A population model for the leukopenic effect of etoposide*

We present a new model-dependent approach to quantify hematologic toxicity in a patient population after anticancer therapy. The population model consists of three submodels that are simultaneously fit to the data: (1) a cubic spline function describing the average response of the population versus time ("structural model"), (2) a covariate model, which relates parameters of the structural model to measured demographic or therapeutic variables that are found to be of predictive value (in this study: white blood cell (WBC) count baseline, drug concentration, serum albumin, and serum bilirubin concentration), and (3) a variance model, which estimates the contribution to the response from random variability between patients and from variability within patients, both between courses and within courses, between days. To demonstrate the approach, previously reported data from 118 courses of etoposide therapy in 71 patients with cancer were used to model the decrease in WBC count after 3-day continuous infusions of drug. The estimated typical response profile is characterized by (1) a lag-time of 4 1/2 days before any WBC count decline is observed, (2) a duration of time below baseline of 22 days, and (3) half-maximal effect (i.e., decrease to 50% of baseline WBC count) after exposure to C50 = 3 mg/L etoposide (mean) over 3 days. Lower serum albumin concentrations, higher bilirubin concentrations, or both are associated with greater effects at a given etoposide exposure. Large variability in the estimated response was found between individuals and within individuals, between courses. The total variabilities (SD) in lag-time, duration of the decrease, and C50 were 1 day, 6 days, and 1.8 mg/L, respectively. The population model can also be used to predict the consequence of as-yet untested therapy and sampling strategies, as well as to relate acceptable risks of toxicity to target drug exposure.