Bridging sunitinib exposure to time-to-tumor progression in hepatocellular carcinoma patients with mathematical modeling of an angiogenic biomarker.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14690-e14690
Author(s):  
Sihem Ait-Oudhia ◽  
Donald E. Mager ◽  
Garin Tomaszewski ◽  
Adrienne E. Groman ◽  
Patricia D. Zagst ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Hepatocellular Carcinoma ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Time Course ◽  
Drug Exposure ◽  
Plasma Concentrations ◽  
Target Range ◽  
Tumor Growth Inhibition ◽  
Time To Tumor Progression

e14690 Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with 250,000 new annual cases in the US. Sunitinib (SU), an oral tyrosine kinase inhibitor, inhibits tumor cell proliferation, selectively binds to the angiogenesis biomarker (VEGFR2), and is metabolized to an equipotent metabolite (SU12662). The objective of this study is to utilize mathematical modeling to bridge drug exposure and VEGFR2 dynamics to tumor growth inhibition (TGI) and time-to-tumor progression (TTP). Methods: Plasma concentrations of SU, SU12662, and VEGFR2, and tumor growth and TTP measurements were obtained from a phase-II study in 16 patients with unresectable HCC. SU was administered at 37.5 mg daily 7-days prior to chemoembolization, then on days 15-35. A MAP Bayesian approach was utilized to model SU and SU12662 pharmacokinetics (PK), both captured with a two-compartment model including linear clearances. Inhibition of VEGFR2 production was mediated by predicted active unbound concentrations (ACub) of SU and SU12662. VEGFR2 concentrations were the driver for TGI. The TTP probability was modeled with exponential hazard function dependent on a time varying covariate -the difference in VEGFR2 concentration from its baseline (ΔVEGFR2). Results: Drug and metabolite clearances (CLd, CLm) were estimated at 30.3 (19, %RSE) and 19.7L/h (14). Their volumes of distribution (Vd, Vm) were 1,780 (39) and 1840L (25). SU exposure was within target range for VEGFR2 inhibition. VEGFR2 half-life in plasma was calculated at 4h. The slope (α) for ACub effect on VEGFR2 production was 0.77(µg/mL)-1 (14). The ΔVEGFR2 effect on TGI was assumed maximal, whereas its potency (ΔIC50) was estimated at 1.83x10-2µg/mL (41). The between-subjects variabilities were 37.4, 51, 44.7, 64.8, 21, and 36% for CLd, CLm, Vd, Vm, α, and ΔIC50. The median observed tumor size baseline was 91 mm3. The simulated mean TTP was 7 months. Conclusions: The time-course of SU, SU12662, and VEGFR2 were captured well with final PK/pharmacodynamic models. VEGFR2 profiles successfully linked drug exposure to TGI and TTP. This model may serve as a general platform for the dynamics of anti-angiogenic drugs.

scholarly journals Regorafenib inhibits tumor progression through suppression of ERK/NF-κB activation in hepatocellular carcinoma bearing mice

2018 ◽  
Vol 38 (3) ◽  
Author(s):  
Mao-Chi Weng ◽  
Mei-Hui Wang ◽  
Jai-Jen Tsai ◽  
Yu-Cheng Kuo ◽  
Yu-Chang Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Body Weight ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Ex Vivo ◽  
Luciferase Reporter ◽  
Pathological Examination ◽  
Tumor Bearing ◽  
Phosphorylated Akt

Regorafenib has been demonstrated in our previous study to trigger apoptosis through suppression of extracellular signal-regulated kinase (ERK)/nuclear factor-κB (NF-κB) activation in hepatocellular carcinoma (HCC) SK-Hep1 cells in vitro. However, the effect of regorafenib on NF-κB-modulated tumor progression in HCC in vivo is ambiguous. The aim of the present study is to investigate the effect of regorafenib on NF-κB-modulated tumor progression in HCC bearing mouse model. pGL4.50 luciferase reporter vector transfected SK-Hep1 (SK-Hep1/luc2) and Hep3B 2.1-7 tumor bearing mice were established and used for the present study. Mice were treated with vehicle or regorafenib (20 mg/kg/day by gavage) for 14 days. Effects of regorafenib on tumor growth and protein expression together with toxicity of regorafenib were evaluated with digital caliper and bioluminescence imaging (BLI), ex vivo Western blotting immunohistochemistry (IHC) staining, and measurement of body weight and pathological examination of liver tissue, respectively, in SK-Hep1/luc2 and Hep3B 2.1-7 tumor bearing mice. The results indicated regorafenib significantly reduced tumor growth and expression of phosphorylated ERK, NF-κB p65 (Ser536), phosphorylated AKT, and tumor progression-associated proteins. In addition, we found regorafenib induced both extrinsic and intrinsic apoptotic pathways. Body weight and liver morphology were not affected by regorafenib treatment. Our findings present the mechanism of tumor progression inhibition by regorafenib is linked to suppression of ERK/NF-κB signaling in SK-Hep1/luc2 and Hep3B 2.1-7 tumor bearing mice.

The effect of route of administration on the enantioselective pharmacokinetics of ketamine and norketamine in rats

2018 ◽  
Vol 32 (10) ◽  
pp. 1127-1132 ◽  
Author(s):  
Martin Le Nedelec ◽  
Paul Glue ◽  
Helen Winter ◽  
Chelsea Goulton ◽  
Natalie J Medlicott
Keyword(s):  
Intravenous Infusion ◽  
Time Course ◽  
Drug Exposure ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Drug Efficacy ◽  
Route Of Administration ◽  
Routes Of Administration ◽  
Similar Drug ◽  
Treatment Of Depression

Background: Ketamine has been shown to produce a rapid and potent antidepressant response in patients with treatment-resistant depression. Currently ketamine is most commonly administered as a 40-minute intravenous infusion, though it is unknown whether this is the optimal route of administration. Aims: To determine the plasma concentration time course of the R- and S-enantiomers of ketamine and norketamine following administration of ketamine by four different routes of administration. Methods: Plasma from conscious non-anaesthetised rats was collected following administration of ketamine by either subcutaneous (SC), intramuscular (IM), intravenous infusion (IVI) or intravenous bolus (IVB) routes of administration. Concentrations of the enantiomers of ketamine and norketamine were determined by LC/MS. Results: Administration by the SC, IM and IVI routes produced an overall similar drug exposure. In contrast, administration by the IVB route produced approximately 15-fold higher peak plasma concentrations for the enantiomers of ketamine and an approximately four-fold lower AUC for the enantiomers of norketamine. Conclusions: Route of administration can significantly influence ketamine and norketamine exposures. These differences may influence safety and tolerability, and potentially drug efficacy in humans. This knowledge adds to current research into the optimisation of the use of ketamine for the treatment of depression.

Phase I and DCE-MRI evaluation of CDP791, a di-Fab PEG conjugate that inhibits VEGFR2

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3523-3523 ◽  
Author(s):  
G. C. Jayson ◽  
C. Ton ◽  
G. J. Parker ◽  
A. Jackson ◽  
S. Mullamitha ◽  
...  
Keyword(s):  
Blood Flow ◽  
Tumor Growth ◽  
Vascular Permeability ◽  
Dose Level ◽  
Plasma Concentrations ◽  
Growth Patterns ◽  
Tumor Growth Inhibition ◽  
Dce Mri ◽  
Dependent Inhibition ◽  
Inhibition Of Tumor Growth

3523 Background: VEGF inhibitors are of proven clinical value. However, very few drugs specifically inhibit VEGFR2. CDP791 is a di-Fab PEG conjugate that binds VEGFR2 with a Kd of 49pM. Methods: We performed a single site, open label, dose-escalation study of CDP791. Cohorts of patients received between 0.3 and 30 mg/kg every 3 weeks until disease progression. DCE-MRI was performed at each dose level. Results: Thirty-one patients with colorectal, ovarian or renal cancer or other tumors were treated. There was no observed dose limiting toxicity or maximum tolerated dose. At doses of 10mg/kg or above, 7/16 patients developed cutaneous hemangiomata that regressed upon drug withdrawal. Biopsy of these confirmed that CDP791 was co-located with unphosphorylated VEGFR2. DCE-MRI revealed a dose- dependent inhibition of tumor growth over 20 days post-treatment, although there was no measurable change in Ktrans, an indicator of blood flow and capillary permeability. Fourteen patients received extended treatment and 5 (with renal (x2), colorectal, endometrial cancer and melanoma) had stable disease after 6 cycles. Plasma concentrations of CDP791 >10mcg/mL were sustained across the 21-day cycle for doses 10mg/kg and above. Conclusions: CDP791 is a pure VEGFR2 antagonist that is well tolerated up to doses of 30mg/kg. The drug is mechanistically active, associated with hemangiomata and dose-level dependent inhibition of tumor growth but not with reduction in vascular permeability or blood flow on DCE-MRI. These data imply that the drug is active in patients but challenge our understanding of the regulation of tumor vascular permeability. In addition, they suggest that serial 3-dimensional measurements of short-term tumor growth patterns are a sensitive method to detect biological therapy-related tumor growth inhibition. [Table: see text]

scholarly journals Experimental and computational modeling for signature and biomarker discovery of renal cell carcinoma progression

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Lindsay S. Cooley ◽  
Justine Rudewicz ◽  
Wilfried Souleyreau ◽  
Andrea Emanuelli ◽  
Arturo Alvarez-Arenas ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Renal Cell Carcinoma ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Primary Tumor ◽  
Renal Cell ◽  
Genomic Variation ◽  
Primary Tumor Growth

Abstract Background Renal Cell Carcinoma (RCC) is difficult to treat with 5-year survival rate of 10% in metastatic patients. Main reasons of therapy failure are lack of validated biomarkers and scarce knowledge of the biological processes occurring during RCC progression. Thus, the investigation of mechanisms regulating RCC progression is fundamental to improve RCC therapy. Methods In order to identify molecular markers and gene processes involved in the steps of RCC progression, we generated several cell lines of higher aggressiveness by serially passaging mouse renal cancer RENCA cells in mice and, concomitantly, performed functional genomics analysis of the cells. Multiple cell lines depicting the major steps of tumor progression (including primary tumor growth, survival in the blood circulation and metastatic spread) were generated and analyzed by large-scale transcriptome, genome and methylome analyses. Furthermore, we performed clinical correlations of our datasets. Finally we conducted a computational analysis for predicting the time to relapse based on our molecular data. Results Through in vivo passaging, RENCA cells showed increased aggressiveness by reducing mice survival, enhancing primary tumor growth and lung metastases formation. In addition, transcriptome and methylome analyses showed distinct clustering of the cell lines without genomic variation. Distinct signatures of tumor aggressiveness were revealed and validated in different patient cohorts. In particular, we identified SAA2 and CFB as soluble prognostic and predictive biomarkers of the therapeutic response. Machine learning and mathematical modeling confirmed the importance of CFB and SAA2 together, which had the highest impact on distant metastasis-free survival. From these data sets, a computational model predicting tumor progression and relapse was developed and validated. These results are of great translational significance. Conclusion A combination of experimental and mathematical modeling was able to generate meaningful data for the prediction of the clinical evolution of RCC.

The correlation between the decrease of intratumoral arterial enhancement and time-to-tumor progression in patients with hepatocellular carcinoma treated with sorafenib.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 167-167
Author(s):  
Y. Kojima ◽  
S. Mitsunaga ◽  
M. Ikeda ◽  
H. Takahashi ◽  
S. Shimizu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Progression ◽  
Prothrombin Time ◽  
Univariate Analysis ◽  
Rank Test ◽  
Arterial Phase ◽  
Arterial Enhancement ◽  
Sorafenib Therapy ◽  
The Impact ◽  
Time To Tumor Progression

167 Background: In the diagnostic work-up of hepatocellular carcinoma (HCC), intratumoral enhancement in the arterial phase (IE) of dynamic computed tomography (CT) or magnetic resonance imaging (MRI) represents tumor viability. Although such IE has been known to disappear during the course of sorafenib therapy, the precise impact of decreased IE has not yet been elucidated. Therefore, we focused on the impact of decreased IE on the time-to-tumor progression (TTP) in HCC patients (pts) treated with sorafenib. Methods: The change in IEduring the course of sorafenib therapy was reviewed in 52advanced HCC patients treated between January 2004 and April 2010. decreased IE was defined as the disappearance of arterial enhancement to a level equal to or less than that of the surrounding cancer-free hepatic parenchyma on dynamic CT or MRI. Even if one of the HCC tumors in a patient showed decreased IE, that patient was regarded as showing decreased IE. The impact of the pretreatment variables, decreased IE, and adverse events on the TTP were evaluated by the log-rank test. The Cox proportional hazard model was used to determine the most significant variables related to TTP. Results: Of the 52 pts, 48 were males and 4 females, and the median age was 70.5 years. The Child-Pugh classification was A in 28 pts and B in 24 pts. HCV Ab positivity, HBs Ag positivity, and seronegativity for both were observed in 39 pts, 7 pts and 6 pts, respectively. Decreased IE was found in 23 patients. The median TTP was 114 days in all patients, 165 days in patients showing decreased IE, and 89 days in patients who did not show decreased IE. The median time to decreased IE was 41 days. In the univariate analysis, decreased IE, female, prothrombin time, and serum PIVKA II were identified as being significantly associated with the TTP. Multivariate analysis using the Cox proportional hazards model revealed decreased IE (p=0.04) and prothrombin time (p=0.04) to be independently associated with a favorable TTP. Conclusions: Decreased IE is correlated with a favorable time-to-tumor progression in HCC pts treated with sorafenib. No significant financial relationships to disclose.

scholarly journals Quantitative mathematical modeling of clinical brain metastasis dynamics in non-small cell lung cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
M. Bilous ◽  
C. Serdjebi ◽  
A. Boyer ◽  
P. Tomasini ◽  
C. Pouypoudat ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Lung Cancer ◽  
Tumor Growth ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Patient Specific ◽  
Tumor Growth Inhibition ◽  
Small Cell Lung ◽  
Therapeutic Decisions

Abstract Brain metastases (BMs) are associated with poor prognosis in non-small cell lung cancer (NSCLC), but are only visible when large enough. Therapeutic decisions such as whole brain radiation therapy would benefit from patient-specific predictions of radiologically undetectable BMs. Here, we propose a mathematical modeling approach and use it to analyze clinical data of BM from NSCLC. Primary tumor growth was best described by a gompertzian model for the pre-diagnosis history, followed by a tumor growth inhibition model during treatment. Growth parameters were estimated only from the size at diagnosis and histology, but predicted plausible individual estimates of the tumor age (2.1–5.3 years). Multiple metastatic models were further assessed from fitting either literature data of BM probability (n = 183 patients) or longitudinal measurements of visible BMs in two patients. Among the tested models, the one featuring dormancy was best able to describe the data. It predicted latency phases of 4.4–5.7 months and onset of BMs 14–19 months before diagnosis. This quantitative model paves the way for a computational tool of potential help during therapeutic management.

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