Pharmacometric modeling of anti-cancer agents: Application to gemcitabine, PQIP and irinotecan

We performed pharmacometric modeling of irinotecan, PQIP and gemcitabine. Irinotecan is a DNA topoisomerase-I inhibitor used in colorectal and brain tumors. One of our aims was to show that that cranial radiation, delivered during irinotecan administration, can enhance uptake in to cerebral-spinal fluid (CSF), and also to characterize the pharmacokinetics of irinotecan and its metabolites SN38 and APC in plasma and CSF in rats. The concentration-time data in plasma and CSF were analyzed by nonlinear mixed-effects modeling using FOCE-I method in NONMEM. The analysis showed that cranial radiation delivered during irinotecan administration enhances uptake in to CSF. The second aim of dissertation was to quantitatively evaluate the drug administration sequence effects of insulin-like growth factor type-1 receptor inhibitors (IGF-1R) with gemcitabine in vitro. Gemcitabine is a nucleoside analogue approved for a variety of solid tumors, while PQIP is an investigational IGF-1R inhibitor. In vitro experiments were conducted in 24-well tissue culture plates using MCF-7, MDA-MB-231 and Hs-578T human breast cancer cell lines. Viable cells were counted every day following the day of drug exposure. The effect of sequence on cell-kill was analyzed by bayesian techniques using WinBUGS. We found that exposure with gemcitabine first, followed by PQIP (GP sequence) was either superior or equivalent to the reverse sequence (PG sequence) with these drugs. The third aim of dissertation was to perform a population pharmacokinetic analysis of gemcitabine and its metabolites dFdU and dFdCTP in patients with solid tumors and to determine patient specific covariates associated with their disposition. Concentration data were obtained in 40 patients with solid tumors. The concentration-time data were analyzed by nonlinear mixed-effects modeling using first-order conditional estimation method with interaction (FOCE-I) in NONMEM. We found that Body surface area (BSA) and age were significant covariates for the disposition of gemcitabine, while creatinine clearance (CLCR) and BSA were found to be significant covariates for the disposition of dFdU. We also found that patients who received gemcitabine at a rate less that 25 mg/m 2/min had higher formation of dFdCTP than those who received gemcitabine at a rate greater than 25 mg/m2/min.