Developmental Pharmacokinetics of Gentamicin in Preterm and Term Neonates: Modelling and Simulation Based on Data from a Prospective Study
Elisabet I Nielsen (1,2), Marie Sandström (1,3), Per Hartvig (2,4), Uwe Ewald (5), Lena E Friberg (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Sweden; (2) Hospital Pharmacy, University Hospital, Uppsala, Sweden; (3) AstraZeneca, R&D, Mölndal, Sweden; (4) Department of Pharmacology and Pharmacotherapy, University of Copenhagen, Denmark; (5) Department of Neonatology, University Children’s Hospital, Uppsala, Sweden
Objectives: Knowledge and use of predictive covariates could lead to faster attainment of therapeutic gentamicin levels and reduce the need of concentration monitoring. The objectives of this study were (1) to characterize the population pharmacokinetics of gentamicin in preterm and term newborn infants and to identify predictive covariates and (2) to perform simulations to evaluate the effectiveness of current as well as alternative dosing guidelines.
Methods: A total of 894 serum gentamicin samples from 61 newborn infants (gestational age, GA: 23-42 weeks, postnatal age, PNA: 0-45 days) were collected in a prospective study performed in the NICU, University Children's hospital, Uppsala, Sweden. An interim analysis of this study has been presented earlier [1]. Predictive performance was evaluated using an independent, external dataset [2]. Simulations from the final model were performed to evaluate the performance of three dosing regimens (4 mg/kg τ=24 h, 4 mg/kg τ=36 h and 5 mg/kg τ=48 h) in achieving targeted peak and trough levels in preterm and term neonates during gentamicin treatment in the first postnatal week.
Results: The gentamicin concentration-time profile was described using a 3-compartment model with body weight included as the primary covariate according to an allometric power model. Gentamicin clearance was found to increase with GA and PNA (included in a nonlinear fashion). GA was also identified to have a significant influence on central volume of distribution. The external dataset was well predicted by the developed model. The simulations showed that a substantial number of neonates with GA<30 weeks (32 and 60% at PNA=1 and PNA=7, respectively) reached potentially toxic trough concentrations (>2 mg/L) when administered 4 mg/kg once daily. The same dose also produced a peak concentration (1h post infusion) <6 mg/L after the initial dose in 12% of these neonates. For the other investigated dosing regimens, a high degree (>90%) of target fulfilment was achieved.
Conclusions: Body weight and age (GA and PNA) were found to be major factors contributing to inter-individual variability in gentamicin clearance in neonates. Based on simulations from the developed model, the majority of the preterm neonates do not reach targeted peak and trough gentamicin levels after a standard dosage regimen of 4 mg/kg given once daily, suggesting a need for higher loading doses and a prolonged dosing interval in this patient population.
References:
[1] Nielsen EI., Ewald U., Friberg LE. Population Pharmacokinetics of Gentamicin in Preterm and Term Newborn Infants. PAGE 15 (2006) Abstr 1034 [www.page-meeting.org/?abstract=1034]
[2] Thomson AH, Way S, Bryson SM, McGovern EM., Kelman AW., Whiting B. Population pharmacokinetics of gentamicin in neonates. Dev Pharmacol Ther 1988;11 (3): 173-9.