Combination Therapy for Multi-Target Manipulation of Secondary Brain Injury Mechanisms

Abstract

Traumatic brain injury (TBI) is a major healthcare problem that affects millions of people worldwide. Despite advances in understanding and developing preventative and treatment strategies using preclinical animal models, clinical trials to date have failed, and a 'magic bullet' for effectively treating TBI-induced damage does not exist. Thus, novel pharmacological strategies to effectively manipulate the complex and heterogeneous pathophysiology of secondary injury mechanisms are needed. Given that goal, this paper discusses the relevance and advantages of combination therapies (COMTs) for 'multi-target manipulation' of the secondary injury cascade by administering multiple drugs to achieve an optimal therapeutic window of opportunity (e.g., temporally broad window) and compares these regimens to monotherapies that manipulate a single target with a single drug at a given time. Furthermore, we posit that integrated mechanistic multiscale models that combine primary injury biomechanics, secondary injury mechanobiology/neurobiology, physiology, pharmacology and mathematical programming techniques could account for vast differences in the biological space and time scales and help to accelerate drug development, to optimize pharmacological COMT protocols and to improve treatment outcomes.

Keywords: Combination therapy; brain; model; multi-target; neurotherapeutic; secondary injury..

Fig. (1)

Pathogenesis of secondary brain injury mechanisms in response to primary injury (e.g., primary blast-induced or direct impact). This schematic illustrates the injury progression from primary (macroscale biomechanics) to post-primary injury (microscale mechanobiology) and culminates at the onset of time-dependent secondary injury mechanisms (biological); these pathways are largely based on preclinical models. The long duration and complexity of secondary injury provide opportunities for rational interventions, pharmacological or psychological protection, and treatment of the brain injury.

Fig. (2)

Conceptual diagram of multi-target manipulation of the dynamically evolving secondary injury cascade using combination therapy as illustrated on the temporal axis (t₁-t₅). Different drugs (e.g., D₁-D₅) act on their respective targets, i.e., on the specific injury mechanism, within the time windows (Δt₁-₅). The combined drug actions aim to broaden the therapeutic window of opportunity to achieve better treatment outcomes.

Fig. (3)

TBI combination pharmacotherapy and multi-target manipulation of secondary injury pathways. (A) Combinations of drug administration routes (i.e., delivery routes such as intravenous bolus, intravenous infusion and oral) and (B-C) conceptual illustrations of expected pharmacological responses based on the drug sequencing (concurrent or delayed). In the context of the COMT described here, the drugs are not physically combined; instead, they are separately administered to effectively manipulate the desired targets (i.e., injury mechanisms) in the time-dependent secondary TBI cascade. In concurrent administration, the drugs are administered (i.e., delivered) at the same time point t₁, whereas in delayed administration, the drugs are administered at different times (i.e., t₁, t₂, and t₃). The pharmacokinetic profiles, C(t), the drug bioavailability, the pharmacodynamic responses in the brain and the therapeutic window of opportunity (i.e., the number of secondary injury time windows, Δt, that can be targeted by a combination pharmacotherapy protocol, termed ’overall coverage’ here) will rely on the proper selection of drug candidates, administration routes, drug sequencing and ‘administration scenarios’ (i.e., prophylaxis or treatment, not to be confused with administration routes). Model-guided simulations can help identify the optimal drugs and their sequence and can help design pharmacotherapy protocols to achieve the desired outcomes (i.e., safety and efficacy) by optimizing these therapeutic variables.

Fig. (4)

An integrated multiscale TBI model linking the model components across different spatial and temporal scales for the rational design and optimization of pharmacotherapies (i.e., MONTs and COMTs), drug evaluation and research. This article identifies the need to develop such models in the near future and supports the notion that model-guided approaches can help to accelerate drug development and rationalize treatment protocols to improve treatment outcomes.