Current methods of drug dosing rely on physical parameters (such as sex, age and weight) that do not account for genetic and physiological differences among individual patients. These differences can greatly affect how drugs are processed in the body and can result in ineffective underdosing or toxic overdosing. Here, we describe a generalizable closed-loop system consisting of a biosensor, controller and infusion pump, and a model of drug pharmacokinetics that continuously monitors and adjusts the concentration of a given drug in the body. As proof of concept, we demonstrate that the system can maintain the concentration of doxorubicin—a widely used chemotherapy drug—in live rabbits and rats at any desired set point and in real time, while automatically compensating for large pharmacokinetic differences among individual animals and stabilizing dramatic perturbations arising from acute drug–drug interactions. The feedback-loop system opens up the possibility of tightly controlled, patient-specific dosing of chemotherapeutics and other drugs within narrow therapeutic windows.
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We are grateful for the financial support of the Garland Initiative, Army Research Office (W911NF-10-2-0114, W911QY-15-C-0026) and the W. M. Keck Foundation Medical Research Program. We thank B. Eisenhower, D. Hoggarth, J. Somerson, D. Mamerow, A. Pressman, G. Marcus, S. Hall, M. Eisenstein, M. Nakamoto, K. Plaxco and F. Doyle for helpful discussions. We also thank A. Griffin, R. Wynn, and M. Garcia at the UCSB Animal Resource Center for their technical expertise and assistance with the animal studies.
The authors declare no competing financial interests.
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Mage, P., Ferguson, B., Maliniak, D. et al. Closed-loop control of circulating drug levels in live animals. Nat Biomed Eng 1, 0070 (2017) doi:10.1038/s41551-017-0070
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