Pharmacokinetics of Budesonide Administered with Surfactant in Premature Lambs: Implications for Neonatal Clinical Trials

Abstract

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of premature human infants, which may persist through adulthood. Airway inflammation has been firmly established in the pathogenesis of BPD. Previous studies to reduce airway inflammation with high-dose dexamethasone demonstrated adverse neurological outcomes, despite lower incidences of BPD. Instillation of budesonide and surfactant can facilitate early extubation and reduce the incidence of BPD and death among very low birth weight infants. However, the pharmacokinetics of budesonide and its distribution into the lung and brain are unknown. Therefore, 5 premature lambs were administered 0.25 mg/kg budesonide, with surfactant as the vehicle. Plasma and tissue samples were taken from the lambs for measurement of budesonide, 16α-hydroxy prednisolone, and budesonide palmitate using LC/MS/MS. Peak plasma budesonide concentrations were inversely correlated with the oxygenation index (correlation coefficient of −0.75). Plasma budesonide concentrations were extremely low (~10% of expected) for two lambs that had high oxygenation indices and were excluded from further analyses. For the remaining 5 premature lambs, a non-compartmental analysis demonstrated an AUCinf of 148.77 ± 28.16 h*μg/L, half-life of 4.76 ± 1.79 h, and Cmax of 46.17 ± 17.71 μg/L. Using population pharmacokinetic methods, a one-compartment model with exponential residual error and first-order absorption adequately described the data. The apparent clearance and apparent volume of distribution of budesonide were estimated at 6.29 L/h (1.99 L/h/kg) and 29.1 L (9.2 L/kg), respectively. Budesonide and budesonide palmitate, but not 16α-hydroxy prednisolone, were detected in lung tissue. In this study, budesonide and its metabolites were not detected in the brain, which suggests that intratracheal instillation suggests that after local pulmonary deposition, there is no evidence of budesonide accumulation in the central nervous system. Overall, these results show that peak plasma budesonide concentrations are inversely correlated with the oxygenation index and that lung-specific delivery of budesonide avoids accumulation of budesonide in the brain.

Antiinflammatory Effects of Budesonide in Human Fetal Lung

“…These latter results suggest that the antiinflammatory effects of budesonide in vivo after a single dose will last considerably longer than predicted by the observed plasma half-life of 4.3 hours (8). Esterification of budesonide by fatty acids in the lung, which we observed but could not quantitate with our LC-MS/MS approach, is consistent with previous studies in adult lung in vitro (48) and fetal lamb in vivo (20) and could provide a reservoir of budesonide that would extend the biological effect in lung cells.…”

“…We used LC-MS/MS and positive electrospray ionization detection as described (20) to investigate the levels of budesonide and selected major metabolites in the explants and culture medium. Medium was extracted as described previously (20); for tissue extraction, 30 mg lung was sonicated in ethanol and shaken for 5 hours at 4 8 C. Samples were reconstituted in 30:70 MeOH:H 2 O for analysis.…”

“…Medium was extracted as described previously (20); for tissue extraction, 30 mg lung was sonicated in ethanol and shaken for 5 hours at 4 8 C. Samples were reconstituted in 30:70 MeOH:H 2 O for analysis. The limit of quantification was 0.5 ng/ml for budesonide palmitate and 16a-hydroxyprednisolone, and 2.0 ng/ml for budesonide.…”

“…In vivo, budesonide is metabolized in the liver to 16a-hydroxyprednisolone and other minor metabolites and has a half-life of z4 hours in both infants and lambs (8,20,26). We used LC-MS/MS to examine the metabolism of budesonide in cultured fetal lung, testing both the culture medium and tissue after exposure to 30 nM budesonide for 48-72 hours.…”

Update on Postnatal Steroids

“…In a recent pharmacokinetic study in preterm lambs, budesonide and its metabolites were not detected in the brain, suggesting that after intratracheal instillation despite local pulmonary deposition there is no evidence of budesonide in the central nervous system [30]. In another recent study in piglets treatment with diluted surfactant lavage followed by intratracheal instillation of budesonide had a synergistic and beneficial effect on severe meconium-injured newborn lungs [31].…”