Predicting etoposide toxicity: Relationship to organ function and protein binding

Purpose: To investigate the effect of organ function on total and free etoposide pharmacokinetics and hematologic toxicity, Patients and Methods: Seventy-two patients who received single-agent intravenous (IV) etoposide over 5 or 8 days (total dose, 500 mg/m(2)) were studied. Pharmacokinetic parameters were derived after analysis of total plasma etoposide by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection, and etoposide protein binding by ultrafiltration of an etoposide-spiked, pretreatment serum sample, followed by HPLC analysis. Free etoposide area under the concentration-time curve (AUG) was derived from the total AUC and protein binding, Results: Patients with renal impairment (serum creatinine level > 130 mu mol/L) had a lower plasma etoposide clearance (13.6 v 18.5 ml/min/m(2); P = .016), resulting in an increased total-drug and free-drug AUC (total etoposide AUC 615 v 452 mu g/mL hr; P = .016; free etoposide AUC 26.0 v 17.6 mu g/mL hr; P = .026) and increased hematologic toxicity (nadir neutrophil count 0.3 v 1.9 x 10(9)/L; P = .005), Patients with albumin levels less than 35 g/L had no change in total etoposide kinetics but had an increase in unbound etoposide (5.2% v 4.1%; P = .01), resulting in an increase in free etoposide AUC (27.5 v 16.5 mu g/mL hr; P = .003) and more profound toxicity (nadir neutrophil count 0.6 v 1,.9 x 10(9)/L; P = .004). In patients with normal albumin and creatinine, increased toxicity in those older than 65 years was associated with a reduced drug clearance, and in those with increased liver enzymes by a trend toward an increase in free etoposide AUC. Conclusion: Increased hematologic toxicity after etoposide in patients with abnormal organ function is mediated by an increase in free etoposide AUC. A reduction in dose is clearly indicated in such patients. (C) 1996 by American Society of Clinical Oncology.