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Precision Dosing of Doxapram in Preterm Infants Using Continuous Pharmacodynamic Data and Model-Based
Jarinda A Poppe1, Willem van Weteringen1,2, Lotte L G Sebek3
1Department of Pediatrics, Division of Neonatology, Erasmus University Medical Center-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands.
Insights
Optimizing drug therapy in preterm infants using continuous physiological monitoring and pharmacokinetic modeling improves treatment effectiveness and reduces adverse drug reactions (ADRs). This precision medicine approach allows for individualized care, moving beyond standardized dosing for better patient outcomes.
Area of Science:
- Neonatal pharmacology
- Clinical pharmacokinetics
- Precision medicine
Background:
- Standardized drug dosing in preterm infants often relies on body weight, but factors like gestational and postnatal age significantly impact drug pharmacokinetics and pharmacodynamics.
- Objective pharmacodynamic parameters are typically lacking, making drug therapy evaluation challenging in this population.
- Integrating continuous physiological data with drug exposure and adverse drug reaction (ADR) data can optimize individual pharmacotherapy.
Purpose of the Study:
- To demonstrate the benefit of integrating continuous physiological monitoring with model-based drug exposure and ADR data for optimizing pharmacotherapy in preterm infants.
- To evaluate the effectiveness of doxapram therapy using non-invasive physiological parameters.
- To provide recommendations for improving individualized drug therapy in neonates.
Main Methods:
- Continuous monitoring of oxygen saturation (SpO2) and fraction of inspired oxygen (FiO2) as indicators of doxapram effectiveness.
- Analysis of continuous effect data alongside doxapram exposure and ADR parameters in preterm infants.
- Simulation of doxapram and keto-doxapram exposure using a population pharmacokinetic model.
- Retrospective comparison of infants based on doxapram indication, response, dose-response relationship, and dosage over time.
Main Results:
- Case studies illustrating correct/incorrect doxapram indications, patient responses, and overexposure with ADRs.
- Identification of opportunities for objective evaluation of doxapram's added effect.
- Recommendations for preventing overdosing through earlier dose adjustments or discontinuation.
- Strategies for preventing hypoxia and agitation by measuring specific parameters at key time-points.
Conclusions:
- Real-time, non-invasive drug therapy monitoring combined with model-based exposure data offers valuable clinical insights.
- Individualized, objective evaluation of pharmacotherapy is crucial due to significant patient variability.
- Integration of physiological measurements and ADR data enables precision medicine in neonatology at the bedside.
Introduction:
Current drug dosing in preterm infants is standardized, mostly based on bodyweight. Still, covariates such as gestational and postnatal age may importantly alter pharmacokinetics and pharmacodynamics. Evaluation of drug therapy in these patients is very difficult because objective pharmacodynamic parameters are generally lacking. By integrating continuous physiological data with model-based drug exposure and data on adverse drug reactions (ADRs), we aimed to show the potential benefit for optimized individual pharmacotherapy.
Materials And Methods:
Continuous data on oxygen saturation (SpO2), fraction of inspired oxygen (FiO2) and composite parameters, including the SpO2/FiO2 ratio and the cumulative oxygen shortage under the 89% SpO2 limit, served as indicators for doxapram effectiveness. We analyzed these continuous effect data, integrated with doxapram exposure and ADR parameters, obtained in preterm infants around the start of doxapram therapy. The exposures to doxapram and the active metabolite keto-doxapram were simulated using a population pharmacokinetic model. Infants were selected and retrospectively compared on the indication to start doxapram, the first response to doxapram, a potential dose-response relationship, and the administered dosage over time. Recommendations were made for individual improvements of therapy.
Results:
We provide eight cases of continuous doxapram administration that illustrate a correct and incorrect indication to start doxapram, responders and non-responders to therapy, and unnecessary over-exposure with ADRs. Recommendations for improvement of therapy include: objective evaluation of added effect of doxapram after start, prevention of overdosing by earlier down-titration or termination of therapy, and the prevention of hypoxia and agitation by measuring specific parameters at strategical time-points.
Conclusion:
Real-time and non-invasive effect monitoring of drug therapy combined with model-based exposure provides relevant information to clinicians and can importantly improve therapy. The variability between and within patients emphasizes the importance of individual, objective evaluation of pharmacotherapy. These measurements, together with data on ADRs, allow for precision medicine in neonatology that should be brought to the bedside.
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