Pharmacokinetic interaction between etoposide and tamoxifen in patients with hepatocellular carcinoma

The effect of tamoxifen (TAM) on the pharmacokinetics of oral administration of etoposide (VP-16) in patients with nonoperable hepatocellular carcinoma was investigated. The pharmacokinetics of VP-16 was studied by using a validated limited sampling strategy. The pharmacokinetic parameters of VP-16, such as area under curve (AUC), free AUC and protein binding, were determined from drug plasma concentrations at 1 and 4 h after VP-16 administration on the first day (day -1) and at the end of the chemotherapy cycle (day -21) for VP-16 alone and VP-16+TAM, respectively. When VP-16 was administered in association with TAM, the median total systemic exposure was not significantly (p = NS) different from that observed when VP-16 was administered alone [33.74 (range 11.19-56.58) versus 32.97 (range 20.23-119.28) mg/l/h]. Moreover, TAM did not affect significantly (p = NS) the levels of protein binding of VP-16 [median 94.6 (range 87.7-98.2) versus median 94.9 (range 91.6-98.0)% for VP-16+TAM and VP-16 alone, respectively] and the systemic exposure of the free drug (free AUC) [1.86 (range 0.21-4.57) versus median 1.78 (range 0.59-3.73) mg/l/h for VP-16+TAM and VP = 16 alone, respectively]. These results indicate a lack of pharmacokinetic interaction between VP-16 and TAM, and suggest that the increased hematological toxicity observed when TAM is given in combination with VP-16 could be related to pharmacodynamic interactions.