Intravenous indometacin in preterm infants with symptomatic patent ductus arteriosus. A population pharmacokinetic study

Abstract

AimsTo characterize the population pharmacokinetics of indometacin in preterm infants with symptomatic patent ductus arteriosus and to investigate the influence of various factors on the response to treatment. MethodsData were collected from 35 infants (gestational age 25-34 weeks; postnatal age 1-77 days) in neonatal units in Belfast and Copenhagen. Infants received an initial course of up to three doses of intravenous indometacin (0.1-0.2 mg kg -1 ) as considered appropriate by the treating physician. For those infants who did not respond to therapy or in whom the ductus reopened, a second course was sometimes g iven. Population analysis of the 185 plasma concentrations obtained was conducted using NONMEM and pharmacokinetic and demographic differences between responders and nonresponders were compared. ResultsThe concentration-time course of indometacin was best described by a one-compar tment model. The final population parameter estimates of clearance (CL) and volume of distribution (V) (standardized to the median weight of 1.17 kg) were 0.00711 l h -1 and 0.266 l, respectively. CL increased from birth by approximately 3.38% per day and V by approximately 1.47% per day. Concomitant digoxin therapy resulted in a 30% decrease in V. Interindividual variability in CL and V was 41% and 21%, respectively. Interoccasion variability for CL was 43%. Residual variability corresponded to a standard deviation of 0.148 mg l -1 . Closure occurred in 75% of infants with a plasma concentration ≥ 0.4 mg l -1 24 h after the last dose. ConclusionsDosing regimens for indometacin should take into account the weight and postnatal age of the infant and any concomitant digoxin therapy. The population estimates can be used to determine typical values of CL and V allowing the prediction of individualized doses of indometacin that should increase the probability of achieving a 24 h plasma concentration ≥ 0.4 mg l -1 . Although the pharmacokinetic estimates will be affected by both interindividual and within-individual variation, it is anticipated that this approach will decrease the variability of exposure and optimize treatment outcome.J. M. Smyth et al. 25058 :3 Br J Clin Pharmacol

Recent developments in the pharmacological management of pain in children

“…Ibuprofen clearance increases from 2.06 mL/h/kg at 22-31 weeks PCA [20], 9.49 mL/h/kg at 28 weeks PCA [21] to 140 mL/h/kg at 5 years [22]. Similar maturation is now reported for indometacin [23]. The volume of distribution is increased in neonates compared with older children and adults.…”

Polymorphisms in CYP2C9 are associated with response to indomethacin among neonates with patent ductus arteriosus

“…Shaffer et al concluded that indomethacin clearance is solely due to individual pharmacokinetic differences regardless of weight (5). Smyth et al also reported high interindividual variability, although indomethacin metabolism did vary by weight (6). Validation studies to demonstrate the value of these polymorphisms in predicting response to indomethacin should be performed and translated into clinical practice to reduce the morbidity associated with prolonged PDA and indomethacin toxicity where indomethacin treatment is likely to be futile.…”

“…Importantly, post-treatment plasma concentrations and inter-patient pharmacokinetic differences have been shown to affect closure rates. Pharmacokinetic studies demonstrate considerable variability in indomethacin clearing among preterm infants with PDA (5, 6). Furthermore, PDA requiring indomethacin therapy has been reported as highly heritable, as has failure to respond to indomethacin therapy (7).…”

Meta-Analysis to Assess Efficacy and Safety of High-Dose Ibuprofen Compared with Standard Treatment of Patent Ductus Arteriosus in Premature Infants

“…Most immature infants are likely to require pharmaceutical treatment to close the ductus, thereby avoiding the need for PDA ligation (10,11). Pharmaceutical treatment enables doctors to cope with more patients and save operation costs for infants (12,13).…”