A Microfluidic Perfusion Platform for In Vitro Analysis of Drug Pharmacokinetic-Pharmacodynamic (PK-PD) Relationships

• Published in: The AAPS journal 2020-03, Vol.22 (2), p.53, Article 53
• Main Authors: Guerrero, Yadir A., Desai, Diti, Sullivan, Connor, Kindt, Erick, Spilker, Mary E., Maurer, Tristan S., Solomon, Deepak E., Bartlett, Derek W.
• Format: Article
• Language: English
• Subjects: Antineoplastic Combined Chemotherapy Protocols - chemistry; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biochemistry; Biomedical and Life Sciences; Biomedicine; Biotechnology; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell Survival - drug effects; Deoxycytidine - analogs & derivatives; Deoxycytidine - chemistry; Deoxycytidine - pharmacokinetics; Deoxycytidine - pharmacology; Dose-Response Relationship, Drug; Doxorubicin - chemistry; Doxorubicin - pharmacokinetics; Doxorubicin - pharmacology; Humans; Lab-On-A-Chip Devices; MCF-7 Cells; Microfluidic Analytical Techniques; Models, Biological; Perfusion; Pharmacology/Toxicology; Pharmacy; Proof of Concept Study; Research Article; Tissue Culture Techniques
• ISSN: 1550-7416; 1550-7416
• DOI: 10.1208/s12248-020-0430-y

Static in vitro cell culture studies cannot capture the dynamic concentration profiles of drugs, nutrients, and other factors that cells experience in physiological systems. This limits the confidence in the translational relevance of in vitro experiments and increases the reliance on empirical testing of exposure-response relationships and dose optimization in animal models during preclinical drug development, introducing additional challenges owing to species-specific differences in drug pharmacokinetics (PK) and pharmacodynamics (PD). Here, we describe the development of a microfluidic cell culture device that enables perfusion of cells under 2D or 3D culture conditions with temporally programmable concentration profiles. Proof-of-concept studies using doxorubicin and gemcitabine demonstrated the ability of the microfluidic PK-PD device to examine dose- and time-dependent effects of doxorubicin as well as schedule-dependent effects of doxorubicin and gemcitabine combination therapy on cell viability using both step-wise drug concentration profiles and species-specific (i.e., mouse, human) drug PK profiles. The results demonstrate the importance of including physiologically relevant dynamic drug exposure profiles during in vitro drug testing to more accurately mimic in vivo drug effects, thereby improving translatability across nonclinical studies and reducing the reliance on animal models during drug development.