Supporting Precision Dosing in Drug Labeling

Neely, Michael; Onufrak, Nikolas J.; Scheetz, Marc H.; Avedissian, Sean N.; Lakota, Elizabeth A; Deitchman, Amelia N.; González, Daniel

doi:10.1002/cpt.2054

Cited by 8 publications

(15 citation statements)

References 11 publications

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“…118 As more information on the impact of ARC is obtained for older antibiotics, it will be helpful if product labels are reviewed and updated as appropriate. 119,120 With regard to AKI, a recent retrospective analysis of 18,500 unique patient encounters found that AKI present at admission in infected patients resolved within 48 hours after admission in more than half of the patients; 33 in view of the lag-time associated with estimates and measurements of CL CR , it was considered likely that AKI resolved earlier than 48 hours in many cases. Given the importance of early, effective antibiotic therapy, it has been suggested that in such circumstances it would be prudent to not rush to decrease the dose of renally cleared antibiotics with a wide therapeutic window (e.g., βlactams).…”

Section: How Might Treatment Of Bacterial Infections In Critically Ilmentioning

confidence: 99%

“…Interestingly, in the product label for the recently FDA‐approved agent cefiderocol the impact of ARC has been recognized through specific dosing recommendations for patients with a CL CR ≥ 120 mL/min 118 . As more information on the impact of ARC is obtained for older antibiotics, it will be helpful if product labels are reviewed and updated as appropriate 119,120 . With regard to AKI, a recent retrospective analysis of 18,500 unique patient encounters found that AKI present at admission in infected patients resolved within 48 hours after admission in more than half of the patients; 33 in view of the lag‐time associated with estimates and measurements of CL CR , it was considered likely that AKI resolved earlier than 48 hours in many cases.…”

Section: How Might Treatment Of Bacterial Infections In Critically Ilmentioning

confidence: 99%

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Key Challenges in Providing Effective Antibiotic Therapy for Critically Ill Patients with Bacterial Sepsis and Septic Shock

Landersdorfer

Nation

2021

Clin Pharma and Therapeutics

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Early initiation of effective antibiotic therapy is vitally important for saving the lives of critically ill patients with sepsis or septic shock. The susceptibility of the infecting pathogen and the ability of the selected dosage regimen to safely achieve the required antibiotic exposure need to be carefully considered to achieve a high probability of a successful outcome. Critically ill patients commonly experience substantial pathophysiological changes that impact the functions of various organs, including the kidneys. Many antibiotics are predominantly renally eliminated and thus renal function is a major determinant of the regimen needed to achieve the required antibiotic exposure. However, currently, there is a paucity of guidelines to inform antibiotic dosing in critically ill patients, including those with sepsis or septic shock. This paper briefly reviews methods that are commonly used in critically ill patients to provide a measure of renal function, and approaches that describe the relationship between the exposure to an antibiotic and its antibacterial effects. Two common conditions that very substantially complicate the use of antibiotics in critically ill patients with sepsis, unstable renal function, and augmented renal clearance, are considered in detail and their potential therapeutic implications are explored. Suggestions are provided on how treatment of bacterial infections in critically ill patients with sepsis might be improved. Of high potential are model-informed approaches that aim to individualize initial treatment regimens based on patient and bacterial characteristics, with refinement of regimens during treatment in response to monitoring antibiotic concentrations, responsive measures of renal function, and other important clinical data.

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Section: How Might Treatment Of Bacterial Infections In Critically Ilmentioning

confidence: 99%

Section: How Might Treatment Of Bacterial Infections In Critically Ilmentioning

confidence: 99%

Key Challenges in Providing Effective Antibiotic Therapy for Critically Ill Patients with Bacterial Sepsis and Septic Shock

Landersdorfer

Nation

2021

Clin Pharma and Therapeutics

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“…This issue includes examples of model‐informed precision dosing to improve the clinical benefit for sickle cell anaemia patients treated with hydroxyurea 17 and optimize pharmacological care in neonates with opioid withdrawal syndrome, 18 a significant clinical need during the current opioid abuse crisis in the United States. Current drug labels are often inadequate to support precision dosing for many drugs, and some relatively simple changes could help increase the acceptance and use of precision dosing 19 . Regulatory authorities recognise the value that precision dosing can bring for some drugs 11 and a recent FDA workshop brought together many interested parties from academia, industry, patients, and the health authorities, delivering some critical viewpoints and ideas to increase uptake 20 …”

Section: Goldilocks Principle: One Dose Does Not Fit Allmentioning

confidence: 99%

“…Current drug labels are often inadequate to support precision dosing for many drugs, and some relatively simple changes could help increase the acceptance and use of precision dosing. 19 Regulatory authorities recognise the value that precision dosing can bring for some drugs 11 and a recent FDA workshop brought together many interested parties from academia, industry, patients, and the health authorities, delivering some critical viewpoints and ideas to increase uptake. 20 Ideally, model-informed precision dosing will be built into drug development for those drugs where it is most likely to be useful.…”

Section: Editorialmentioning

confidence: 99%

Precision Dosing: The Clinical Pharmacology of Goldilocks

Peck

Shahin

Vinks

2020

Clin Pharma and Therapeutics

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“…Precision dosing has recently gained momentum in the clinical pharmacology literature 2 but its application in clinical practice or in the broader drug development context remains rare. The “one‐size‐fits‐all” paradigm and the incentive to formulate uniform label claims in terms of dosing regimen 3 are confining the applicability of precision dosing to very few approved drugs. Yet, precision medicine is gaining momentum and key stakeholders are beginning to recognize its importance 4 .…”

Section: Introductionmentioning

confidence: 99%

Model enhanced reinforcement learning to enable precision dosing: A theoretical case study with dosing of propofol

Ribba

Bräm

Baverel

et al. 2022

CPT Pharmacom & Syst Pharma

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Extending the potential of precision dosing requires evaluating methodologies offering more flexibility and higher degree of personalization. Reinforcement learning (RL) holds promise in its ability to integrate multidimensional data in an adaptive process built toward efficient decision making centered on sustainable value creation. For general anesthesia in intensive care units, RL is applied and automatically adjusts dosing through monitoring of patient's consciousness. We further explore the problem of optimal control of anesthesia with propofol by combining RL with state‐of‐the‐art tools used to inform dosing in drug development. In particular, we used pharmacokinetic‐pharmacodynamic (PK‐PD) modeling as a simulation engine to generate experience from dosing scenarios, which cannot be tested experimentally. Through simulations, we show that, when learning from retrospective trial data, more than 100 patients are needed to reach an accuracy within the range of what is achieved with a standard dosing solution. However, embedding a model of drug effect within the RL algorithm improves accuracy by reducing errors to target by 90% through learning to take dosing actions maximizing long‐term benefit. Data residual variability impacts accuracy while the algorithm efficiently coped with up to 50% interindividual variability in the PK and 25% in the PD model's parameters. We illustrate how extending the state definition of the RL agent with meaningful variables is key to achieve high accuracy of optimal dosing policy. These results suggest that RL constitutes an attractive approach for precision dosing when rich data are available or when complemented with synthetic data from model‐based tools used in model‐informed drug development.

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Supporting Precision Dosing in Drug Labeling

Cited by 8 publications

References 11 publications

Key Challenges in Providing Effective Antibiotic Therapy for Critically Ill Patients with Bacterial Sepsis and Septic Shock

Key Challenges in Providing Effective Antibiotic Therapy for Critically Ill Patients with Bacterial Sepsis and Septic Shock

Precision Dosing: The Clinical Pharmacology of Goldilocks

Model enhanced reinforcement learning to enable precision dosing: A theoretical case study with dosing of propofol

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