Etoposide pharmacokinetics and pharmacodynamics after acute and chronic exposure to cisplatin

The objectives of this study were to determine etoposide pharmacokinetics after both acute and chronic exposure to cisplatin and to evaluate the relationship between etoposide systemic exposure and toxicity in children with neuroblastoma.

Seventeen children with newly diagnosed stage C or D neuroblastoma were given continuous infusions of 780 mg/m2 etoposide over 72 hours as part of multiagent chemotherapy. Etoposide pharmacokinetic parameters were estimated on three occasions in each patient: (1) 21 days after the first cisplatin dose (etoposide was given immediately after cyclophosphamide; cumulative cisplatin dose, 90 mg/m2), (2) 2 days after the third cisplatin dose (cumulative cisplatin dose, 270 mg/m2), and (3) 21 days after the final cisplatin dose (etoposide again immediately after cyclophosphamide; cumulative cisplatin dose, 360 mg/m2). Toxicity was scored on the basis of transfusion requirements and need for hospitalization.

Etoposide systemic clearance decreased acutely when administered 2 days after cisplatin (median of 15.5 ml/min/m2) compared with both the first study (20.0 ml/min/m2) and the third study (19.7 ml/min/m2; p < 0.001). The decrease in clearance resulted in a median 31% increase in etoposide area under the concentration-time curve (AUC) compared with the first study and a 36% increase compared with the third study. Toxicity scores were higher after the second study than after the first or third study (p = 0.01), and etoposide AUC was significantly correlated with toxicity score (p = 0.006). Neither etoposide renal clearance nor catechol excretion differed significantly among the courses.

There was an acute decrease in etoposide systemic clearance when etoposide immediately followed cisplatin. No persistent decrease in etoposide clearance was noted after a cumulative dose of 360 mg/m2 cisplatin. Etoposide AUC was positively correlated with toxicity in a multidrug regimen.