1. Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.204
Figure 3 PK/PD modelling of haematological toxicity and dosing optimization
Figure 3 | PK/PD modelling of haematological toxicity and dosing optimization. Comparison between predicted (plain lines) and observed ANC values (circles) in a patient treated with docetaxel–epirubicin combination chemotherapy. To obtain the optimal dosing regimen the fixed total drug amount per cycle was distributed according to a fixed schedule so that the average tumour size over an entire cycle was minimized (PD-efficacy model), and the haematological constraints were respected. As individual model parameters were initially unknown, the first cycle of the dosing regimen was determined a priori and was similar for all patients. Serum concentrations and absolute neutrophil counts (ANCs) measured during the first cycle were used to identify individual parameters by Bayesian estimation. With these individual parameters, the ANC–time profile with the associated 95% confidence intervals was simulated for subsequent cycles. If the simulated profiles fulfilled the haematological constraints, the a priori dosing regimen remained unchanged for the next cycle; otherwise the model was used to individualize the optimal distribution of the total drug amount for the first 3 days of the second cycle. The same strategy was applied to the following cycles; thus, the individual administration of chemotherapy was guided by the model at each cycle according to haematological toxicity and drug concentrations measured during previous cycles. Dashed lines represent the confidence bounds. Dark-grey circles represent the values measured after the standard dose regimen, and light-grey circles, the values obtained after the computed regimen was used. The PK/PD model adequately predicts the effects of treatment on circulating neutrophil numbers and thus drug-induced neutropenia.
Barbolosi, D. et al. (2015) Computational oncology — mathematical modelling of drug regimens for precision medicine
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