between the area under the plasma concentration-time curve (AUC)/MIC ratio and 14-day survival (50% effective pharmacodynamic index [EI50], 321.3 [95% CI, 222.7 to 463.4]). Near-maximum survival was reached at an AUC/MIC ratio of nearly 1,000. These results indicate that treatment of infections with A. fumigatus strains for which MICs are 0.5 mg/liter requires doses exceeding the present licensed doses. Increasing the standard dosing regimen may have some effect and may be clinically useful if no alternatives are available.

scholarly journals In Vivo Biomarker Analysis of the Effects of Intranasally Dosed PC945, a Novel Antifungal Triazole, on Aspergillus fumigatus Infection in Immunocompromised Mice

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Genki Kimura ◽  
Takahiro Nakaoki ◽  
Thomas Colley ◽  
Garth Rapeport ◽  
Pete Strong ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Interleukin 17 ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Once Daily ◽  
Content Type ◽  
Treatment Regimens ◽  
Biomarker Analysis ◽  
Immunocompromised Mice

ABSTRACT PC945 is a novel triazole optimized for lung delivery, and the objective of this study is to determine the effects of intranasally dosed PC945 on Aspergillus fumigatus infection and associated biomarkers in immunocompromised mice. PC945, posaconazole, or voriconazole was administered intranasally once daily on days 0 to 3 (early intervention) or days 1 to 3 (late intervention) postinfection in temporarily neutropenic A/J mice infected intranasally with A. fumigatus, and bronchoalveolar lavage fluid (BALF) and serum were collected on day 3. The effects of extended prophylaxis treatment (daily from days −7 to +3 or days −7 to 0) were also compared with those of the shorter treatment regimens (days −1 to +3 or days −1 and 0). Early and late interventions with PC945 (2.8 to 350 μg/mouse; approximately 0.11 to ∼14 mg/kg of body weight) were found to inhibit lung fungal loads and to decrease the concentrations of galactomannan (GM) in both BALF and serum as well as several biomarkers in BALF (interferon gamma [IFN-γ], interleukin-17 [IL-17], and malondialdehyde) and serum (tumor necrosis factor alpha [TNF-α] and IL-6) in a dose-dependent manner and were >3- and >47-fold more potent than intranasally dosed posaconazole and voriconazole, respectively. Furthermore, extended prophylaxis with low-dose PC945 (0.56 μg/mouse; 0.022 mg/kg) was found to inhibit fungal loads and to decrease the concentrations biomarkers more potently than did the shorter treatment regimens. Thus, PC945 dosed intranasally once daily showed potent antifungal effects, and the effects of PC945 accumulated upon repeat dosing and were persistent. Therefore, PC945 has the potential to be a novel inhaled therapy for the treatment of A. fumigatus infection in humans.

scholarly journals Efficacy of Amphotericin B at Suboptimal Dose Combined with Voriconazole in a Murine Model of Aspergillus fumigatus Infection with PoorIn VivoResponse to the Azole

2013 ◽  
Vol 57 (9) ◽  
pp. 4540-4542 ◽  
Author(s):  
Marcelo Sandoval-Denis ◽  
F. Javier Pastor ◽  
Javier Capilla ◽  
Josep Guarro
Keyword(s):  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Murine Model ◽  
Combined Treatment ◽  
Content Type ◽  
Disseminated Infection ◽  
Suboptimal Dose ◽  
Tissue Burden

ABSTRACTThe combination of amphotericin B at a suboptimal dose (0.3 mg/kg) with voriconazole has shown efficacy in prolonging survival and reducing tissue burden in a murine model of disseminated infection by an isolate ofAspergillus fumigatusthat had showed a poorin vivoresponse to the azole. The efficacy of the combined treatment was higher than that obtained with amphotericin B at 0.8 mg/kg.

scholarly journals A New Marker of Echinocandin Activity in an In Vitro Pharmacokinetic/Pharmacodynamic Model Correlates with an Animal Model of Aspergillus fumigatus Infection

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Joseph Meletiadis ◽  
Maria Siopi ◽  
Athanassios Tsakris ◽  
Johan W. Mouton ◽  
Spyros Pournaras
Keyword(s):  
Aspergillus Fumigatus ◽  
Antifungal Susceptibility ◽  
Free Drug ◽  
Resistant Isolate ◽  
Dose Fractionation ◽  
Time Curve ◽  
Closed Model ◽  
Content Type

ABSTRACT The lack of a quantifiable marker for echinocandin activity hinders in vitro pharmacokinetic/pharmacodynamic (PK/PD) studies for Aspergillus spp. We developed an in vitro PK/PD model simulating the pharmacokinetics of anidulafungin and assessing its pharmacodynamics against Aspergillus fumigatus with a new, easily quantifiable, sensitive, and reproducible marker. Two clinical A. fumigatus isolates previously used in animals (AZN8196 and V52-35) with identical anidulafungin EUCAST (0.03 μg/ml) and CLSI (0.015 μg/ml) minimal effective concentrations (MEC) and one isolate (strain AFU79728) with an MEC of >16 μg/ml were tested in a two-compartment PK/PD dialysis/diffusion closed model containing a dialysis membrane (DM) tube inoculated with 10 3 CFU/ml. During anidulafungin exposure, two types of fungal forms were observed inside the DM tube: floating conidia that were quantified by cultures and aberrant mycelia that were quantified by the vertical height of the mycelia attached on the DM tube. No aberrant mycelia were found for the resistant isolate or in the drug-free controls. An in vitro exposure-effect relationship was similar to that found in animals using survival as an endpoint, with a free-drug area under the concentration-time curve from 0 to 24 h ( f AUC 0–24 ) associated with 50% of maximal activity of 2.21 (range, 1.81 to 2.71) mg · h/liter in vitro versus 2.62 (range, 1.88 to 3.65) mg · h/liter in vivo ( P = 0.41). The hillslopes were also similar, with 1.96 versus 1.34 ( P = 0.29). Analysis of each isolate separately showed increased antifungal susceptibility between AZN8196 and V52-35 ( P < 0.001) even though they have the same CLSI and EUCAST MECs, but the strains have two 2-fold dilutions lower MICs using Etest and the XTT {2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide} method. Dose fractionation studies with all three echinocandins showed that their activities are best described by f AUC and not the maximum concentration of free drug ( fC max ). The new marker correlated with in vivo outcome and can be used for in vitro PK/PD studies exploring the pharmacodynamics of echinocandins against Aspergillus spp.

scholarly journals Ciprofloxacin Treatment Failure in a Murine Model of Pyelonephritis Due to an AAC(6′)-Ib-cr-Producing Escherichia coli Strain Susceptible to CiprofloxacinIn Vitro

2013 ◽  
Vol 57 (12) ◽  
pp. 5830-5835 ◽  
Author(s):  
T. Guillard ◽  
E. Cambau ◽  
F. Chau ◽  
L. Massias ◽  
C. de Champs ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Murine Model ◽  
Resistance Mechanism ◽  
Bacterial Count ◽  
Coli Strain ◽  
Content Type ◽  
E Coli ◽  
Fixed Concentration

ABSTRACTAAC(6′)-Ib-cr is a plasmid-mediated quinolone resistance mechanism described worldwide forEscherichia coli. Since it confersin vitroonly a low level of resistance to ciprofloxacin, we evaluated its impact on thein vivoactivity of ciprofloxacin. Isogenic strains were obtained by transferring plasmid p449, harboringaac(6′)-Ib-cr, into the quinolone-susceptible strainE. coliCFT073-RR and its D87GgyrAmutant. MICs were 0.015, 0.06, 0.25, and 0.5 μg/ml againstE. colistrains CFT073-RR, CFT073-RR/p449, CFT073-RR GyrAr, and CFT073-RR GyrAr/p449, respectively. Bactericidal activity was reduced at 1× the MIC for the three resistant derivatives, while at a fixed concentration of 0.5 μg/ml, 99.9% killing was observed for all strains exceptE. coliCFT073-RR GyrAr/p449. In the murine model of pyelonephritis, an optimal regimen of ciprofloxacin (10 mg/kg of body weight twice a day [b.i.d.]) significantly decreased the bacterial count in the kidneys of mice infected withE. coliCFT073 (1.6 versus 4.3 log10CFU/g of kidney compared to untreated controls;P= 0.0001), while no significant decrease was observed forE. coliCFT073-RR/p449 (2.7 versus 3.1 log10CFU/g;P= 0.84),E. coliCFT073-RR GyrAr(4.2 versus 4.1 log10CFU/g;P= 0.35), orE. coliCFT073-RR GyrAr/p449 (2.9 versus 3.6 log10CFU/g;P= 0.47). While pharmacokinetic and pharmacodynamic (PK/PD) parameters accounted for ciprofloxacin failure againstgyrA-containing mutants, this was not the case for theaac(6′)-Ib-cr-containing strains, suggesting anin situhydrolysis of ciprofloxacin in the latter case.

scholarly journals Impact of cyp51A Mutations on the Pharmacokinetic and Pharmacodynamic Properties of Voriconazole in a Murine Model of Disseminated Aspergillosis

2010 ◽  
Vol 54 (11) ◽  
pp. 4758-4764 ◽  
Author(s):  
Eleftheria Mavridou ◽  
Roger J. M. Bruggemann ◽  
Willem J. G. Melchers ◽  
Paul E. Verweij ◽  
Johan W. Mouton
Keyword(s):  
Murine Model ◽  
Maximum Effect ◽  
Wild Type ◽  
Time Curve ◽  
Unbound Fraction ◽  
Once Daily ◽  
Type Population ◽  
Disseminated Aspergillosis ◽  
Wild Type Control

ABSTRACT The in vivo efficacy of voriconazole against 4 clinical Aspergillus fumigatus isolates with MICs ranging from 0.125 to 2 mg/liter (CLSI document M38A) was assessed in a nonneutropenic murine model of disseminated aspergillosis. The study involved TR/L98H, M220I, and G54W mutants and a wild-type control isolate. Oral voriconazole therapy was started 24 h after intravenous infection of mice and was given once daily for 14 consecutive days, with doses ranging from 10 to 80 mg/kg of body weight, using survival as the endpoint. Survival for all isolates was dependent on the voriconazole dose level (R 2 value of 0.5 to 0.6), but a better relationship existed for the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) or the AUC for the free, unbound fraction of the drug divided by the MIC (fAUC/MIC ratio) (R 2 value of 0.95 to 0.98). The 24-h fAUC/MIC ratio showed a clear relationship to effect, with an exposure index for amount of free drug required for 50% of maximum effectiveness (fEI50) of 11.17 at day 7. Maximum effect was reached at values of around 80 to 100, comparable to that observed for posaconazole and A. fumigatus. Mice infected with an isolate having a MIC of 2 mg/liter required an exposure that was inversely correlated with the increase in MIC compared to that of the wild-type control, but due to nonlinear pharmacokinetics, this required only doubling of the voriconazole dose. The efficacy of voriconazole for isolates with high MICs for other triazoles but voriconazole MICs within the wild-type population range was comparable to that for the wild-type control. Finally, we used a grapefruit juice-free murine model of aspergillosis and concluded that this model is appropriate to study pharmacokinetic/pharmacodynamic relationships of voriconazole.

scholarly journals Azole Resistance of Aspergillus fumigatus Biofilms Is Partly Associated with Efflux Pump Activity

2011 ◽  
Vol 55 (5) ◽  
pp. 2092-2097 ◽  
Author(s):  
Ranjith Rajendran ◽  
Eilidh Mowat ◽  
Elaine McCulloch ◽  
David F. Lappin ◽  
Brian Jones ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Azole Resistance ◽  
Dependent Manner ◽  
Content Type ◽  
Quantitative Expression ◽  
Pump Activity ◽  
Competitive Substrate

ABSTRACTThis study investigated the phase-dependent expression and activity of efflux pumps inAspergillus fumigatustreated with voriconazole. Fourteen strains were shown to become increasingly resistant in the 12-h (16- to 128-fold) and 24-h (>512-fold) phases compared to 8-h germlings. An Ala-Nap uptake assay demonstrated a significant increase in efflux pump activity in the 12-h and 24-h phases (P< 0.0001). The efflux pump activity of the 8-h germling cells was also significantly induced by voriconazole (P< 0.001) after 24 h of treatment. Inhibition of efflux pump activity with the competitive substrate MC-207,110 reduced the voriconazole MIC values for theA. fumigatusgermling cells by 2- to 8-fold. Quantitative expression analysis ofAfuMDR4mRNA transcripts showed a phase-dependent increase as the mycelial complexity increased, which was coincidental with a strain-dependent increase in azole resistance. Voriconazole also significantly induced this in a time-dependent manner (P< 0.001). Finally, anin vivomouse biofilm model was used to evaluate efflux pump expression, and it was shown thatAfuMDR4was constitutively expressed and significantly induced by treatment with voriconazole after 24 h (P< 0.01). Our results demonstrate that efflux pumps are expressed in complexA. fumigatusbiofilm populations and that this contributes to azole resistance. Moreover, voriconazole treatment induces efflux pump expression. Collectively, these data may provide evidence for azole treatment failures in clinical cases of aspergillosis.

scholarly journals Pharmacodynamics of Voriconazole against Wild-Type and Azole-Resistant Aspergillus flavus Isolates in a Nonneutropenic Murine Model of Disseminated Aspergillosis

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Shivaprakash M. Rudramurthy ◽  
Seyedmojtaba Seyedmousavi ◽  
Manpreet Dhaliwal ◽  
Arunaloke Chakrabarti ◽  
Jacques F. Meis ◽  
...  
Keyword(s):  
Aspergillus Flavus ◽  
Murine Model ◽  
Drug Exposure ◽  
Resistant Isolate ◽  
Dependent Manner ◽  
Wild Type ◽  
Time Curve ◽  
Content Type ◽  
Significant Difference ◽  
Susceptible Isolate

ABSTRACT Invasive aspergillosis (IA) due to Aspergillus flavus is associated with high mortality. Although voriconazole (VRC) is widely recommended as the first-line treatment for IA, emergence of azole resistance in Aspergillus spp. is translating to treatment failure. We evaluated the efficacy of voriconazole in a nonneutropenic murine model of disseminated A. flavus infection using two voriconazole-resistant isolates (one harboring the Y319H substitution in the cyp51C gene) and two wild-type isolates without mutations. All isolates exhibited a dose-response relationship, and voriconazole treatment improved mouse survival in a dose-dependent manner. At 40 mg/kg of body weight, 100% efficacy was observed for 1 susceptible isolate and 1 resistant isolate (with mutation), whereas for another susceptible isolate and resistant isolate (without mutation), survival rates were 81% and 72%, respectively. The Hill equation with a variable slope fitted the relationship between the area under the concentration-time curve (AUC)/MIC ratio and 14-day survival well for each strain. An F test showed the 50% effective doses to be significantly different from each other (P = 0.0023). However, contrary to expectation, there was a significant difference in exposure-response relationships between strains, and it appeared that the susceptible strains required a relatively higher exposure than the resistant ones to result in the same treatment effect, the 50% effective pharmacokinetic/pharmacodynamic (PK/PD) index (EI50) required being negatively and log-linearly related to the MIC (P = 0.04). We conclude that the efficacy of voriconazole depended on drug exposure and the voriconazole MIC of the isolates, but lower exposures are required for strains with higher MICs. These findings may have profound significance in clinical practice with respect to dosing and drug choice.

scholarly journals Pharmacodynamics and Dose-Response Relationships of Liposomal Amphotericin B against Different Azole-Resistant Aspergillus fumigatus Isolates in a Murine Model of Disseminated Aspergillosis

2013 ◽  
Vol 57 (4) ◽  
pp. 1866-1871 ◽  
Author(s):  
Seyedmojtaba Seyedmousavi ◽  
Willem J. G. Melchers ◽  
Johan W. Mouton ◽  
Paul E. Verweij
Keyword(s):  
Aspergillus Fumigatus ◽  
Dose Response ◽  
Tandem Repeat ◽  
Murine Model ◽  
Promoter Region ◽  
Liposomal Amphotericin ◽  
Resistance Mechanism ◽  
Azole Resistance ◽  
Wild Type ◽  
Content Type

ABSTRACTThe management of invasive aspergillosis (IA) has become more complicated due to the emergence of acquired azole resistance inAspergillus fumigatus, which is associated with treatment failure and a mortality rate of 88%. Treatment with liposomal amphotericin B (L-AmB) may be a useful alternative to improve therapeutic outcome in azole-resistant IA. Four clinicalA. fumigatusisolates obtained from patients with proven IA were studied in a nonneutropenic murine model of infection: a wild-type isolate without mutations in thecyp51Agene and three azole-resistant isolates harboring a single mutation at codon 220 (M220I) and tandem repeat mutations (a 34-bp tandem repeat mutation in the promoter region of thecyp51Agene in combination with substitutions at codon L98 [TR34/L98H] and a 46-bp tandem repeat mutation in the promoter region of thecyp51Agene in combination with mutation at codons Y121 and T289 [TR46/Y121F/T289A]), respectively. Female CD-1 mice were infected intravenously 24 h prior to the start of therapy. Groups of 11 mice were treated at days 1, 2, and 5 postchallenge with increasing 4-fold doses of L-AmB ranging from 0.004 to 16 mg/kg/day and observed for 14 days. Survival for all 4 isolates at day 14 was significantly better than that of controls. A dose-response relationship was observed independent of the azole resistance mechanism. The Hill-type model with a variable slope fitted the relationship between the dose and 14-day survival well for all isolates, withR2values of 0.95 (wild-type), 0.97 (M220I), 0.85 (TR34/L98H), and 0.94 (TR46/Y121F/T289A), respectively. Multiple logistic regression analysis confirmed that there was no significant difference between groups. The results of these experiments indicate that L-AmB was able to prolong survivalin vivoin disseminated IA independent of the presence of an azole resistance mechanism in a dose-dependent manner, and therefore, they support a role for L-AmB in the treatment of azole-resistant IA.

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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