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1. Johan E Wallin, Lena E Friberg and Mats O Karlsson Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden Model Based Neutrophil Guided Dose Adaptation in Chemotherapy; Evaluation of Predicted Outcome with Different Type and Amount of Information Introduction: Chemotherapy-induced neutropenia has been reported being predictive of patient survival (1-3). Severe neutropenia is one of the most important dose limiting events in many anticancer regimens, and one of the most employed approaches to this problem has been to reduce the consecutive dose in fixed steps, commonly by 25%. Another investigated approach has been to use pharmacokinetic (PK) sampling to tailor dosing, but only rarely have model-guided computer-based approaches utilizing PK and/or pharmacodynamic (PD) data been used. A previously described semi-mechanistic model for myelosuppression has been used to characterize a wide range of anticancer drugs(4), and both interindividual and interoccasion variability (IIV/IOV) has been described for a number of agents (5). This knowledge could be used in a clinical setting to make model-based dose individualization, which compared to current stepwise procedures, may tailor doses in a more precise manner, and allow increased overall dose intensity in the population without increasing the risk for severe toxicity. Results: In the presence of PD measurements, PK data provided little additional information. By a limited PD sampling the number of patients on target could be increased with the model-based approach compared to standard dose-adjustment methods. Thereby the model-based dose-adjustment method could facilitate increased overall dose intensity in the population, without a corresponding increase in patients experiencing severe neutropenia. The number of patients achieving target range neutropenia was increased by 27% compared to the standard method. Successful dose adaptation seemed to be more sensitive to IOV magnitude in the drug efficacy parameter than in other PK or PD parameters, whereas IIV magnitude was of little importance. Conclusions: A model-based dose adaptation procedure with a limited neutrophil measurement schedule may increase the chance of success in treatment as it allows for increased dose intensity. When neutrophil counts are available PK data provide little additional information on the expected myelosuppression time-course. References: 1. Cameron et al. Moderate neutropenia with adjuvant CMF confers improved survival in early breast cancer. Br J Cancer 2003;89(10):1837-1842. 2. Di Maio et al. Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: a pooled analysis of three randomised trials. Lancet Oncol 2005;6(9):669-677. 3. Poikonen et al. Leucocyte nadir as a marker for chemotherapy efficacy in node-positive breast cancer treated with adjuvant CMF. Br J Cancer 1999;80(11):1763-1766. 4. Friberg et al. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol 2002;20(24):4713-4721. 5. Hansson et al. Comparison of Inter-Occasion and Inter-Individual Variability in Chemotherapy- Induced Myelosuppression. PAGE Abstracts of the Annual Meeting of the Population Approach Group in Europe 2008:Abstract 1328. Hypothetical utility function given that grade of chemotherapy-induced neutropenia being related to probability of survival Objectives: In this study we investigated by simulations the outcome of model-based dose adaptation, and the influence of type and amount of data provided to the model. We also investigated the influence of IIV and IOV magnitudes for adaptation outcome. Methods: PK and PD data were simulated for one thousand patients in five treatment courses. Different portions of data were used to obtain empirical Bayes estimates that were subsequently used to adjust the dose to a level predicted to result in a target neutrophil nadir. Performance of the approaches for dose-adjustment were evaluated with differentlevels of IIV and IOV. The semi-mechanistic myelosuppression model Fraction of patients experiencing life-threatening toxicity, target neutropenia or sub-therapeutic/mild toxicity with different optimization methods Fraction of patients in target range (Gr 2 or 3 neutropenia) using the limited PD sampling strategy with varying levels of variability. Fraction of patients experiencing life-threatening toxicity, target neutropenia or sub-therapeutic/mild toxicity with increasing courses of treatment Estimation of individual parameters and adaptation of dose