Model‐informed drug repurposing: A pharmacometric approach to novel pathogen preparedness, response and retrospection

Abstract

Funding information Bill and Melinda Gates Foundation During a pandemic caused by a novel pathogen (NP), drug repurposing offers the potential of a rapid treatment response via a repurposed drug (RD) while more targeted treatments are developed. Five steps of model-informed drug repurposing (MIDR) are discussed: (i) utilize RD product label and in vitro NP data to determine initial proof of potential, (ii) optimize potential posology using clinical pharmacokinetics (PK) considering both efficacy and safety, (iii) link events in the viral life cycle to RD PK, (iv) link RD PK to clinical and virologic outcomes, and optimize clinical trial design, and (v) assess RD treatment effects from trials using model-based metaanalysis. Activities which fall under these five steps are categorized into three stages: what can be accomplished prior to an NP emergence (preparatory stage), during the NP pandemic (responsive stage) and once the crisis has subsided (retrospective stage). MIDR allows for extraction of a greater amount of information from emerging data and integration of disparate data into actionable insight.

Applications of Model-Based Meta-Analysis in Drug Development

“…Additional collaborations are also possible with the health economics and outcomes research (HEOR) function, with which outputs from the MBMA could be integrated into other, non-clinically focused models, such as cost-effectiveness models or financial forecasting models, potentially leading to improved commercial and financial strategies [45]. Therefore, continued education and communication among project stakeholders, team collaborators, and [19,[107][108][109][110] Correlation between early and late endpoints Allow the use of a biomarker or an early clinical efficacy time point to detect a signal of the treatment effect [38,42,63,111] Pharmacokinetic and pharmacodynamic relationship Establishing the relationship between exposure and an efficacy or safety biomarker, possibly a less frequently reported one and would need data from a large population to be detected [41,[112][113][114][115][116][117] Simulation of established MBMA models Simulate various scenarios using established MBMA models to optimize clinical trial design [62,118] Pharmacoeconomics Incorporate cost-effectiveness into a MBMA model [119] other pharmacometric specialty experts regarding MBMA and MIDD approaches in general are warranted [1]. Another important ally of MIDD approaches is from statistics.…”

Twice neglected? Neglected diseases in neglected populations

“…28 A more rational stepwise model-informed drug repurposing approach has been proposed, integrating preparatory, reactive, and retrospective action in response to new pathogens. 29,30 In essence, situations of desperation call for more highquality rational science, and not less.…”

Science fiction has become reality: Best practice for future viral pandemics

“…Preparedness for future pandemics therefore requires the development of policies and processes to identify, react to, and control future pandemics in a timely and efficient manner. This is introduced by Dodds et al [5] and further developed by Davda et al [6] who present a five-stage blueprint that will allow us to be prepared for, and react to, future viral outbreaks. Importantly, the blueprint is centred on pre-pandemic preparedness, including surveillance for new pathogens, high through-put screening for potential therapeutic options using human derived pulmonary cells and the identification of key pharmacological indices such as IC50 values (or better EC90 values) using prior work on reference viruses [6].…”

“…This concept was extended by Dodds et al [10], who used a similar platform to show how targeting different aspects of the viral lifecycle with combinations of repurposed (or novel) agents will optimise treatment success. The use of in silico tools was also emphasised by Dodds et al [5] and Davda et al [6] as important platforms to allow for expedited drug repurposing efforts and drug development in future pandemics. In addition, in silico tools can be used to ensure that the basic principles of clinical pharmacology are not ignored in the haste to propose possible treatments, an important lesson from early in the COVID-19 crisis echoed in the contribution from Smith et al [11] and the ASCEPT-BPS statement on drug repurposing [12].…”