Physiologically based pharmacokinetic (PBPK) modeling of anticancer drugs

This dissertation is an application of physiologically based pharmacokinetic (PBPK) modeling to characterize the physiological and biochemical basis for the altered pharmacokinetics and associated toxicity for four anticancer drugs-methotrexate, doxorubicin, cisplatin and carboplatin.; Methotrexate disposition. Patients with advanced cancer may develop malignant effusions that significantly affect the disposition of anticancer drugs. A PBPK model was constructed for methotrexate that included effusions located at the peritoneal, pleural and pericardial spaces. The presence of these malignant effusions produces a profound decrease in the elimination of the drug resulting in significant systemic toxicity. The theoretical predictions exactly reproduced the drug concentration-time profile in a patient with osteosarcoma.; Doxorubicin early disposition. The administration of doxorubicin has been associated with cardiotoxicity. The elderly and females are most vulnerable to this toxicity. The purpose of this study was to determine the relationship between cardiotoxicity and both age and sex. Following intravenous doxorubicin administration, drug concentrations in the blood decline rapidly. However the rate of this decline markedly decreases with age. Using a PBPK model, we were able to show that this phenomenon was due to reduced blood flow in the elderly. Simulation also demonstrated higher doxorubicin concentration in the heart tissue of older patients.; Doxorubicin clearance. Subsequent analysis of the same population described above revealed a sex dependent difference in the clearance of doxorubicin with age; specifically P-glycoprotein-mediated biliary excretion of doxorubicin declined with age in females. This reduced elimination caused an elevation in doxorubicin heart tissue. A much smaller decline in doxorubicin clearance was seen in males.; Cisplatin and carboplatin. A PBPK model was constructed for both cisplatin and carboplatin in mice. The relative tissue uptake and binding of both drugs in the tissues, including the kidney, was evaluated. It was determined that although the total amount of cisplatin and carboplatin in kidney tissue was the same for both drugs, the binding rate constant of cisplatin was ∼10-fold greater compared with carboplatin, consistent with the respective nephrotoxicity of the two drugs.