Table 3.

Illustration of the mathematical optimization of COMT protocols to maximize efficacy without compromising the safety constraints (i.e., drug toxicity). Multiscale integrated models of brain injury linked to whole-body PK/PD/TD that are embedded with optimization techniques can accelerate drug development, experimental and regulatory testing, evaluation, and clinical translation.

Objective: To achieve the desired therapeutic window of opportunity (e.g., broad overall coverage) for the effective multi-target manipulation of secondary injury mechanisms Constraints: Regulatory constraints, i.e., safety and efficacy Safety (e.g., toxicity due to drug overload, washout to unintended areas, DDIs in the in vivo environment, antagonistic effects) Efficacy (e.g., primary and secondary biomarkers of treatment outcomes) Optimization parameters (i.e., the pharmacotherapy design variables/parameters): What to administer (drug candidates) How to administer (concurrent or delayed, inlet concentration, and other related factors) Delivery route (intravenous bolus or infusion, oral or other) When to administer (treatment or prophylaxis, i.e., pre- and/or post-injury administration times, termed as ‘administration scenarios’)

Expected outcome(s): In silico model-guided design of optimal pharmacotherapy protocol(s) can be implemented to effectively manipulate secondary brain injury mechanisms within the safety limits and to gain insights into the systemic pharmacokinetics, bioavailability and action of drug(s) in the brain microenvironment (pharmacodynamics).