Franziska D. Weber (1), Henning Schmidt (2), Marc Pfister (1,3) John van den Anker (1,4)
(1) Department of Paediatric Pharmacology and Pharmacometrics Research Center, University Children’s Hospital Basel, Switzerland, (2) Novartis Pharma AG, Basel, Switzerland, (3) Quantitative Solutions LP, Menlo Park, CA, USA (4) Division of Clinical Pharmacology, Children’s National Medical Center, Washington, DC, USA
Objectives: Neonates of all gestational ages perceive pain [1]. Due to undesired side effects of opioids, acetaminophen (APAP) is used as an alternative [2]. Risk for hepatotoxicity associated with APAP [3,4]depends on its metabolism, which changes during the first weeks of life [5]. Preterm (< 37 gestational age (GA)) neonates may have less drug metabolism/elimination capacity than term (>= 37 GA) neonates. Characterizing population pharmacokinetics (PK) of APAP and its key metabolites is critical for establishing safe and effective IV dosing schemes for use of APAP in neonates.
Methods: A total of 2500 plasma samples for APAP and metabolites measurements were available from 35 neonates with gestational ages (GAs) between 23 and 41 weeks. The major metabolites, APAP-glucuronide (Mgluc) and APAP-sulfate (Msulf) were quantitated in serum, as well as two surrogate markers of APAP-induced toxicity, (Mcys) and APAP-mercapturate (Mnac). Neonates with GAs <29 weeks were dosed 5x 15 mg/kg every 12h, whereas GAs >29 weeks were dosed 7x 15 mg/kg every 8h. Non-linear mixed effect models were applied to characterize population PK of APAP and its key metabolites.
Results: Population PK of APAP and its metabolites were described by linear metabolic formation rate constants (FRCs) and one-compartment models with linear elimination. Body weight (BW) at study beginning was found to be a statistically significant covariate on all model parameters in preterm and term neonates. Given available data, postnatal age (PNA) was a statistically significant covariate on several PK parameters in preterm but not term neonates: FRC of Msulf, Mnac, Mcys, CL of Mgluc and CLnac. In term neonates CL and volume of distribution (V) of parent drug were estimated to be 0.47 l/h and 2.98 l, respectively, and half-lives of investigated metabolites ranged from 4 to 8h. In preterm neonates CL and V of parent drug were estimated to be 0.14 l/h and 1.06 l, respectively, with half-lives of metabolites prolonged up to 30% as compared to values in term neonates.
Conclusions: For the first time the population PK of APAP and its key metabolites was characterized in preterm and term neonates. Model results suggest that PNA (in addition to BW) is affecting PK of APAP’s metabolites in preterm neonates. This finding is consistent with the hypothesis that preterm neonates have less mature drug metabolism/elimination capacity than term neonates and may benefit most from organ maturation during the first weeks of life. The developed model will be applied to fine-tune APAP dosing strategies in neonates.
References:
[1] Anand KJS, Hickey PR. Pain and Its Effects in the Human Neonate and Fetus. N Engl J Med. 1987;317: 1321–1329. doi:10.1056/NEJM198711193172105
[2] Kahn DJ, Richardson DK, Gray JE, Bednarek F, Rubin LP, Shah B, et al. Variation among neonatal intensive care units in narcotic administration. Arch Pediatr Adolesc Med. 1998;152: 844–851.
[3] Anand KJS, Hall RW. Morphine, hypotension, and intraventricular hemorrhage. Pediatrics. 2006;117: 250–252; author reply 252–253. doi:10.1542/peds.2005-2250
[4] Rajanayagam J, Bishop JR, Lewindon PJ, Evans HM. Paracetamol-associated acute liver failure in Australian and New Zealand children: high rate of medication errors. Arch Dis Child. 2015;100: 77–80. doi:10.1136/archdischild-2013-304902
[5] Allegaert K, Rayyan M, De Rijdt T, Van Beek F, Naulaers G. Hepatic tolerance of repeated intravenous paracetamol administration in neonates. Pediatr Anesth. 2008;18: 388–392. doi:10.1111/j.1460-9592.2008.02535.x
Reference: PAGE 24 (2015) Abstr 3472 [www.page-meeting.org/?abstract=3472]
Poster: Drug/Disease modeling - Paediatrics