Precision Dosing of Doxapram in Preterm Infants Using Continuous Pharmacodynamic Data and Model-Based Pharmacokinetics: An Illustrative Case Series
Frontiers in Pharmacology, vol. 11, pp. 665
Abstract
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: 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.
Authors 7
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Jarinda A. Poppe corresponding
Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Pediatrics, Division of Neonatology, Erasmus University Medical Center-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
Department of Pediatrics, Division of Neonatology, Erasmus University Medical Center—Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Pediatric Surgery, Erasmus University Medical Center-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
Department of Pediatrics, Division of Neonatology, Erasmus University Medical Center-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
Department of Pediatric Surgery, Erasmus University Medical Center—Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
Department of Pediatrics, Division of Neonatology, Erasmus University Medical Center—Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
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Erasmus MC · Erasmus University Rotterdam
Affiliation as printed
Department of Hospital Pharmacy, Erasmus University Medical Center, University Medical Center Rotterdam, Rotterdam, Netherlands
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Catherijne A. J. Knibbe Aachen Systems Biomedicine and Pharmacology Leiden Academic Centre for Drug Research
Leiden University · Erasmus MC · St. Antonius Ziekenhuis · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, Netherlands
Department of Pediatrics, Division of Neonatology, Erasmus University Medical Center-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands
Department of Pediatrics, Division of Neonatology, Erasmus University Medical Center—Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Pediatrics, Division of Neonatology, Erasmus University Medical Center-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
Department of Pediatrics, Division of Neonatology, Erasmus University Medical Center—Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Pediatrics, Division of Neonatology, Erasmus University Medical Center-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
Department of Pediatrics, Division of Neonatology, Erasmus University Medical Center—Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital · Erasmus University Rotterdam
Affiliation as printed
Department of Hospital Pharmacy, Erasmus University Medical Center, University Medical Center Rotterdam, Rotterdam, Netherlands
Department of Pediatrics, Division of Neonatology, Erasmus University Medical Center-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
Department of Pediatrics, Division of Neonatology, Erasmus University Medical Center—Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
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