Merja Kokki1,2, Marja Heikkinen3, Pyry Välitalo4, Heidi Hautajärvi5, Juho Hokkanen5, Hanna Pitkänen1,2, Ulla Sankilampi2,6, Veli-Pekka Ranta7, Hannu Kokki1,2. 1. Department of Anaesthesia and Operative Services, Kuopio University Hospital, Kuopio, Finland. 2. School of Medicine, University of Eastern Finland, Kuopio, Finland. 3. Department of Paediatric Surgery, Kuopio University Hospital, Kuopio, Finland. 4. Division of Pharmacology, Leiden University, Leiden, The Netherlands. 5. Admescope Ltd, Oulu, Finland. 6. Department of Paediatrics, Kuopio University Hospital, Kuopio, Finland. 7. School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
Abstract
AIMS: This study aimed to characterize the pharmacokinetics of oxycodone and its major metabolites in infants and covered the age range between extremely preterm neonates and 2-year-old infants. METHODS: Seventy-nine infants (gestational age 23-42 weeks; postnatal age 0-650 days) received intravenous oxycodone hydrochloride trihydrate at a dose of 0.1 mg kg-1 during or after surgery. Three to seven blood samples were taken from each infant, and plasma concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were quantified. The unconjugated forms of these compounds were determined in urine collected after up to 24 or 48 h from 25 infants. Pharmacokinetics was determined using noncompartmental analysis and reported for six clinically relevant age groups based on postmenstrual age. RESULTS: Oxycodone pharmacokinetics changed markedly with patient age. Preterm neonates were found to have the highest pharmacokinetic variability out of the study population. In extremely preterm neonates (n = 6) median of elimination half-life was 8.8 h (range 6.8-12.5), in preterm (n = 11) 7.4 h (4.2-11.6), and in older neonates (n = 22) 4.1 h (2.4-5.8), all of which were significantly longer than that in infants aged 6-24 months (n = 12) 2.0 h (1.7-2.6). Median renal clearance was fairly constant in all age groups, whereas non-renal clearance markedly increased with age. Noroxycodone was the major metabolite in plasma and urine. CONCLUSIONS: Oxycodone elimination is slower and pharmacokinetic variability more pronounced in neonates when compared to older infants. These findings highlight the importance of careful dose titration for neonates.
AIMS: This study aimed to characterize the pharmacokinetics of oxycodone and its major metabolites in infants and covered the age range between extremely preterm neonates and 2-year-old infants. METHODS: Seventy-nine infants (gestational age 23-42 weeks; postnatal age 0-650 days) received intravenous oxycodone hydrochloride trihydrate at a dose of 0.1 mg kg-1 during or after surgery. Three to seven blood samples were taken from each infant, and plasma concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were quantified. The unconjugated forms of these compounds were determined in urine collected after up to 24 or 48 h from 25 infants. Pharmacokinetics was determined using noncompartmental analysis and reported for six clinically relevant age groups based on postmenstrual age. RESULTS:Oxycodone pharmacokinetics changed markedly with patient age. Preterm neonates were found to have the highest pharmacokinetic variability out of the study population. In extremely preterm neonates (n = 6) median of elimination half-life was 8.8 h (range 6.8-12.5), in preterm (n = 11) 7.4 h (4.2-11.6), and in older neonates (n = 22) 4.1 h (2.4-5.8), all of which were significantly longer than that in infants aged 6-24 months (n = 12) 2.0 h (1.7-2.6). Median renal clearance was fairly constant in all age groups, whereas non-renal clearance markedly increased with age. Noroxycodone was the major metabolite in plasma and urine. CONCLUSIONS:Oxycodone elimination is slower and pharmacokinetic variability more pronounced in neonates when compared to older infants. These findings highlight the importance of careful dose titration for neonates.
Authors: Malin M Rhodin; Brian J Anderson; A Michael Peters; Malcolm G Coulthard; Barry Wilkins; Michael Cole; Etienne Chatelut; Anders Grubb; Gareth J Veal; Michael J Keir; Nick H G Holford Journal: Pediatr Nephrol Date: 2008-10-10 Impact factor: 3.714
Authors: Chad M Thompson; Heidi Wojno; Elisabeth Greiner; Everette L May; Kenner C Rice; Dana E Selley Journal: J Pharmacol Exp Ther Date: 2003-11-04 Impact factor: 4.030
Authors: Hannu Kokki; Ilpo Rasanen; Matti Reinikainen; Pekka Suhonen; Kari Vanamo; Ilkka Ojanperä Journal: Clin Pharmacokinet Date: 2004 Impact factor: 6.447
Authors: Pyry Välitalo; Merja Kokki; Veli-Pekka Ranta; Klaus T Olkkola; Andrew C Hooker; Hannu Kokki Journal: Pharm Res Date: 2017-02-15 Impact factor: 4.200
Authors: Antti Valtola; James D Morse; Pawel Florkiewicz; Heidi Hautajärvi; Pasi Lahtinen; Tadeusz Musialowicz; Brian J Anderson; Veli-Pekka Ranta; Hannu Kokki Journal: J Drug Assess Date: 2020-07-28