Use of an Anti-Vascular Endothelial Growth Factor Antibody in a Pharmacokinetic Strategy to Increase the Efficacy of Intraperitoneal Chemotherapy

Shah, Dhaval K.; Shin, Beom Soo; Veith, Jean; Tóth, Károly; Bernacki, Ralph J.; Balthasar, Joseph P.

doi:10.1124/jpet.108.149443

Cited by 38 publications

(48 citation statements)

References 22 publications

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“…These models are indicative of how PBPK models can represent mechanistic drug-dependent features that should lead to more accurate predictions, and provide insight on physiological variables can influence drug disposition and whether coadministered drugs might interact. In addition, PBPK modeling and simulation approaches can be used to evaluate and design novel drug formulations and delivery systems (23,24).…”

Section: Whole-body Physiologically Based Pharmacokinetic Modelsmentioning

confidence: 99%

The Pharmacokinetic/Pharmacodynamic Pipeline: Translating Anticancer Drug Pharmacology to the Clinic

Zhou

Gallo

2011

AAPS J

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Abstract. Progress in an understanding of the genetic basis of cancer coupled to molecular pharmacology of potential new anticancer drugs calls for new approaches that are able to address key issues in the drug development process, including pharmacokinetic (PK) and pharmacodynamic (PD) relationships. The incorporation of predictive preclinical PK/PD models into rationally designed early-stage clinical trials offers a promising way to relieve a significant bottleneck in the drug discovery pipeline. The aim of the current review is to discuss some considerations for how quantitative PK and PD analyses for anticancer drugs may be conducted and integrated into a global translational effort, and the importance of examining drug disposition and dynamics in target tissues to support the development of preclinical PK/ PD models that can be subsequently extrapolated to predict pharmacologic characteristics in patients. In this article, we describe three different physiologically based (PB) PK modeling approaches, i.e., the whole-body PBPK model, the hybrid PBPK model, and the two-pore model for macromolecules, as well as their applications. General conclusions are that greater effort should be made to generate more clinical data that could validate scaled preclinical PB-PK/PD tumor-based models and, thus, stimulate a framework for preclinical to clinical translation. Finally, given the innovative techniques to measure tissue drug concentrations and associated biomarkers of drug responses, development of predictive PK/ PD models will become a standard approach for drug discovery and development.KEY WORDS: anticancer drugs; drug discovery and development; pharmacokinetic/pharmacodynamic model; physiologically based pharmacokinetic model.

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Section: Whole-body Physiologically Based Pharmacokinetic Modelsmentioning

confidence: 99%

The Pharmacokinetic/Pharmacodynamic Pipeline: Translating Anticancer Drug Pharmacology to the Clinic

Zhou

Gallo

2011

AAPS J

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“…Recently, works by Shah et al (2009) and Gremonprez et al (2015) showed similar improvement in drug penetration after vascular normalization therapy for IP chemotherapy. We attempted to mimic vascular normalization to test whether our model would be able to reproduce the results from these works.…”

Section: Parameter Studymentioning

confidence: 94%

“…As tissue permeability is notoriously difficult to quantify, no reliable values are currently present in literature, and most models use an arbitrary tenfold of the healthy tissue value (Baxter & Jain, 1989). The influence of this assumption on the penetration depth of the drug was investigated by varying the permeability and comparing the penetration depth Shah et al (2009) to the baseline cases. A summary of the permeability range used can be found in Table 2.…”

Section: Parameter Studymentioning

confidence: 99%

“…Previous models in the area of peritoneal transport include pharmacokinetic compartmental models describing the transport processes occurring during peritoneal dialysis (Flessner et al, 1984;Stachowska-Pietka et al, 2006) and peritoneal chemotherapy (Flessner, 2005;Shah et al, 2009). Additionally, a theoretical model describing the IP transport of cisplatin was created (El-Kareh & Secomb, 2004) but no convective transport was taken into account.…”

Section: Introductionmentioning

confidence: 99%

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Mathematical modeling of intraperitoneal drug delivery: simulation of drug distribution in a single tumor nodule

et al. 2017

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The intraperitoneal (IP) administration of chemotherapy is an alternative treatment for peritoneal carcinomatosis, allowing for higher intratumor concentrations of the cytotoxic agent compared to intravenous administration. Nevertheless, drug penetration depths are still limited to a few millimeters. It is thus necessary to better understand the limiting factors behind this poor penetration in order to improve IP chemotherapy delivery. By developing a threedimensional computational fluid dynamics (CFD) model for drug penetration in a tumor nodule, we investigated the impact of a number of key parameters on the drug transport and penetration depth during IP chemotherapy. Overall, smaller tumors showed better penetration than larger ones, which could be attributed to the lower IFP in smaller tumors. Furthermore, the model demonstrated large improvements in penetration depth by subjecting the tumor nodules to vascular normalization therapy, and illustrated the importance of the drug that is used for therapy. Explicitly modeling the necrotic core had a limited effect on the simulated penetration. Similarly, the penetration depth remained virtually constant when the Darcy permeability of the tissue changed. Our findings illustrate that the developed parametrical CFD model is a powerful tool providing more insight in the drug transport and penetration during IP chemotherapy.

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“…In addition, bevacizumab significantly enhanced sensitivity to cisplatin. It may be speculated that enhancement of drug-induced tumour cell apoptosis by VEGF immunoneutralisation is the molecular basis which has been shown recently for cisplatin-treated ovarian cancer (21).…”

Section: Discussionmentioning

confidence: 99%

Systemic administration of bevacizumab prolongs survival in an in vivo model of platinum pre-treated ovarian cancer

Rein

Volkmer

et al. 2012

Oncology Letters

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Abstract. Ovarian cancer patients often suffer from malignant ascites and pleural effusion. Apart from worsening the outcome, this condition frequently impairs the quality of life in patients who are already distressed by ovarian cancer. This study investigated whether single intraperitoneal administration of the anti-VEGF antibody bevacizumab is capable of reducing the ascites-related body surface and prolonging survival. The study was performed in an orthotopic murine model of peritoneal disseminated platin-resistant ovarian cancer. Mice were treated with bevacizumab and/or paclitaxel or buffer (control). Reduction of body surface and increased survival rates were assessed as therapeutic success. Survival of mice in all treatment groups was significantly enhanced when compared to the non-treatment control group. The combination of paclitaxel plus bevacizumab significantly improved body surface as well as overall survival in comparison to a treatment with only one of the drugs. Treatment of malignant effusion with a single dose of bevacizumab as an intraperitoneal application, with or without cytostatic co-medication, may be a powerful alternative to systemic treatment.

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Use of an Anti-Vascular Endothelial Growth Factor Antibody in a Pharmacokinetic Strategy to Increase the Efficacy of Intraperitoneal Chemotherapy

Cited by 38 publications

References 22 publications

The Pharmacokinetic/Pharmacodynamic Pipeline: Translating Anticancer Drug Pharmacology to the Clinic

The Pharmacokinetic/Pharmacodynamic Pipeline: Translating Anticancer Drug Pharmacology to the Clinic

Mathematical modeling of intraperitoneal drug delivery: simulation of drug distribution in a single tumor nodule

Systemic administration of bevacizumab prolongs survival in an in vivo model of platinum pre-treated ovarian cancer

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