Abstract
Background
Dobutamine is particularly suited to treatment of haemodynamic insufficiency caused by increased peripheral vascular resistance and myocardial dysfunction in the preterm infant. Knowledge of the elimination half-life is essential to estimate the steady state when its efficacy/safety can be evaluated.
Methods
Analysis of pharmacokinetic data in ten preterm newborns treated with a new neonatal formulation of dobutamine (IMP) after screening for haemodynamic insufficiency within the first 72 h from birth. Blood samples were withdrawn at the end of IMP infusion and at a random time after the end of infusion (5 min, 15 min, 45 min, 2 h and 6 h). IMP concentration in each sample was measured by ultra-high performance liquid chromatography with electrochemical detection.
Results
Median duration of IMP infusion was 37.7 h (IQR 21.2). Calculated IMP half-life ranged between 3.06 and 36.1 min (median 10.6 min), leading to a time to reach the steady-state concentration between 15 min and >2 h. Adverse events were not related to IMP.
Conclusions
The wide variability in dobutamine metabolism in preterm infants requires awareness about the risk of under- or overtreatment. A delay of up to 3 h might be required before drawing blood samples to evaluate the effective dose.
Impact
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Small trials suggest dobutamine as the optimal drug in the preterm infant with haemodynamic insufficiency after birth.
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Age-related differences in drug pharmacokinetics may result in suboptimal treatments.
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The lack of formal studies in preterms results in inadequate data on efficacy and safety.
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This study provides data on the variability of the elimination half-life of dobutamine in the very preterm infant during transitional circulation.
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There is a wide variation in the time to reach the plasma concentration corresponding to steady state, the moment when its efficacy/safety can be reliably evaluated.
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This information is crucial for planning future trials on cardiovascular support.
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Acknowledgements
The authors thank all participants, parents, and healthcare providers. This work was supported by the European Union Frame Programme Seventh grant number FP7: HEALTH-2011.4.2-1 [Investigator-driven clinical trials on off-patent medicines for children].
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A.P., V.J., F.C., and H.R. conceptualised and designed the study; C.G., H.R.-A., A.K. and A.S. supported the study design; A.P., R.F., M.C.B., P.L.O., L.S., and M.Y. assisted with acquisition of the data; A.K. and A.S. analysed the data; A.P. wrote the initial draft; A.P., V.J., C.G., H.R.-A., A.K., A.S. and H.R. provided administrative, technical, and material support. All authors critically reviewed the revised versions of the paper and approved the final draft for submission. All authors had access to the data and contributed to the submitted report. A.P. is the guarantor.
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Ethics approval for this study was obtained from the Ethics Committee for Clinical Research at La Paz University Hospital (HULP 3969) and the NRES Committee South East Coast-Brighton and Sussex (13/LO/1426).
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Pellicer, A., Fernández, R., Jullien, V. et al. Pharmacokinetic study (phase I−II) of a new dobutamine formulation in preterm infants immediately after birth. Pediatr Res 89, 981–986 (2021). https://doi.org/10.1038/s41390-020-1009-0
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DOI: https://doi.org/10.1038/s41390-020-1009-0
