Yuma A Bijleveld1, Timo R de Haan2, Hanneke J H van der Lee3, Floris Groenendaal4, Peter H Dijk5, Arno van Heijst6, Rogier C J de Jonge7, Koen P Dijkman8, Henrica L M van Straaten9, Monique Rijken10, Inge A Zonnenberg11, Filip Cools12, Alexandra Zecic13, Debbie H G M Nuytemans14, Anton H van Kaam2, Ron A A Mathot1. 1. Department of Pharmacy, Academic Medical Center, Amsterdam. 2. Department of Neonatology, Emma Children's Hospital, Academic Medical Center, Amsterdam. 3. Pediatric Clinical Research Office, Division Woman-Child, Academic Medical Center, University of Amsterdam, Amsterdam. 4. Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht. 5. Department of Neonatology, University Medical Center Groningen, Groningen. 6. Department of Neonatology, Radboud University Medical Center, Nijmegen. 7. Department of Pediatrics, Division of Neonatology, Erasmus MC-Sophia Children's Hospital, Rotterdam. 8. Department of Neonatology, Máxima Medical Center Veldhoven, Veldhoven. 9. Department of Neonatology, Isala Clinics, Zwolle. 10. Department of Neonatology, Leiden University Medical Center, Leiden. 11. Department of Neonatology, VU University Medical Center, Amsterdam, The Netherlands. 12. Department of Neonatology, Vrije Universiteit Brussel, Brussels. 13. Department of Neonatology, Academic Medical Center, Gent, Belgium. 14. Clinical Research Coordinator PharmaCool Study.
Abstract
AIM(S): Little is known about the pharmacokinetic (PK) properties of gentamicin in newborns undergoing controlled hypothermia after suffering from hypoxic−ischaemic encephalopathy due to perinatal asphyxia. This study prospectively evaluates and describes the population PK of gentamicin in these patients METHODS: Demographic, clinical and laboratory data of patients included in a multicentre prospective observational cohort study (the ‘PharmaCool Study’) were collected. A non-linear mixed-effects regression analysis (nonmem®) was performed to describe the population PK of gentamicin. The most optimal dosing regimen was evaluated based on simulations of the final model. RESULTS: A total of 47 patients receiving gentamicin were included in the analysis. The PK were best described by an allometric two compartment model with gestational age (GA) as a covariate on clearance (CL). During hypothermia the CL of a typical patient (3 kg, GA 40 weeks, 2 days post-natal age (PNA)) was 0.06 l kg−1 h−1 (inter-individual variability (IIV) 26.6%) and volume of distribution of the central compartment (Vc) was 0.46 l kg−1 (IIV 40.8%). CL was constant during hypothermia and rewarming, but increased by 29% after reaching normothermia (>96 h PNA). CONCLUSIONS: This study describes the PK of gentamicin in neonates undergoing controlled hypothermia. The 29% higher CL in the normothermic phase compared with the preceding phases suggests a delay in normalization of CL after rewarming has occurred. Based on simulations we recommend an empiric dose of 5 mg kg−1 every 36 h or every 24 h for patients with GA 36–40 weeks and GA 42 weeks, respectively.
AIM(S): Little is known about the pharmacokinetic (PK) properties of gentamicin in newborns undergoing controlled hypothermia after suffering from hypoxic−ischaemic encephalopathy due to perinatal asphyxia. This study prospectively evaluates and describes the population PK of gentamicin in these patients METHODS: Demographic, clinical and laboratory data of patients included in a multicentre prospective observational cohort study (the ‘PharmaCool Study’) were collected. A non-linear mixed-effects regression analysis (nonmem®) was performed to describe the population PK of gentamicin. The most optimal dosing regimen was evaluated based on simulations of the final model. RESULTS: A total of 47 patients receiving gentamicin were included in the analysis. The PK were best described by an allometric two compartment model with gestational age (GA) as a covariate on clearance (CL). During hypothermia the CL of a typical patient (3 kg, GA 40 weeks, 2 days post-natal age (PNA)) was 0.06 l kg−1 h−1 (inter-individual variability (IIV) 26.6%) and volume of distribution of the central compartment (Vc) was 0.46 l kg−1 (IIV 40.8%). CL was constant during hypothermia and rewarming, but increased by 29% after reaching normothermia (>96 h PNA). CONCLUSIONS: This study describes the PK of gentamicin in neonates undergoing controlled hypothermia. The 29% higher CL in the normothermic phase compared with the preceding phases suggests a delay in normalization of CL after rewarming has occurred. Based on simulations we recommend an empiric dose of 5 mg kg−1 every 36 h or every 24 h for patients with GA 36–40 weeks and GA 42 weeks, respectively.
Entities:
Keywords:
controlled hypothermia; gentamicin; neonates; population pharmacokinetics
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