Physiologically based PK-PD model of Cisplatin文献综述

1. Objective：

To investigate pharmacokinetics and tissue distribution following administration of cisplatin.

1. Introduction

Cisplatin has been especially interesting since it has shown anticancer activity in a

variety of tumors including ovarian, testicular cancer and solid tumors of the head and neck. However it has multiple toxicities including renal and gastrointestinal problems, ototoxicity, ophthalmic toxicities and allergic reactions.

Cisplatin does not undergo the instantaneous and reversible binding to plasma proteins that is characteristic of normal drug-protein binding. However, the platinum from cisplatin, but not cisplatin itself, becomes bound to several plasma proteins, including albumin, transferrin, and gamma globulin.

The parent compound, cisplatin, is excreted in the urine and accounts for 13% to 17% of the dose excreted. The renal clearance of free (ultrafilterable) platinum exceeds the glomerular filtration rate indicating that cisplatin or other platinum-containing molecules are actively secreted by the kidneys. Although small amounts of platinum are present in the bile and large intestine after administration of cisplatin, the fecal excretion of platinum appears to be insignificant.

1. Method
2. Data and physiological parameters

bull; Cisplatin concentration-time data will be extracted from the published literature including plasma, liver, kidney, lung, spleen and GI tract. Record or digitize the data and make a concentration-time curve to compare the pharmacokinetic profile from different publications. Organize information by name of the author, drug formulation, dose, route of administration, animal species, and collection and detection methods. In order to compare the data of different author due to the different dose, we normalize the dose to 1mg/kg.

bull; Physiological parameters for organ volumes and plasma flow rates were fixed to

physiological values .

bull; Tissues without data were lumped into a remainder compartment.

1. Modeling Process

bull; The general structural model for individual organs is shown in Figure 1. Vascular and extravascular compartments allows for compatibility with PBPK models for particulate formulations;

bull; The structure of the whole-body PBPK model is shown in Figure 2;

bull; All parameters were estimated by using ADAPT 5 software and MATLAB.

Figure 1 tissue level model Figure 2 whole PBPK model

1. Simulation process

Model structure and parameters estimate from the data will be used to predict the pharmacokinetics profile in mice and extrapolate to humans and rats. Various interspecies scaling approaches will be evaluated. Compare the data from simulation and the data from literature to assess the modelrsquo;s applicability.

1. Conclusion

Build an appropriate model to simulate the data from the pool of published literature and extrapolate that to humans and rats. Provide some proper recommendation to the clinical use of cisplatin.

Student signature: Zonghui.Yao

time(MM-DD-YYYY): 03-28-2016

Evaluation by Instructor：

Instructor signature：

time(MM-DD-YYYY):

Opinion of department：

Department signature：

time(MM-DD-YYYY):