Interindividual variability in the development (rate and extent) of drug clearance pathways1 may contribute to the observed 14-fold variability in indomethacin (IND) systemic exposure,2 and thus the drug’s unpredictable efficacy and toxicity profile following standard dosing regimens. IND is prescribed commonly in the neonatal intensive care unit (NICU) for prophylaxis from intraventricular hemorrhage (IVH) and medical closure of patent ductus arteriosus (PDA). Up to 25% of preterm infants fail medical closure with IND and other nonsteroidal anti-inflammatory drugs and go on to require surgical PDA ligation. Thus, improved understanding of IND dosing in individual infants could improve medical care. IND is primarily metabolized to inactive moieties by direct acylglucuronidation by UGT2B7 and UGT1A93 and cytochrome P450 2C9-mediated O-demethylation.4 In the context of a rapidly maturing preterm infant, assessment of the relative contribution of the competing glucuronidation and CYP pathways via urine collection over the first 24–48 h following drug administration, a common practice in neonatal research,5,6 may not reflect the relative metabolic contributions later in the treatment course when the patients are older (and more mature).
Dramatic increases in clearance occurring over a relatively short treatment period (1–2 weeks) could have an important impact on subsequent dosing decisions to maintain adequate drug exposures. Preliminary analysis of 24-h urine collections revealed <1% dose recovery requiring a change to a longitudinal study design. We wish to share our initial observation regarding the magnitude of the observed “ontogeny” effect on IND clearance in preterm infants. These data provide new insights into the dynamic nature of the dose–exposure–response relationship in newborns, with implications for the design of future studies in neonates.
An institutional review board-approved prospective cohort study of IND metabolic variability in preterm infants is enrolling at a large NICU at a free-standing children’s hospital. Preterm infants <32 weeks gestational age at birth treated with IND per routine clinical care (IVH prophylaxis or PDA closure) had urine collected with each diaper change for up to 7 days after the last dose. Each infant received a total of between 2 and 12 doses of IND. Demographic data, dosing data, and clinical outcomes were collected from the electronic medical record. IND and metabolites were quantified by liquid chromatography with tandem mass spectrometry and statistical comparisons conducted using JMP Pro12.
Urine (709 samples) were collected from 16 preterm infants (birthweight 500–1290 g, gestational age 22–29 weeks, postnatal age (PNA) 3.3 h to 14 days) who received 2–12 intravenous doses of IND (Table 1). Urine recovery was predominated by three IND moieties: unchanged IND, IND-glucuronide (IND-G), and O-desmethylindomethacin (ODM). Among the population, ODM formation was delayed relative to IND-G, and three distinct patterns of metabolite recovery were observed. Figure 1 displays three representative preterm infants from each pattern. Group 1 has a primary recovery of glucuronide metabolite. Both metabolites are excreted in Group 2, but demethylation is delayed. Group 3 displays robust ODM excretion, consistent with increased formation. Furthermore, the pattern of metabolite recovery 24 h after the first dose does not represent the contribution of competing pathways when the infant is more mature (Fig. 2).
The percentage of total IND dose recovered in the urine was higher in the high ODM group (35.7%) compared to the other groups (7.7 and 7.2%), and associated with PNA at the end of urine collection (r2 = 0.497; p = 0.002). There were no statistically significant differences in demographics between the three metabolic groups, but infants in Group 3 (high ODM excretions) tended to be older in gestational age and PNA. In addition, Group 2 was majority African American. None of the infants were concomitantly treated with drugs which induce (phenobarbital, rifampin) or inhibit (fluconazole) the major indomethacin metabolic enzymes. There was one infant who failed to close their PDA and required surgical ligation in Group 3. There was one infant diagnosed with severe IVH (Grade IV) in Group 2.
Discussion
Changes in the relative contributions of competing biotransformation pathways over time will not be captured by sampling strategies limited to the first 24 h after treatment begins. Although labor intensive, the data collected from longitudinal designs provide valuable new insights into the developmental changes occurring over a course of treatment and should be considered in the design of future drug studies in this population. The observation of distinct developmental patterns for IND clearance pathways implies that different dosing strategies may be required. Development of dosing models incorporating changes in fractional contribution of various metabolic pathways over time will allow for individualized patient dosing. If an individual patient’s IND dose is simulated a priori with this model, and subsequently refined by a urine or plasma sample, this may lead to more predictable drug exposure, efficacy, and toxicity profiles in preterm infants treated with IND for PDA.
References
Kearns, G. L. et al. Developmental pharmacology—drug disposition, action, and therapy in infants and children. N. Engl. J. Med. 349, 1157–1167 (2003).
Smyth, J. M. et al. Intravenous indometacin in preterm infants with symptomatic patent ductus arteriosus. A population pharmacokinetic study. Br. J. Clin. Pharmacol. 58, 249–258 (2004).
Mano, Y., Usui, T. & Kamimura, H. Contribution of UDP-glucuronosyltransferases 1A9 and 2B7 to the glucuronidation of indomethacin in the human liver. Eur. J. Clin. Pharmacol. 63, 289–296 (2007).
Nakajima, M. et al. Cytochrome P450 2C9 catalyzes indomethacin O-demethylation in human liver microsomes. Drug Metab. Dispos. 26, 261–266 (1998).
Kokki, M. et al. Maturation of oxycodone pharmacokinetics in neonates and infants: oxycodone and its metabolites in plasma and urine. Br. J. Clin. Pharmacol. 83, 791–800 (2017).
Krekels, E. H. et al. Developmental changes rather than repeated administration drive paracetamol glucuronidation in neonates and infants. Eur. J. Clin. Pharmacol. 71, 1075–1082 (2015).
Acknowledgements
This work was supported by 1 U54 HD090258-01 from NICHD.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Rights and permissions
About this article
Cite this article
Lewis, T., Van Haandel, L., Scott, A. et al. Intensive and prolonged urine collection in preterm infants reveals three distinct indomethacin metabolic patterns: potential implications for drug dosing. Pediatr Res 84, 325–327 (2018). https://doi.org/10.1038/s41390-018-0051-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41390-018-0051-7