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Pharmacokinetics of Etoposide in Patients with Abnormal Renal and Hepatic Function¹

Istituto di Ricerche Farmacologiche "Mario Negri," Via Eritrea 62, 20157 Milan, Italy [M. D., C. R., M. Z., R. U.]; Ospedale San Giovanni, Bellinzona, Switzerland [M. Z., F. C., Y. W., C. S.]; and Clinica Ostetrico-Ginecologica, Università di Milano, Ospedale S. Gerardo, 20052 Monza (Milano), Italy [C. M.]

Etoposide (VP16) pharmacokinetics was investigated in three groups of cancer patients: a control group of 18 patients with renal and hepatic function tests in the normal range; a group of 8 patients with renal insufficiency; and a group of 15 patients with abnormal hepatic function. In the control group plasma clearance (Cl_p), volume of distribution (V_d), and elimination half-life (t ß) of VP16 were, respectively, 22.8 ± 1.0 (SE) ml/min/m², 11.4 ± 0.8 liters/m², and 5.6 ± 0.4 h.

In patients with renal insufficiency Cl_p was 12.8 ± 1.1 ml/min/m², V_d was 20.8 ± 4.9 liters/m², and t ß was 19.2 ± 4.7 h. A statistically significant correlation (P = 0.0000001) was found between VP16 Cl_p and creatinine clearance.

In 12 of 15 patients with abnormal liver tests Cl_p, V_d and t ß were, respectively, 27.9 ± 2.7 ml/min/m², 12.4 ± 1.5 liters/m², and 5.4 ± 0.6 h and are thus similar to those of the control group. In the other three cases with abnormal liver function VP16 plasma levels were very low. In these cases VP16 t ß values were similar (5.1, 4.4, and 5.1 h) whereas Cl_p values (320, 87, and 96 ml/min/m²) and V_d values (142, 33, and 42 liters/m²) were much larger than in controls.

These results suggest that VP16 doses should be reduced in patients with renal function impairment but not necessarily in patients with liver impairment. The high VP16 V_d and Cl_p values found in a subset of patients with liver impairment require further elucidation.

¹ This work was supported by the Italian Association for Cancer Research. Presented in part at the 76th Annual Meeting of the American Association for Cancer Research (1).

² To whom requests for reprints should be addressed, at the Instituto di Ricerche Farmacologiche "Mario Negri," Via Eritrea, 62, 20157 Milan, Italy.

Received 7/16/85. Revised 12/16/85. Accepted 1/14/86.

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