Precision Dosing of Doxapram in Preterm Infants Using Continuous Pharmacodynamic Data and Model-Based Pharmacokinetics: An Illustrative Case Series

Poppe, Jarinda A.; Weteringen, Willem van; Sebek, L.L.G.; Knibbe, Catherijne A. J.; Reiss, Irwin K M; Simons, Sinno H P; Flint, Robert B.

doi:10.3389/fphar.2020.00665

Cited by 12 publications

(11 citation statements)

References 31 publications

(43 reference statements)

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“…[49] It is however also suggested to be effective in reducing the number of apnoea and desaturations in preterm infants[8, 9, 50], although this effect is not observed in every infant treated with doxapram. [51] Decades ago, small randomized controlled trials compared doxapram with either placebo or theophylline without evaluating the long-term effects. [52][53][54][55] An observational study found a higher cumulative doxapram dosage in preterm infants with neurodevelopmental impairment compared to matched controls with a normal mental development, although this association could be confounded by indication.…”

Section: Discussionmentioning

confidence: 99%

“…[57] The rate of apnoea and hypoxic events can also uctuate largely within and between patients, and detection can be di cult. [51,58] We therefore chose for a more pragmatic design with less strict inclusion criteria. The decisions to start doxapram in routine clinical care, to adjust its dosage, or to stop doxapram therapy are made by the attending physicians.…”

Section: Discussionmentioning

confidence: 99%

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Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-Trial)

Poppe,

Flint,

Smits

et al. 2023

Preprint

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Background Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age. Methods The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18–24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics, and cost-effectiveness. Analysis will be on an intention-to-treat principle. Discussion Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants. Trial registration ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-Trial)

Poppe,

Flint,

Smits

et al. 2023

Preprint

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“…Furthermore, our population PK model serves to predict the exposure to doxapram and keto-doxapram in individual patients. By integrating continuous physiological PD data with model-based drug exposure and data on adverse drug reactions (ADRs), we might set one step towards precision medicine in neonatology, as has been illustrated by Poppe et al 40 ADRs are also important to take into account as the use of one bodyweight-based dosage may have led to overexposure to doxapram in a proportion of this vulnerable population in the past. This may have increased the frequency of ADRs that have been reported in preterm infants, including QT interval lengthening 41 possibly resulting in an atrioventricular heart block, 42 gastrointestinal problems, 41,43 tachycardia, 23 increased electroencephalographic activity and less sleep-wake cycling, 44 irritability and agitation, 23,43 and hypokalemia.…”

Section: Discussionmentioning

confidence: 99%

The bioavailability and maturing clearance of doxapram in preterm infants

et al. 2020

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BACKGROUND: Doxapram is used for the treatment of apnea of prematurity in dosing regimens only based on bodyweight, as pharmacokinetic data are limited. This study describes the pharmacokinetics of doxapram and keto-doxapram in preterm infants. METHODS: Data (302 samples) from 75 neonates were included with a median (range) gestational age (GA) 25.9 (23.9-29.4) weeks, bodyweight 0.95 (0.48-1.61) kg, and postnatal age (PNA) 17 (1-52) days at the start of continuous treatment. A population pharmacokinetic model was developed using non-linear mixed-effects modelling (NONMEM®). RESULTS: A two-compartment model best described the pharmacokinetics of doxapram and keto-doxapram. PNA and GA affected the formation clearance of keto-doxapram (CL FORMATION KETO-DOXAPRAM ) and clearance of doxapram via other routes (CL DOXAPRAM OTHER ROUTES ). For a median individual of 0.95 kg, GA 25.6 weeks, and PNA 29 days, CL FORMATION KETO-DOXAPRAM was 0.115 L/h (relative standard error (RSE) 12%) and CL DOXAPRAM OTHER ROUTES was 0.645 L/h (RSE 9%). Oral bioavailability was estimated at 74% (RSE 10%). CONCLUSIONS: Dosing of doxapram only based on bodyweight results in the highest exposure in preterm infants with the lowest PNA and GA. Therefore, dosing may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. For switching to oral therapy, a 33% dose increase is required to maintain exposure.

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“… 37 In the field of pharmacology, recent analysis of electronically captured vital signs has begun to demonstrate the potential vital signs data have for better informing drug provision and dosing in neonatal units. Poppe et al 38 retrospectively identified responders and nonresponders to doxapram therapy (a respiratory stimulant sometimes used as an adjunct to caffeine therapy for the treatment of apnea of prematurity, though not currently recommended for routine use due to limited evidence of efficacy and safety), 39 and those infants who were overexposed and risked unnecessary adverse effects. Interestingly, their case series also presented infants who may have unnecessarily started doxapram despite clinical review of observational charts at the time suggesting its indication, highlighting the disadvantage of intermittent review of vital signs.…”

Section: Vital Signs—an Underutilized Resource?mentioning

confidence: 99%

Toward personalized medicine for pharmacological interventions in neonates using vital signs

Hartley

2021

Paediatric and Neonatal Pain

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Vital signs, such as heart rate and oxygen saturation, are continuously monitored for infants in neonatal care units. Pharmacological interventions can alter an infant's vital signs, either as an intended effect or as a side effect, and consequently could provide an approach to explore the wide variability in pharmacodynamics across infants and could be used to develop models to predict outcome (efficacy or adverse effects) in an individual infant. This will enable doses to be tailored according to the individual, shifting the balance toward efficacy and away from the adverse effects of a drug. Pharmacological analgesics are frequently not given in part due to the risk of adverse effects, yet this exposes infants to the short‐ and long‐term effects of painful procedures. Personalized analgesic dosing will be an important step forward in providing safer effective pain relief in infants. The aim of this paper was to describe a framework to develop predictive models of drug outcome from analysis of vital signs data, focusing on analgesics as a representative example. This framework investigates changes in vital signs in response to the analgesic (prior to the painful procedure) and proposes using machine learning to examine if these changes are predictive of outcome—either efficacy (with pain response measured using a multimodal approach, as changes in vital signs alone have limited sensitivity and specificity) or adverse effects. The framework could be applied to both preterm and term infants in neonatal care units, as well as older children. Sharing vital signs data are proposed as a means to achieve this aim and bring personalized medicine rapidly to the forefront in neonatology.

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Precision Dosing of Doxapram in Preterm Infants Using Continuous Pharmacodynamic Data and Model-Based Pharmacokinetics: An Illustrative Case Series

Cited by 12 publications

References 31 publications

Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-Trial)

Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-Trial)

The bioavailability and maturing clearance of doxapram in preterm infants

Toward personalized medicine for pharmacological interventions in neonates using vital signs

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