Research question: Does the dosing regimen (dose and dose interval) proposed by the dose calculator result in serum concentrations closer to the target concentration than the dose regimen achieved by currently used protocols?
Background: A dosing calculator has been developed based on a pharmacokinetic analysis of vancomycin (532 subjects, 1676 concentrations), amikacin (682 subjects, 1717 concentrations) and gentamicin (85 subjects, 1392 concentrations) in premature and full term neonates and infants. The data were collected as part of routine clinical care at sites in Belgium, Portugal, Malaysia and New Zealand. This data set is the largest such data set compiled for these medicines and has been analysed using a principle based pharmacokinetic model (1-5). The potential benefits of the dosing calculator include improved ability to reach desired drug concentration targets and simpler and less error prone calculation of the dose. Improved targeting of concentration is expected to improve clinical outcomes such as faster resolution of infection and reduced mortality.
Qualification: In order to verify correct operation of the dose calculator system, it has been qualified by making predictions for the hundreds of patients that were used to develop the original model. These predictions have been compared to those made with model development software to ensure the output is equivalent.
Endpoint: The primary endpoint is how close the measured concentration is to the target concentration. The first set of serum concentrations measured (trough and/or peak) will be compared to the target in each trial arm to see if the dose calculator is effective in reducing this difference. The primary statistical analysis will be a comparison of the mean prediction error in the two groups (conventional vs dose calculator) subsetted according to medicine. Prediction error for each measured concentration is calculated from (Measured – Target)/Target. The Target is the target concentration defined by the average of the range of concentrations in the treatment protocol for each medicine.
Power: The prediction error using the dosing calculator method has been estimated in a validation data set of 554 vancomycin concentrations measured in neonates and infants (6). The mean prediction error was 1.1% with a standard deviation of 44%. A clinically significant difference in mean prediction error would be 25%. The number of subjects in each arm to be able to reject the null using a two tailed t-test with a power of 80% is 50.
Summary: The Antibiotic Dosing Calculator for Neonates and Children Trial will test if a web based dosing calculator can achieve target concentrations of gentamicin, amikiacn and vancomycin more reliably than standard protocols in 3 neonatal/paediatric intensive cure units.
Australia New Zealand Clinical Trial Registry: ACTRN12610001038088
www.firstdose.org
References:
- Allegaert, K., B. J. Anderson, et al. (2006). “Limited predictability of amikacin clearance in extreme premature neonates at birth.” Br J Clin Pharmacol 61(1): 39-48.
- Anderson, B. J., K. Allegaert, et al. (2007). “Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance.” Br J Clin Pharmacol 63(1): 75-84.
- Lo, Y. L., J. G. van Hasselt, et al. (2010). “Population pharmacokinetics of vancomycin in premature malaysian neonates: identification of predictors for dosing determination.” Antimicrob Agents Chemother 54(6): 2626-2632.
- Sherwin, C. M., E. Kostan, et al. (2009). “Evaluation of the effect of intravenous volume expanders upon the volume of distribution of gentamicin in septic neonates.” Biopharm Drug Dispos 30(5): 276-280.
- Sherwin, C. M., F. McCaffrey, et al. (2009). “Discrepancies between predicted and observed rates of intravenous gentamicin delivery for neonates.” J Pharm Pharmacol 61(4): 465-471.
- Grimsley, C. and A. H. Thomson (1999). “Pharmacokinetics and dose requirements of vancomycin in neonates.” Arch Dis Child Fetal Neonatal Ed 81(3): F221-227.