Pharmacokinetic interaction between etoposide and tamoxifen in patients with hepatocellular carcinoma

The effect of tamoxifen (TAM) on the pharmacokinetics of oral administratio n of etoposide (VP-16) in patients with non-operable hepatocellular carcino ma was investigated. The pharmacokinetics of VP-16 was studied by using a v alidated limited sampling strategy. The pharmacokinetic parameters of VP-16 , such as area under curve (AUC), free AUC and protein binding, were determ ined from drug plasma concentrations at 1 and 4 h after VP-16 administratio n 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 administere d in association with TAM, the median total systemic exposure was not signi ficantly (p=NS) different from that observed when VP-16 was administered al one [33.74 (range 11.19-56.58) versus 32.97 (range 20.23-119.28) mg/l/h]. M oreover, TAM did not affect significantly (p=NS) the levels of protein bind ing 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 expos ure 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]. Thes e results indicate a lack of pharmacokinetic interaction between VP-16 and TAM, and suggest that the increased hematological toxicity observed when TA M is given in combination with VP-16 could be related to pharmacodynamic in teractions. [(C) 1999 Lippincott Williams & Wilkins.].