THERAPEUTIC DRUG-MONITORING OF 21-DAY ORAL ETOPOSIDE IN PATIENTS WITHADVANCED NONSMALL CELL LUNG-CANCER

The purpose of this study was to prospectively test a pharmacodynamic model for therapeutic drug monitoring of 21-day oral etoposide, In our previous studies, etoposide trough concentrations on this schedule we re related to the hematological toxicity, expressed as WBC and neutrop hil counts at the nadir, The following pharmacodynamic model estimated the absolute neutrophil count at the nadir (ANC(n)) based on the etop oside concentration (E-C) and the pretreatment count (ANC(p)): ANC(n) = 0.32(1 + ANC(p) x e(-2.47 x Ec)) Patients were treated with 40 mg/m( 2)/day etoposide p.o. x 21 days and 100 mg/m(2) cisplatin i.v. on day 1. All patients had non-small cell lung cancer stage IIIB or IV, had a performance status of 0-2, and had a median age of 66 (range, 42-80). Etoposide was measured in the plasma on day 8 by high-performance liq uid chromatography, and dosage adjustments were made for the remainder of the course, We targeted for grade 3 neutropenia (ANC(n), 500 to 99 9/mu l) and attempted to avoid grade 4 neutropenia (ANC(n), < 500/mu l ). Of 25 patients entered, 22 were evaluable for therapeutic drug moni toring in the first course. Three patients developed grade 3 neutropen ia, and seven patients developed grade 4 neutropenia, Etoposide concen trations were significantly correlated with ANC(n) in the first course (r = -0.50, P < 0.02). For those patients whose dosages were not chan ged, the estimated correlation between predicted and actual ANC(n) was 0.77 (P < 0.01). No evidence of significant bias of the pharmacodynam ic model was detected. The etoposide dosages were increased in 12 pati ents and were not changed in the remaining patients. The precision of the model was good in patients whose dosages were not changed but poor in patients whose dosages were increased. The actual observed ANC(n) was compared with the predicted ANC(n) based on the pharmacodynamic mo del, The prediction was considered accurate if the predicted and actua l ANC(n) values were within 500/mu l of each other. Using this margin, the ANC(n) was accurately predicted in 10 of 22 patients. Etoposide c oncentrations > 0.3 mu g/ml on this schedule were significantly correl ated with combined grades 3 and 4 neutropenia (P < 0.0001). In conclus ion, the pharmacodynamic model is statistically sound when applied to a population of patients. However, when applied to individual patients for therapeutic drug monitoring, the model lacks precision and accura cy.