Populatiekinetiek van indometacine bij profylactische behandeling van patent ductus arteriosus direct na de geboorte van zeer jonge prematuren

OBJECTIVE: In the neonatal intensive care unit of the Maastricht University Medical Centre patent ductus arteriosus is treated directly after birth with three gifts of 0.1 mg/kg indometacin in prematures with a birth weight below 1250 g or a gestational age below 30 weeks. We studied indometacin pharmacokinetics, because information about this treatment modality is not available. DESIGN: In this observational study we analysed surplus serum samples collected for routine analysis. METHODS: Indometacin concentrations were measured with a validated HPLC-RP system. A priori a one compartment indometacin pharmacokinetic model was programmed in MW\Pharm 3.60 based on kinetic parameters from the literature. Individual kinetic parameters were calculated with MW\Pharm after iterative Bayesian fitting. The ductal status was determined after three days with echocardiography. RESULTS: In this study 34 premature infants with a median birth weight of 880 g were included. The elimination rate constants (k_el) and apparent volumes of distribution (V) were graphically analysed. A general population of 29 premature infants was established with k_el = 0.022 ± 0.005 h^-1 (t _1/2 = 31 h) and V = 0.38 ± 0.05 L/kg. A subgroup of 5 patients was distinguished with a significantly different k_el = 0.042 ± 0.004 h^-1 (t_1/2 = 16 h) and V = 0.17 ± 0.04 L/kg. In 32 out of 34 patients ductus closure was observed. CONCLUSIONS: On the basis of this study it can be concluded that interindividual variability in indometacin pharmacokinetics is small during the prophylactic treatment in the first three days after birth if patients are stratified for their ductal status.