Pharmacokinetic study (phase I-II) of a new dobutamine formulation in preterm infants immediately after birth

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 Blood samples were withdrawn at the end of IMP infusion and at a random time after the end of infusion (5 min, 15 min, 45 min, 2 h and 6 h).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: - Small trials suggest dobutamine as the optimal drug in the preterm infant with haemodynamic insufficiency after birth. - Age-related differences in drug pharmacokinetics may result in suboptimal treatments. - The lack of formal studies in preterms results in inadequate data on efficacy and safety. - This study provides data on the variability of the elimination half-life of dobutamine in the very preterm infant during transitional circulation. - 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. - This information is crucial for planning future trials on cardiovascular support.