Population pharmacokinetic study of gentamicin in a large cohort of premature and term neonates

Abstract

AIMThis study aims to investigate the clinical and demographic factors influencing gentamicin pharmacokinetics in a large cohort of unselected premature and term newborns and to evaluate optimal regimens in this population. METHODSAll gentamicin concentration data, along with clinical and demographic characteristics, were retrieved from medical charts in a Neonatal Intensive Care Unit over 5 years within the frame of a routine therapeutic drug monitoring programme. Data were described using non-linear mixed-effects regression analysis ( NONMEM®). RESULTSA total of 3039 gentamicin concentrations collected in 994 preterm and 455 term newborns were included in the analysis. A two compartment model best characterized gentamicin disposition. The average parameter estimates, for a median body weight of 2170 g, were clearance (CL) 0.089 l h −1 (CV 28%), central volume of distribution (Vc) 0.908 l (CV 18%), intercompartmental clearance (Q) 0.157 l h −1 and peripheral volume of distribution (Vp) 0.560 l. Body weight, gestational age and post-natal age positively influenced CL. Dopamine co-administration had a significant negative effect on CL, whereas the influence of indomethacin and furosemide was not significant. Both body weight and gestational age significantly influenced Vc. Model-based simulations confirmed that, compared with term neonates, preterm infants need higher doses, superior to 4 mg kg −1 , at extended intervals to achieve adequate concentrations. CONCLUSIONSThis observational study conducted in a large cohort of newborns confirms the importance of body weight and gestational age for dosage adjustment. The model will serve to set up dosing recommendations and elaborate a Bayesian tool for dosage individualization based on concentration monitoring. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Gentamicin is one of the most frequently administered drugs to neonates for suspected or proven infections.• Therapeutic drug monitoring (TDM) has been highly recommended in the past due to variability in drug disposition.• Very preterm newborns need higher doses and longer dosing intervals than term newborns. WHAT THIS STUDY ADDS• This study is the largest ever done on an unselected cohort of neonates and confirms the major influence of body weight, gestational and post-natal ages on gentamicin pharmacokinetics.• Our model confirms that recent guidelines for gentamicin dosage decisions are appropriate to reach concentration targets considered effective and safe in neonates.

Development and Evaluation of a Gentamicin Pharmacokinetic Model That Facilitates Opportunistic Gentamicin Therapeutic Drug Monitoring in Neonates and Infants

“…The values of the PK parameters for a typical infant from the model-building data set (weight, 2.12 kg; PMA, 33.0 weeks; PNA, 5.4 days; MSCr, 78 mol/liter; TSCr, 71.4 mol/liter) were 0.077 liters/h and 0.80 liters (and 0.10 liters/h and 0.78 liters for a neonate from the evaluation data set) for CL and V, respectively. These values are in agreement with clearance estimates from previous neonatal studies of gentamicin pharmacokinetics (13,14,18,(22)(23)(24). The reported value (0.026 liters/h) for CL from Nielsen et al (21) may appear to be lower, but using our median demographic values in their model, the CL value becomes similar to our estimates (0.095 liters/h).…”

“…3). However, due to unavailability of some covariates in our data set, three models were used without all of the covariates (Apgar score [15,19], sepsis [19], and comedication with dopamine [23]) included, which could explain their worse predictive performance.…”

“…Deriving a Bayesian prior for TDM requires a nonlinear mixed-effect PK model, and several such studies of neonatal gentamicin were previously published (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). However, those studies were limited by their heterogeneity and use of sparse data (often identifying only a 1-compartment model, whereas gentamicin follows multicompartment kinetics [25,26]) and failed to account for age-related differences in creatinine levels during the immediate newborn period.…”

Population Pharmacokinetics and Dosing Considerations for Gentamicin in Newborns with Suspected or Proven Sepsis Caused by Gram-Negative Bacteria

“…To do so, a new PK model of gentamicin in neonates was developed, as previously reported PK models of gentamicin in neonates (9,11,12) did not describe our data well. The results for bias (MPE) and precision (RMSE) of these candidate models showed that all concentrations (peak, trough, and other concentrations) and peak concentrations alone of our patient population were overpredicted.…”

“…In the study of De Cock et al (12), the percentage of patients with ibuprofen as comedication was much higher than in our population (43% versus 8%). Fuchs et al (11) incorporated dopamine comedication as a covariate on Cl in their PK model. We did not, however, retrieve data on dopamine use in our cohort of neonates, as there is conflicting literature on the effect of dopamine on the glomerular filtration rate and Cl of aminoglycosides in neonates (13)(14)(15)(16)(17), and at the time of study design, the PK model of Fuchs et al (11) was not yet published.…”