Abstract: A microphysiological system (MPS) includes at least one first inlet for receiving a fluid medium. The MPS includes a brain module comprising brain tissue. The MPS includes a blood-brain-barrier (BBB) module comprising BBB tissue, the BBB module configured to receive the fluid medium. The MPS includes a crosstalk channel between the brain module and the BBB module, the crosstalk channel configured to promote a bidirectional crosstalk between the brain tissue and the BBB tissue in response to receiving the fluid medium at the BBB module. The MPS is configured for treating the brain tissue and the BBB tissue with a drug or a combination of drugs to determine a phenotypic effect and a transcriptomic effect of the drug. A drug perturbation is related to the phenotypic effect and the transcriptomic effect based on kinetic optimization.