Yunjiao Wu (1), Swantje Völler (1), Elke H.J. Krekels (1), Daniëlla W.E. Roofthooft (2), Sinno H.P. Simons (2), Dick Tibboel (3), Robert B. Flint (2,4), Catherijne A.J. Knibbe (1,2,5)
(1) Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. (2). Department of Pediatrics, Division of Neonatology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands (3) Department of Pediatric Surgery, Erasmus University MC–Sophia Children’s Hospital, Rotterdam, The Netherlands (4) Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands (5) Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands.
OBJECTIVES: Intravenous paracetamol (PCM) is increasingly used to control mild-to-moderate pain in preterm neonates, yet it’s use is off-label in preterm neonates and few studies have been conducted to describe the maturation of paracetamol metabolic pathways. The aim of this study was to quantify the maturation of PCM glucuronidation, sulfation and oxidation in preterm neonates, and to identify the covariates that drive this maturation.
METHODS: A dataset from the DINO (Drug optimizing In preterm NeOnates) study (n=78) and a previously published study (n=60) [1] were pooled, resulting in data on a total of 146 preterm neonates [median gestational age (GA) 27.7 (range 24.0-31.9) weeks, birth weight (BWb) 988 (462-1925) grams, postnatal age (PNA) 5.0 (0-29.7) days, current weight (CW) 1013 (462-1959) grams] and 507 plasma PCM samples together with its metabolites PCM-glucuronide, PCM-sulfate, PCM-cysteine, and PCM-mercapturate samples after single (n=290) or multiple (n=217) intravenous PCM doses (median 9 (range 4-25) mg/kg).
All metabolite concentrations were expressed in PCM equivalents based on molecular weight. For each sample, PCM-cysteine and PCM-mercapturate concentrations were summed up to approximate the total concentration of metabolites formed via the CYP2E1-mediated pathway. The volume of PCM-glucuronide, PCM-sulfate and PCM-oxidative pathway metabolites were set to a fixed fraction of PCM (0.38, 0.29, 0.68, respectively) based on reported literature values [2]. Evaluated covariates included BWb, CW, GA, PNA, postmenstrual age (PMA), sex, being small for gestational age (SGA) and birthweight Z-score [3].The population pharmacokinetic (PopPK) analysis was performed using the NONMEM® 7.4. Goodness-of-fit plots ,bootstrap (n=500) and normalized prediction distribution errors (NPDEs) based on 1000 simulations were used for model evaluation.
RESULTS: The PK of PCM was best described by a 2-compartment model, and 1-compartment models was used for all PCM metabolites. For a neonate with median BWb of 988 grams and PNA of 5 days, formation clearance of the PCM glucuronide, PCM sulfate, and CYP2E1 derived metabolites was 0.0043 L/min, 0.089 L/min, and 0.0184 L/min, respectively. Formation clearance of PCM glucuronide increased with BWb (exponent 1.01) and PNA (linear increase, slope: 0.0802). formation clearance of PCM-sulfate increased with birthweight Z-score (linear increase, slope: 0.0653) and birthweight (exponent: 0.561). Formation clearance of CYP2E1-derived metabolites increased with birthweight (exponent: 0.466) and PNA (linear increase, slope: 0.0935). The renal clearance of unchanged PCM (0.0322 L/min for a neonate with median BWb and PNA) also increased with BWb (exponent: 1.43) and PNA (linear increase, slope: 0.0817). Goodness of fit plots, bootstrap and NPDEs results did not show any obvious misspecification.
CONCLUSION: The developed popPK model successfully described the pharmacokinetics of PCM and its metabolites after intravenous paracetamol in preterm neonates during the first 30 days of life. BWb and PNA were important predictors of the maturational changes in the fraction of paracetamol undergoing glucuronidation, sulfation and oxidation.
References:
[1] Flint RB, Roofthooft DW, van Rongen A, van Lingen RA, van den Anker JN, van Dijk M, Allegaert K, Tibboel D, Knibbe CAJ, Simons SHP. Exposure to acetaminophen and all its metabolites upon 10, 15, and 20 mg/kg intravenous acetaminophen in very-preterm infants. Pediatr Res. 2017 Oct;82(4):678-684. doi: 10.1038/pr.2017.129. Epub 2017 Jun 21. PMID: 28553988.
[2] Cook SF, Stockmann C, Samiee-Zafarghandy S, King AD, Deutsch N, Williams EF, Wilkins DG, Sherwin CM, van den Anker JN. Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent-Metabolite Population Pharmacokinetic Model. Clin Pharmacokinet. 2016 Nov;55(11):1395-1411. doi: 10.1007/s40262-016-0408-1. PMID: 27209292; PMCID: PMC5572771.
[3] Hoftiezer L, Hof MHP, Dijs-Elsinga J, Hogeveen M, Hukkelhoven CWPM, van Lingen RA. From population reference to national standard: new and improved birthweight charts. Am J Obstet Gynecol. 2019 Apr;220(4):383.e1-383.e17. doi: 10.1016/j.ajog.2018.12.023. Epub 2018 Dec 18. PMID: 30576661.
Reference: PAGE 30 (2022) Abstr 10139 [www.page-meeting.org/?abstract=10139]
Poster: Drug/Disease Modelling - Paediatrics