What is needed for a dosing calculator?

Background: Once daily dosing of aminoglycosides is popular because these drugs have a concentration-dependent bactericidal spectrum and nephrotoxicity is related to a saturable uptake by the proximal renal tubules. High peak concentrations and low trough concentrations are consequently desirable. Current dosing of both aminoglycosides and glycopeptides for children in intensive care is protocol driven. Dosing in the paediatric intensive care unit is based on weight and postnatal age. Although there are protocol defined concentration ranges at peak and trough, in practice it is only measured trough concentrations that lead to dose adjustment.  Covariates (e.g. renal function, concomitant drug therapy, mechanical ventilation) that might be used to predict the starting dose not part of standard protocols in Auckland.

Objectives:

  1. To describe the typical pattern of dosing and concentration measurements in neonates receiving gentamicin, amikacin or vancomycin in Auckland intensive care units caring for neonates.
  2. To develop a web based dose calculator suitable for a clinical trial of the usefulness of a dose calculator compared with standard protocol methods.

Audit: A 2-month audit of clinical records of all neonates given gentamcin, amikacin or vancomycin in the Auckland District Hospital Board paediatric intensive care unit and neonatal intensive care unit and the Manukau Health Board KidzFirst intensive care unit.

Calculator: 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. A web based dose calculator has been constructed using Java Script. The calculator uses weight and postmenstrual age as primary predictors of clearance and volume of distribution. Other factors that can be applied include renal function predicted from serum creatinine, use of inotropes or non-steroidal anti-inflammatory drugs, and concomitant mechanical ventilation (1-4). Loading and maintenance doses are predicted from clearance and volume of distribution using a weighted least squares method which aims to get concentrations in the middle of the protocol defined peak and trough concentration ranges. Other exposure metrics e.g. area under the curve or average concentration in the dosing interval can be used instead of peak and trough target concentrations (5, 6).

Results: Many measured concentrations are outside their dosing protocol concentration ranges. Trough concentrations for gentamicin, amikacin and vancomycin were above target 18-40% of occasions, suggesting that overdosing is common.

Concentration Type % Outside % Low %high NConcs
Gentamicin Peak 33 0 33 6
Gentamicin Trough 48 12 37 60
Amikacin Peak 100 100 0 1
Amikacin Trough 18 0 18 17
Vancomycin Peak None None None 0
Vancomycin Trough 40 0 40 5

The calculator is undergoing a usability evaluation by clinical staff and has been qualified by comparison with an external vancomycin database.

References:

  1. Anderson BJ, Allegaert K, Van den Anker JN, Cossey V, Holford NH. Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance. Br J Clin Pharmacol. 2007;63(1):75-84.
  2. Sherwin CM, Kostan E, Broadbent RS, Medlicott NJ, Reith DM. Evaluation of the effect of intravenous volume expanders upon the volume of distribution of gentamicin in septic neonates. Biopharm Drug Dispos. 2009;30(5):276-80.
  3. Allegaert K, Anderson BJ, van den Anker JN, Vanhaesebrouck S, de Zegher F. Renal drug clearance in preterm neonates: relation to prenatal growth. Ther Drug Monit. 2007;29(3):284-91.
  4. Holford NHG, Falcao AC, Debeer A, Anderson BJ, Vialet R, Simon N, et al. Prediction of renal function from premature neonates – Application to neonatal vancomycin, amikacin and gentamicin pharmacokinetics with and without indomethacin and ibuprofen. In Preparation. 2011.
  5. Begg EJ, Vella-Brincat JW, Robertshawe B, McMurtrie MJ, Kirkpatrick CM, Darlow B. Eight years’ experience of an extended-interval dosing protocol for gentamicin in neonates. J Antimicrob Chemother. 2009;63(5):1043-9.
  6. Stickland MD, Kirkpatrick CM, Begg EJ, Duffull SB, Oddie SJ, Darlow BA. An extended interval dosing method for gentamicin in neonates. J Antimicrob Chemother. 2001;48(6):887-93.

Sam Holford

Hi, I'm Sam and I'm the PAGANZ Treasurer. I'm also an Obstetrics & Gynaecology registrar at Middlemore Hospital, dabbling in the practical aspects of improving dosing, as time permits.