Application of Pharmacokinetic and Pharmacodynamic Analysis to the Development of Liposomal Formulations for Oncology

Liposomal formulations of anticancer agents have been developed to prolong drug circulating lifetime, enhance anti-tumor efficacy by increasing tumor drug deposition, and reduce drug toxicity by avoiding critical normal tissues. Despite the clinical approval of numerous liposome-based chemotherapeutics, challenges remain in the development and clinical deployment of micro- and nano-particulate formulations, as well as combining these novel agents with conventional drugs and standard-of-care therapies. Factors requiring optimization include control of drug biodistribution, release rates of the encapsulated drug, and uptake by target cells. Quantitative mathematical modeling of formulation performance can provide an important tool for understanding drug transport, uptake, and disposition processes, as well as their role in therapeutic outcomes. This review identifies several relevant pharmacokinetic/pharmacodynamic models that incorporate key physical, biochemical, and physiological processes involved in delivery of oncology drugs by liposomal formulations. They capture observed data, lend insight into factors determining overall antitumor response, and in some cases, predict conditions for optimizing chemotherapy combinations that include nanoparticulate drug carriers

Pharmacodynamic Modeling to Evaluate the Impact of Cimetidine, an OCT2 Inhibitor, on the Anticancer Effects of Cisplatin

Despite potent anticancer activity, the clinical utilization of cisplatin is limited due to nephrotoxicity. As Organic Cation Transporter 2 (OCT2) has been shown to be one of the key transporters involved in the uptake of cisplatin into renal proximal tubules, OCT2 inhibitors such as cimetidine have been explored to suppress cisplatin-induced nephrotoxicity. Nonetheless, the impact of OCT2 inhibition or cimetidine on the anti-cancer effects of cisplatin has not been extensively examined. The main objective of the present study was to quantitatively characterize the anticancer effects of cisplatin and cimetidine and determine their nature of interactions in two cancer cell lines, OCT2-negative hepatocellular carcinoma (HCC) cell line, Huh7, and OCT2-positive breast cancer cell line, MDA-MB-468. First, we determined the static concentration-response curves of cisplatin and cimetidine as single agents. Next, with the help of three-dimensional (3D) response surface analyses and a competitive interaction model, we determined their nature of interactions at static concentrations to be modestly synergistic or additive in Huh7 and antagonistic in MDA-MB-468. These results were consistent with the cell-level pharmacodynamic (PD) modeling analysis which leveraged the time-course effects of drugs as single agents and drug combinations. Our developed PD model can be further used to design future preclinical studies to further investigate the cisplatin and cimetidine combinations in different in vitro and in vivo cancer models

Pharmacodynamic Modeling to Evaluate the Impact of Cimetidine, an OCT2 Inhibitor, on the Anticancer Effects of Cisplatin

Despite potent anticancer activity, the clinical utilization of cisplatin is limited due to nephrotoxicity. As Organic Cation Transporter 2 (OCT2) has been shown to be one of the key transporters involved in the uptake of cisplatin into renal proximal tubules, OCT2 inhibitors such as cimetidine have been explored to suppress cisplatin-induced nephrotoxicity. Nonetheless, the impact of OCT2 inhibition or cimetidine on the anti-cancer effects of cisplatin has not been extensively examined. The main objective of the present study was to quantitatively characterize the anticancer effects of cisplatin and cimetidine and determine their nature of interactions in two cancer cell lines, OCT2-negative hepatocellular carcinoma (HCC) cell line, Huh7, and OCT2-positive breast cancer cell line, MDA-MB-468. First, we determined the static concentration-response curves of cisplatin and cimetidine as single agents. Next, with the help of three-dimensional (3D) response surface analyses and a competitive interaction model, we determined their nature of interactions at static concentrations to be modestly synergistic or additive in Huh7 and antagonistic in MDA-MB-468. These results were consistent with the cell-level pharmacodynamic (PD) modeling analysis which leveraged the time-course effects of drugs as single agents and drug combinations. Our developed PD model can be further used to design future preclinical studies to further investigate the cisplatin and cimetidine combinations in different in vitro and in vivo cancer models

Advancing Cancer Therapy With Present And Emerging Immuno-Oncology Approaches

Immuno-oncology (I-O) is a young and growing field on the frontier of cancer therapy. Contrary to cancer therapies that directly target malignant cells, I-O therapies stimulate the body\u27s immune system to target and attack the tumor, which is otherwise invisible to, or inhibiting the immune response. To this end, several methods have been developed: First, passive therapies that enable T-cells to fight the tumor without direct manipulation, typically through binding and modifying the intracellular signaling of surface receptors. Checkpoint inhibitors, perhaps the most well known of I-O therapies; are an example of such. These are monoclonal antibodies that block binding of the tumor cell at receptors that inactivate the T-cell. A variety of small molecules can achieve the same effect by affecting metabolic or signaling pathways to boost the immune response or prevent its attenuation. Drugs originally formulated for unrelated disease states are now being used to treat cancer under the I-O approach. Second, active therapies which often involve direct manipulations that occur in vitro and once introduced to the patient will directly attack the tumor. Adoptive cell transfer is the oldest of these methods. It involves the removal of T-cells from the body, which are then expanded and genetically modified for specificity toward tumor-associated antigens (TAAs), and then reintroduced to the patient. A similar approach is taken with cancer vaccines, where TAAs are identified and reintroduced with adjuvants to stimulate an immune response, sometimes in the context of antigen-presenting cells or viral vectors. Oncolytic viruses are genetically modified natural viruses for selectivity toward tumor cells. The resulting cytotoxicity has the potential to elicit an immune response that furthers tumor cell killing. A final active approach is bi-specific T-cell engagers. These modified antibodies act to link a T-cell and tumor cell through surface receptors and thereby forcibly generate immune recognition. The therapies in each of these subfields are all still very new and ongoing clinical trials could provide even further additions. The full therapeutic potential of the aforementioned therapies, alone or in combination, has yet to be realized, but holds great promise for the future of cancer treatment

Pharmacodynamic Modeling of Cell Cycle Effects for Gemcitabine and Trabectedin Combinations in Pancreatic Cancer Cells

Combinations of gemcitabine and trabectedin exert modest synergistic cytotoxic effects on two pancreatic cancer cell lines. Here, systems pharmacodynamic (PD) models that integrate cellular response data and extend a prototype model framework were developed to characterize dynamic changes in cell cycle phase of cancer cell subpopulations in response to gemcitabine and trabectedin as single agents and in combination. Extensive experimental data were obtained for two pancreatic cancer cell lines (MiaPaCa-2 and BxPC-3), including cell proliferation rates over 0-120 h of drug exposure, and the fraction of cells in different cell cycle phases or apoptosis. Cell cycle analysis demonstrated that gemcitabine induced cell cycle arrest in S phase, and trabectedin induced transient cell cycle arrest in S phase that progressed to G2/M phase. Over time, cells in the control group accumulated in G0/G1 phase. Systems cell cycle models were developed based on observed mechanisms and were used to characterize both cell proliferation and cell numbers in the sub G1, G0/G1, S and G2/M phases in the control and drug-treated groups. The proposed mathematical models captured well both single and joint effects of gemcitabine and trabectedin. Interaction parameters were applied to quantify unexplainable drug-drug interaction effects on cell cycle arrest in S phase and in inducing apoptosis. The developed models were able to identify and quantify the different underlying interactions between gemcitabine and trabectedin, and captured well our large datasets in the dimensions of time, drug concentrations and cellular subpopulations

Advancing Cancer Therapy with Present and Emerging Immuno-Oncology Approaches

Immuno-oncology (I-O) is a young and growing field on the frontier of cancer therapy. Contrary to cancer therapies that directly target malignant cells, I-O therapies stimulate the body\u27s immune system to target and attack the tumor, which is otherwise invisible to, or inhibiting the immune response. To this end, several methods have been developed: First, passive therapies that enable T-cells to fight the tumor without direct manipulation, typically through binding and modifying the intracellular signaling of surface receptors. Checkpoint inhibitors, perhaps the most well known of I-O therapies; are an example of such. These are monoclonal antibodies that block binding of the tumor cell at receptors that inactivate the T-cell. A variety of small molecules can achieve the same effect by affecting metabolic or signaling pathways to boost the immune response or prevent its attenuation. Drugs originally formulated for unrelated disease states are now being used to treat cancer under the I-O approach. Second, active therapies which often involve direct manipulations that occur in vitro and once introduced to the patient will directly attack the tumor. Adoptive cell transfer is the oldest of these methods. It involves the removal of T-cells from the body, which are then expanded and genetically modified for specificity toward tumor-associated antigens (TAAs), and then reintroduced to the patient. A similar approach is taken with cancer vaccines, where TAAs are identified and reintroduced with adjuvants to stimulate an immune response, sometimes in the context of antigen-presenting cells or viral vectors. Oncolytic viruses are genetically modified natural viruses for selectivity toward tumor cells. The resulting cytotoxicity has the potential to elicit an immune response that furthers tumor cell killing. A final active approach is bi-specific T-cell engagers. These modified antibodies act to link a T-cell and tumor cell through surface receptors and thereby forcibly generate immune recognition. The therapies in each of these subfields are all still very new and ongoing clinical trials could provide even further additions. The full therapeutic potential of the aforementioned therapies, alone or in combination, has yet to be realized, but holds great promise for the future of cancer treatment

Utility of a Novel Three-Dimensional and Dynamic (3DD) Cell Culture System for PK/PD Studies: Evaluation of a Triple Combination Therapy at Overcoming Anti-HER2 Treatment Resistance in Breast Cancer

Background: Emergence of Human epidermal growth factor receptor 2 (HER2) therapy resistance in HER2-positive (HER2+) breast cancer (BC) poses a major clinical challenge. Mechanisms of resistance include the over-activation of the PI3K/mTOR and Src pathways. This work aims to investigate a novel combination therapy that employs paclitaxel (PAC), a mitotic inhibitor, with everolimus (EVE), an mTOR inhibitor, and dasatinib (DAS), an Src kinase inhibitor, as a modality to overcome resistance.Methods: Static (two dimensional, 2D) and three-dimensional dynamic (3DD) cell culture studies were conducted using JIMT-1 cells, a HER2+ BC cell line refractory to HER2 therapies. Cell viability and caspase-3 expression were examined after JIMT-1 cell exposure to agents as monotherapy or in combination using a 2D setting. A pharmacokinetic/pharmacodynamic (PK/PD) combination study with PAC+DAS+EVE was conducted over 3 weeks in a 3DD setting. PAC was administered into the system via a 3 h infusion followed by the addition of a continuous infusion of EVE+DAS 24 h post-PAC dosing. Cell counts and caspase-3 expression were quantified every 2 days. A semi-mechanistic PK/PD model was developed using the 2D data and scaled up to capture the 3DD data. The final model integrated active caspase-3 as a biomarker to bridge between drug exposures and cancer cell dynamics. Model fittings were performed using Monolix software.Results: The triple combination significantly induced caspase-3 activity in the 2D cell culture setting. In the 3DD cell culture setting, sequential dosing of PAC then EVE+DAS showed a 5-fold increase in caspase-3 activity and 8.5-fold decrease in the total cell number compared to the control. The semi-mechanistic PK/PD models fit the data well, capturing the time-course profiles of drug concentrations, caspase-3 expression, and cell counts in the 2D and 3DD settings.Conclusion: A novel, sequential triple combination therapeutic regimen was successfully evaluated in both 2D and 3DD in vitro cell culture systems. The efficacy of this combination at inhibiting the cellular proliferation and re-growth of HER2/mTOR resistant cell line, JIMT-1, is demonstrated. A biomarker-linked PK/PD model successfully captured all time-course data. The latter can be used as a modeling platform for a direct translation from 3DD in vitro settings to the clinic

Simultaneous Pharmacokinetics/Pharmacodynamics Modeling of Recombinant Human Erythropoietin upon Multiple Intravenous Dosing in Rats

A pharmacokinetics (PK)/pharmacodynamics (PD) model was developed to describe the tolerance and rebound for reticulocyte (RET) and red blood cell (RBC) counts and the hemoglobin (Hb) concentrations in blood after repeated intravenous administrations of 1350 IU/kg of recombinant human erythropoietin (rHuEPO) in rats thrice weekly for 6 weeks. Drug concentrations were described by using a quasi-equilibrium model. The PD model consisted of a lifespan-based indirect response model (LIDR) with progenitor cells [burst colony-forming unit erythroblasts and colony-forming unit erythroblasts (CFUs)], normoblasts (NOR), RETs, and RBCs. Drug–receptor complex stimulatory effects on progenitor cells differentiation and RBC lifespan were expressed by using the Emax model (Smax-epo and SC50-epo, Emax and EC50). The Hb profile was indirectly modeled through a LIDR model for mean corpuscular hemoglobin (with a lifespan Tmch) including a linear (Smax-mch) drug stimulatory effect. The negative feedback from RBCs accounted for the time-dependent rHuEPO clearance decline. A simultaneous PK/PD fitting was performed by using MATLAB-based software. PK parameters such as equilibrium dissociation, erythropoietin receptor degradation, production, and internalization rate constants were 0.18 nM (fixed), 0.08 h−1, 0.03 nM/h, and 2.51 h−1, respectively. The elimination rate constant and central volume of distribution were 0.57 h−1 and 40.63 ml/kg, respectively. CFU and NOR, RET, and RBC lifespans were 37.26 h, 17.25 h, and 30.15 days, respectively. Smax-epo and SC50-epo were 7.3 and 0.47 10−2 nM, respectively. Emax was fixed to 1. EC50 and SC50-epo were equal. Smax-mch and Tmch were 168.1 nM−1 and 35.15 days, respectively. The proposed PK/PD model effectively described rHuEPO nonstationary PK and allowed physiological estimates of cell lifespans