Computer simulation of pharmacokinetic analysis of 161,051 drugs after intraperitoneal (IP) or intravenous (IV) administrations

16042 Background: Recent clinical studies for ovarian cancer have demonstrated the survival benefit of intraperitoneal (IP) administration of anti-cancer drugs, such as platinum agents, or paclitaxel. It is of great interest to investigate whether IP administration of other cytotoxic agents are more effective compared with intravenous (IV) administration. In this study we investigated the pharmacological advantage of IP administration using anti-cancer drugs, of which cytocidal effect is determined by the value of the area under the time concentration curve (AUC), by using computer simulation model. Methods: The 3-compartment pharmacokinetic computer model was used and 161,051 sets of the rate constants were substituted into the model. Because one set of the rate constants determines a pharmacokinetic behavior of one drug, it was considered to simulate over 160,000 drugs in this study. The constants were referred to ones of carboplatin. The simulations were made after 210 mg/body of the drugs were administered. The values of the AUC in the serum and in the IP cavity after IP or IV administration were calculated for each set, and then, these two administration methods were compared. Results: The values of the AUC in the serum by IP vs IV administration were 6.675 ± 21.603 (mean±SD); [0.08 - 106.155 (range)] vs 6.663 ± 21.541; [0.183 - 105.726]. The values of the AUC in the cavity after IP vs IV administration were 128.799 ± 344.491; [0.342 - 2288.48] vs 90.700 ± 283.946; [0.002 - 2259.32]. The ratios of AUC in the serum after IP or IV administrations were 0.995 ± 0.023; [0.401 - 1.020]. 147,201 sets (91.4%) were between 0.99 and 1.01. On the other hand, the ratios in the IP cavity were 25.327 ± 86.515; [1.003 - 548.976]. All the IP/IV ratios in the cavity were more than 1. Conclusions: The simulated probability clearly indicated that IP administration is not a local but a systemic chemotherapy for most drugs. All of the chemotherapeutic agents should be investigated for IP administration as well as conventional IV administration in clinical research protocol, especially in phase I/II study to clarify the effects and toxicities. No significant financial relationships to disclose.