Closed-loop automated drug infusion regulator: A clinically translatable, closed-loop drug delivery system for personalized drug dosing

Louis B DeRidder; Kyle A Hare; Aaron Lopes; Josh Jenkins; Nina Fitzgerald; Emmeline MacPherson; Niora Fabian; Josh Morimoto; Jacqueline N Chu; Ameya R Kirtane; Wiam Madani; Keiko Ishida; Johannes L P Kuosmanen; Naomi Zecharias; Christopher M Colangelo; Hen-Wei Huang; Makaya Chilekwa; Nikhil B Lal; Shriya S Srinivasan; Alison M Hayward; Brian M Wolpin; David Trumper; Troy Quast; Douglas A Rubinson; Robert Langer; Giovanni Traverso

doi:10.1016/j.medj.2024.03.020

Closed-loop automated drug infusion regulator: A clinically translatable, closed-loop drug delivery system for personalized drug dosing

Med. 2024 Jul 12;5(7):780-796.e10. doi: 10.1016/j.medj.2024.03.020. Epub 2024 Apr 24.

Authors

Louis B DeRidder¹, Kyle A Hare², Aaron Lopes³, Josh Jenkins⁴, Nina Fitzgerald³, Emmeline MacPherson⁵, Niora Fabian⁶, Josh Morimoto³, Jacqueline N Chu⁷, Ameya R Kirtane³, Wiam Madani⁴, Keiko Ishida⁸, Johannes L P Kuosmanen⁴, Naomi Zecharias⁹, Christopher M Colangelo¹⁰, Hen-Wei Huang⁸, Makaya Chilekwa¹¹, Nikhil B Lal¹², Shriya S Srinivasan³, Alison M Hayward¹³, Brian M Wolpin¹⁴, David Trumper¹⁵, Troy Quast¹⁶, Douglas A Rubinson¹⁴, Robert Langer¹⁷, Giovanni Traverso¹⁸

Affiliations

¹ Harvard-MIT Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
² David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁴ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁵ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁶ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁷ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Harvard Medical School, Boston, MA 02115, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁸ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁰ Agilent Technologies, Lexington, MA 02421, USA.
¹¹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹² Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; MIT Media Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹³ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁴ Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹⁵ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹⁶ College of Public Health, University of South Florida, Tampa, FL 33612, USA.
¹⁷ Harvard-MIT Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹⁸ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].

PMID: 38663403
DOI: 10.1016/j.medj.2024.03.020

Abstract

Background: Dosing of chemotherapies is often calculated according to the weight and/or height of the patient or equations derived from these, such as body surface area (BSA). Such calculations fail to capture intra- and interindividual pharmacokinetic variation, which can lead to order of magnitude variations in systemic chemotherapy levels and thus under- or overdosing of patients.

Methods: We designed and developed a closed-loop drug delivery system that can dynamically adjust its infusion rate to the patient to reach and maintain the drug's target concentration, regardless of a patient's pharmacokinetics (PK).

Findings: We demonstrate that closed-loop automated drug infusion regulator (CLAUDIA) can control the concentration of 5-fluorouracil (5-FU) in rabbits according to a range of concentration-time profiles (which could be useful in chronomodulated chemotherapy) and over a range of PK conditions that mimic the PK variability observed clinically. In one set of experiments, BSA-based dosing resulted in a concentration 7 times above the target range, while CLAUDIA keeps the concentration of 5-FU in or near the targeted range. Further, we demonstrate that CLAUDIA is cost effective compared to BSA-based dosing.

Conclusions: We anticipate that CLAUDIA could be rapidly translated to the clinic to enable physicians to control the plasma concentration of chemotherapy in their patients.

Funding: This work was supported by MIT's Karl van Tassel (1925) Career Development Professorship and Department of Mechanical Engineering and the Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center.

Keywords: Foundational research; cancer; chemotherapy; closed-loop system; drug delivery; personalized dosing.

MeSH terms

Animals
Antimetabolites, Antineoplastic / administration & dosage
Antimetabolites, Antineoplastic / pharmacokinetics
Drug Delivery Systems* / methods
Fluorouracil* / administration & dosage
Fluorouracil* / pharmacokinetics
Humans
Infusions, Intravenous
Precision Medicine* / methods
Rabbits

Substances

Fluorouracil
Antimetabolites, Antineoplastic