Drug kinetics and drug resistance in optimal chemotherapy
The objective of this work is to contribute to a qualitative understanding of the interplay between the drug decay and drug resistance and the influence of this interplay in the determination of an optimal chemotherapeutic treatment. The equation to be used that relates the drug concentration at the plasma to the actual administered dosage of the drug will consist of a first-order pharmacokinetics dynamics. The drug resistance will be assumed to be acquired by spontaneous mutation, at a certain rate. In Section 2 we formulate the mathematical optimal chemotherapy problem we will work with. We stress that in this work the control variable will be the concentration of drug injection instead of the concentration at the tumor site. Some general preparatory results independent of the specific tumor growth rates used in the model are also presented in this section. They are used in Section 3 to prove that maximum allowed drug injection is the optimal treatment strategy in the case of Malthusian (exponential) model of cell growth. In Section 4 we prove that this strategy is suboptimal in the case of more general models of cell growth. In Section 5 the results found in this work are compared with our previous ones [IMA J. Math. Appl. Med. Biol. 9, No. 3, 215-226 (1992; Zbl 0779.92011); ibid. 11, No. 1, 45-59 (1994; Zbl 0816.92008)] concerning the effect of drug resistance, toxicity, saturation, and pharmacokinetics. To close this section we point out that throughout this work we did not include in the objective function the cumulative toxicity criterion due to the major difficulties that appear in the mathematical analysis of the problem. This subject is still under investigation and we state some of the related mathematical difficulties also in Section 5.
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