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 Met hods: Seventy-two patients who received single-agent intravenous (IV) etoposide over 5 or 8 days (total dose, 500 mg/m(2)) were studied. Pha rmacokinetic parameters were derived after analysis of total plasma et oposide by high-performance liquid chromatography (HPLC) with ultravio let (UV) detection, and etoposide protein binding by ultrafiltration o f an etoposide-spiked, pretreatment serum sample, followed by HPLC ana lysis. Free etoposide area under the concentration-time curve (AUG) wa s derived from the total AUC and protein binding, Results: Patients wi th renal impairment (serum creatinine level > 130 mu mol/L) had a lowe r plasma etoposide clearance (13.6 v 18.5 ml/min/m(2); P = .016), resu lting in an increased total-drug and free-drug AUC (total etoposide AU C 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 les s than 35 g/L had no change in total etoposide kinetics but had an inc rease in unbound etoposide (5.2% v 4.1%; P = .01), resulting in an inc rease in free etoposide AUC (27.5 v 16.5 mu g/mL hr; P = .003) and mor e profound toxicity (nadir neutrophil count 0.6 v 1,.9 x 10(9)/L; P = .004). In patients with normal albumin and creatinine, increased toxic ity in those older than 65 years was associated with a reduced drug cl earance, and in those with increased liver enzymes by a trend toward a n increase in free etoposide AUC. Conclusion: Increased hematologic to xicity after etoposide in patients with abnormal organ function is med iated by an increase in free etoposide AUC. A reduction in dose is cle arly indicated in such patients. (C) 1996 by American Society of Clini cal Oncology.