PKPD Modeling & Simulation

Pharmacokinetic (PK) / pharmacodynamics (PD) models are highly valuable tools for drug efficacy and safety assessment, optimal dose selection and clinical trial design. Mathematical and computational PK/PD models have been successfully utilized in drug development and have played a critical role in reducing the amount of experimentation and accelerating drug development lifecycle. My research related to PK/PD modeling centers on a) Building mechanistic physiologically-based pharmacokinetic (PBPK) models for anticancer drugs, and utilizing these models in their safety assessment and anticancer treatment optimization; b) Developing mechanism-based PK/PD models to optimize drug design, development, and therapeutic application of various drugs, including both small molecule compounds (such as tyrosine kinase inhibitors) and large molecule compounds (such as Epo). These models are expected to be highly beneficial for drug development as well as applied pharmacotherapy and are expected to improve the current state of applied drug therapy.

Representative papers related to this area:

1. An G*, Liu W, Duan WR, Nothaft W, Awni W, Dutta S. Population Pharmacokinetics and Exposure-Uric Acid Analyses After Single and Multiple Doses of ABT-639, a Calcium Channel Blocker, in Healthy Volunteers. AAPS J. 2015;17(2):481-92. * Corresponding author.(PubMed link)

2. Egelund EF, Isaza R, Brock AP, Alsultan A, An G, and Peloquin CA. Population Pharmacokinetics of Rifampin in the Treatment of Mycobacterium Tuberculosis in Elephants. Journal of Veterinary Pharmacology and Therapeutics 2015 ;38(2):137-43(PubMed link)

3. An G*, Liu W, Katz D, Marek G, Awni W, and Dutta S. Population Pharmacokinetics of the Potent, Selective 11ß-Hydroxysteroid Dehydrogenase Type 1 Inhibitor ABT-384 in Healthy Volunteers following Single and Multiple Dose Regimens. Biopharmaceutics & Drug Disposition 2014 Oct;35(7):417-29. * Corresponding author (PubMed link)

4. An G*, Liu W, Katz D, Marek G, Awni W, and Dutta S. Effect of Ketoconazole on the Pharmacokinetics of ABT-384 and Its Two Active Metabolites in Healthy Volunteers: Population Analysis of Data from a Drug-Drug Interaction Study. Drug Metabolism and Disposition 2013; 41(5): 1035-45. * Corresponding author(PubMed link)

5. An G and Morris ME. A physiologically based pharmacokinetic model of mitoxantrone in mice and scale-up to humans: a semi-mechanistic model incorporating DNA and protein binding. The AAPS Journal 2012; 14(2):352-64.(PubMed link)

Transporter-Mediated Natural Product - Drug Interaction

ABC transporters (i.e. efflux transporters) play a crucial role in the development of multidrug resistance (MDR) and drug disposition. Up to date no efflux transporter inhibitor has demonstrated MDR reversal effect in clinical trials. Dose-limiting toxicity of the MDR inhibitors represents one of the critical barriers to their clinical application. My research focuses on developing natural source efflux transporter inhibitors, which have little toxicity, to overcome transporter-mediated MDR. My group will conduct pharmacokinetic and pharmacodynamics studies using a combination of computational, cell-based and xenograft disease models to study the effect of natural products (especially methoxylated flavones from herbal plants and major ingredients from beverage) on drug resistance and drug disposition. Results from these studies will provide highly novel treatment options to circumvent drug resistance in diseases such as cancers, and will be important for prediction of potential drug-drug interactions.

Representative papers related to this area:

1. Fleisher B, Uum J, Shao J, and An G*. Ingredients in Fruit Juice Interact with Dasatinib through Inhibition of BCRP: A New Mechanism of Beverage-Drug Interaction. Journal of Pharmaceutical Sciences 2015 Jan;104(1):266-75 * Corresponding author.(PubMed link)

2. Shao J, Markowitz JS, Bei D, and An G*. Enzyme- and Transporter-Mediated Drug Interactions with Small Molecule Tyrosine Kinase Inhibitors. Journal of Pharmaceutical Sciences 2014 Dec;103(12):3810-33 * Corresponding author.(PubMed link)

3. Deng J, Shao J, Markowitz JS, and An G*. ABC Transporters in the Multi-drug Resistance and ADME-Tox of Small Molecule Tyrosine Kinase Inhibitors. Pharmaceutical Research 2014; 31 (9):2237-55 * Corresponding author. (PubMed link)

4. An G, Wu F, and Morris ME. 5,7-Dimethoxyflavone and multiple flavonoids in combination alter the ABCG2-mediated tissue distribution of mitoxantrone in mice. Pharmaceutical Research 2011;28(5):1090-9.(PubMed link)

5. An G and Morris ME. Effects of single and multiple flavonoids on BCRP-mediated accumulation, cytotoxicity and transport of mitoxantrone in vitro. Pharmaceutical Research 2010;27(7): 1296-308.(PubMed link)