Mechanism-based models for topotecan-induced neutropenia

Objective A semiphysiologic pharmacokinetic-pharmacodynamic model was applied to describe topotecan-induced neutropenia, to quantify interindividual and intraindividual pharmacodynamic variability, and to study the effect of covariates on the model. Methods Data were obtained from patients treated with topotecan given either orally (118 patients) or intravenously (71 patients), according to different schedules (5 to 21 consecutive days), with or without cisplatin. The model mimics the maturation chain of neutrophils. Topotecan concentration-time profiles affected the proliferation of neutrophil precursors (sensitive cells) through an inhibitory linear model (topotecan is assumed to induce cell loss by a function, Edrug, proportional to the topotecan concentration in the central compartment: Edrug = Slope · Concentration). The topotecan plasma concentration versus time profile was generated for each patient by modeling the data according to a 2-compartment pharmacokinetic model and first-order absorption for oral administration by use of NONMEM. Results The model described the time course of neutrophil values well. Topotecan neutropenic effect exhibited a large interpatient variability (coefficient of variation of 82% for the slope values). The oral route was associated with a 43% lower value for slope, corresponding to a lower toxicity. The combination with cisplatin increased the neutropenic effect compared with topotecan alone by a factor 3.5. The intrapatient variability between cycle 1 and cycle 2 on slope was lower for the intravenous administration than for the oral administration. By application of the model to a new weekly schedule of topotecan, neutrophil values at the nadir were consistent with those observed during a phase I study of this regimen. Conclusion This model can be used to describe both the duration and intensity of neutropenia; the area between the curve of neutrophil count versus time and a critical neutrophil count (such as 0.500 × 103/mm3) would be a better toxic endpoint than the unique observed value of neutrophil at nadir. The model may be used to predict neutropenia corresponding to regimens of topotecan not yet explored. Clinical Pharmacology & Therapeutics (2004) 76, 567–578; doi: 10.1016/j.clpt.2004.08.008