A New Approach to Organ Pharmacokinetics Using Noninvasive Radionuclide Measurement Methods

Abstract

Proper chemotherapy requires that the right dose of the right drug be administered to a given patient at the correct rate. This can be achieved if there is proper monitoring of the drug's biodistribution and metabolism in an individual patient. We have documented that radionuclidic measurements, coupled to a systems-based multicompartmental model approach, are ideally suited in providing proper monitoring of the time course of a drug in a patient. The results achieved to date can best be illustrated through the studies we have conducted with cisplatin and with KS1 /4, a monoclonal antibody directed against a human lung tumor. Radiolabeled cisplatin has been used to monitor the relative rate of drug localization and retention in patients with brain astrocytomas, following either standard intravenous (IV) or intraarterial (IA) drug administration. The preliminary results obtained in such patient studies have shown that a much higher amount of radioactive platinum (Pt) was deposited in such tumors during IA infusion. The differential diffusion (washout) rates of radioactive platinum from these tumors are consistent with higher local uptake of the free (eg, active) drug following IA administration. It is of interest to note that no detectable differences could be observed in the blood levels of either the free drug, platinated proteins, or RBC bound Pt, following either IV or IA administration to the same patient. A six-compartment subsystem has been proposed to help analyze and rationalize these data. Similarly, a nine-compartmental model has been shown to represent the biodistribution of KS1 /4 labeled with iodine 131I. The studies reported here illustrate that the pharmacokinetics of drug biodistribution, targeting, and metabolism can be estimated using noninvasive measuring techniques coupled with compartmental model analysis. The availability of such new pharmacokinetic data should be of value in helping to monitor and optimize chemotherapeutic regimens in patients.