Pharmacokinetics of Hepatic Arterial Chemotherapy

Summary

The pharmacokinetic objective of hepatic arterial chemotherapy (HAC) is to generate increased drug exposure in the tumor-bearing liver relative to that generated by standard intravenous administration. The pertinent pharmacokinetic principles have been defined. The increased exposure potentially achievable is directly proportional to the total body clearance (C1TB) of the drug in question, thus making it essential that a drug used for HAC has a relatively high C1_TB. Exposure is inversely proportional to hepatic arterial blood flow. Thus, the ratio of a drug’s C1_TB to the hepatic arterial blood flow is a relative measure of the potential exposure increase.

The amount of drug extracted by passage through the hepatic vasculature is also important in that drugs with higher hepatic extraction (E_H) generate higher hepatic exposure per given degree of systemic exposure. The increased exposure achievable with HAC in a given patient may be limited by the degree of arterial to venous shunting present. Dose rate is also important in that drugs may display nonlinear pharmacokinetics showing decreased C1_TB and E_H with increasing dose rates, thus leading to a decreased exposure advantage at high dose rates.

Recent studies have indicated that tumors within the liver are often hyper vascular at the microcirculatory level. This increased microvascular density provides a mechanism for selective treatment using microsphere therapy either with starch microspheres plus drug or with radiotherapeutic yttrium-90 (⁹⁰Y) microspheres. Phase I studies of starch microspheres have been completed. Studies examining the toxicity of ⁹⁰Y microspheres alone and with the radiosensitizer, 5-bromodeoxyuridine (BUdR), are currently underway in dogs. The pharmacokinetics of BUdR in dogs indicates that it is a rational drug for HAC, at appropriate dose rates, owing to nonlinear pharmacokinetics.