Socially optimal pandemic drug dosing

Strohbehn, Garth W.; Parker, William F.; Reid, Pankti; Gellad, Walid F.

doi:10.1016/s2214-109x(21)00251-5

Cited by 10 publications

(13 citation statements)

References 9 publications

(11 reference statements)

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“…With new evidence emerging, Infectious Diseases Society of America (IDSA) COVID-19 treatment guidelines provide updated recommendations for certain monotherapies and combinations depending on severity and setting 61 . Dose optimization has been increasingly recognized as a key therapy optimization element for maximizing public health benefits from the therapeutic solutions of limited supply 62 . Interestingly, a wide range of AI-based applications have been deployed since the onset of the pandemic, that have significantly accelerated drug development and identified several monotherapy candidates that have entered clinical trials or even have been approved for use against COVID-19.…”

Section: Discussionmentioning

confidence: 99%

The IDentif.AI-x pandemic readiness platform: Rapid prioritization of optimized COVID-19 combination therapy regimens

et al. 2022

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IDentif.AI-x, a clinically actionable artificial intelligence platform, was used to rapidly pinpoint and prioritize optimal combination therapies against COVID-19 by pairing a prospective, experimental validation of multi-drug efficacy on a SARS-CoV-2 live virus and Vero E6 assay with a quadratic optimization workflow. A starting pool of 12 candidate drugs developed in collaboration with a community of infectious disease clinicians was first narrowed down to a six-drug pool and then interrogated in 50 combination regimens at three dosing levels per drug, representing 729 possible combinations. IDentif.AI-x revealed EIDD-1931 to be a strong candidate upon which multiple drug combinations can be derived, and pinpointed a number of clinically actionable drug interactions, which were further reconfirmed in SARS-CoV-2 variants B.1.351 (Beta) and B.1.617.2 (Delta). IDentif.AI-x prioritized promising drug combinations for clinical translation and can be immediately adjusted and re-executed with a new pool of promising therapies in an actionable path towards rapidly optimizing combination therapy following pandemic emergence.

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Section: Discussionmentioning

confidence: 99%

The IDentif.AI-x pandemic readiness platform: Rapid prioritization of optimized COVID-19 combination therapy regimens

et al. 2022

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“…In addition, the current landscape of clinical trials is rapidly evolving and adaptive trials have proven especially useful during this pandemic due to their agile and flexible design in exploring repurposed therapies. Leveraging platform trial design to identify optimal dosing strategies, also known as ‘socially optimal’ dosing, will additionally enable the overall realization of maximum clinical benefits while mitigating inequities that may arise from increasing global demand and local/regional limitations in drug supply [ 59 ]. We highlight here the importance of rational dosing of medications through PK/PD, and strongly advocate that current and future trials incorporate PK/PD considerations into their trial designs in order to better inform optimized dosing strategies at the bedside.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Considerations of Alternate Dosing Strategies of Tocilizumab in COVID-19

Leung

Crass²,

Jorgensen

et al. 2021

Clin Pharmacokinet

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Tocilizumab is one of few treatments that have been shown to improve mortality in patients with coronavirus disease 2019 (COVID-19), but increased demand has led to relative global shortages. Recently, it has been suggested that lower doses, or fixed doses, of tocilizumab could be a potential solution to conserve the limited global supply while conferring equivalent therapeutic benefit to the dosing regimens studied in major trials. The relationship between tocilizumab dose, exposure, and response in COVID-19 has not been adequately characterized. There are a number of pharmacokinetic (PK) parameters that likely differ between patients with severe COVID-19 and patients in whom tocilizumab was studied during the US FDA approval process. Likewise, it is unclear whether a threshold exposure is necessary for tocilizumab efficacy. The safety and efficacy of fixed versus weight-based dosing of tocilizumab has been evaluated outside of COVID-19, but it is uncertain if these observations are generalizable to severe or critical COVID-19. In the current review, we consider the potential advantages and limitations of alternative tocilizumab dosing strategies. Leveraging PK models and simulation analyses, we demonstrate that a fixed single dose of tocilizumab 400 mg is unlikely to produce PK exposures equivalent to those achieved in the REMAP-CAP trial, although weight-stratified dosing appears to produce more uniform exposure distribution. Data from current and future trials could provide PK/pharmacodynamic insight to better inform dosing strategies at the bedside. Ultimately, rational dosing strategies that balance available limited supply with patient needs are required.

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“…Usage of the SOD sacrifices maximal efficacy for each recipient in order to increase population-level benefit by increasing the number of recipients. 4 The SOD, derived from estimates of the population-level dose-response relationship, attempts to maximise the quantity of benefit the drug produces without regard to distribution, and may Open access facilitate allocation strategies that focus solely on maximising population-level efficacy. One real-world example of (more) socially optimal dosing-outside the bounds of a clinical trial-was the use of extended-interval dosing of mRNA vaccines, in which the potential risk of worsened individual-level outcomes due to the extended dose interval was accepted in exchange for the potential benefit of protecting more people, acknowledging recipients may receive suboptimal protection by straying from the evidence base.…”

Section: Socially Optimal Dosementioning

confidence: 99%

“…This second, key piece of information requires an understanding of the relationship between the scarce resource's dose and clinical efficacy. 4 A resource's ability to benefit individuals and populations depends on its abundance or scarcity. For resources that are not abundant, tradeoffs between the relative welfares of individuals and populations become inevitable.…”

Section: Introductionmentioning

confidence: 99%

Dose optimisation and scarce resource allocation: two sides of the same coin

et al. 2022

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ObjectiveA deep understanding of the relationship between a scarce drug's dose and clinical response is necessary to appropriately distribute a supply-constrained drug along these lines.Summary of key dataThe vast majority of drug development and repurposing during the COVID-19 pandemic – an event that has made clear the ever-present scarcity in healthcare systems –has been ignorant of scarcity and dose optimisation's ability to help address it.ConclusionsFuture pandemic clinical trials systems should obtain dose optimisation data, as these appear necessary to enable appropriate scarce resource allocation according to societal values.

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Socially optimal pandemic drug dosing

Cited by 10 publications

References 9 publications

The IDentif.AI-x pandemic readiness platform: Rapid prioritization of optimized COVID-19 combination therapy regimens

The IDentif.AI-x pandemic readiness platform: Rapid prioritization of optimized COVID-19 combination therapy regimens

Pharmacokinetic/Pharmacodynamic Considerations of Alternate Dosing Strategies of Tocilizumab in COVID-19

Dose optimisation and scarce resource allocation: two sides of the same coin

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