Pharmacological analysis of etoposide in elderly patients with lung cancer

To analyze the pharmacological characteristics of etoposide in elderly patients, we conducted a Phase I trial of a 14-day administration of oral etoposide on 12 chemotherapy-naive patients, ages 75 years or older, with lung cancer. The pharmacological profiles of etoposide in elderly patients were compared with those of younger patients in our previous studies (H. Minami et al., J. Clin. Oncol., 11: 1602-1608, 1993; H. Minami et al., J. Clin. Oncol., 13: 191-199, 1995; Y. Ando et al., Jpn. J. Cancer Res., 87: 200-205, 1996). The sigmoid Emax model and logistic regression model were used for pharmacodynamic analysis. The maximum tolerated dose for elderly patients was 75 mg/body/day. The apparent oral clearance in elderly patients was 37 ± 10 (mean ± SD) ml/min, which was not different from that in younger patients (44 ± 12 ml/min). The area under the concentration-versus- time curve of etoposide over the treatment period (total AUC) that produced a 50% decrease in absolute neutrophil counts was significantly different between elderly and younger patients, 14.3 ± 2.5 and 21.6 ± 2.7 mg · min/ml, respectively (P = 0.048). The incidence of grade 3 or 4 neutropenia at total AUC of 30 mg · min/ml (corresponding to a plasma concentration of 1.5 μg/ml for 14 days) was 81% in elderly patients but only 48% in younger patients. Although there was no pharmacokinetic difference between elderly and younger patients, equivalent exposure to etoposide resulted in severer myelosuppression in elderly patients. These findings suggest that prolonged etoposide administration with plasma concentration maintained at 1-2 μg/ml may cause severe myelotoxicity in elderly patients.