Alison H Thomson
Dept of Medicine & Therapeutics, University of Glasgow, Western Infirmary, Glasgow
Drug administration to paediatric patients presents a number of challenges due to their immature renal and hepatic function and differences in body composition. Practical and ethical concerns have restricted pharmacokinetic research in such patients, often resulting in “empirical” dosage guidelines with little evidence to support them. The population approach offers an opportunity to solve this problem but it is not always successful. Three examples of applying the methodology to paediatric data will be described.
In the first study, an audit had found that recommended neonatal doses of vancomycin were too low and that 66% of troughs were outside the target range. NONMEM was used to determine population parameters from 347 concentration measurements collected in 59 neonates. Postconceptual ages ranged from 26 – 45 weeks, weights from 0.57 – 4.23 kg and creatinine concentrations from 18 – 172 m mol/L. Vancomycin clearance (L/h/kg) was 3.56/creatinine concentration (m mol/L) with an interindividual (IIV) coefficient of variation (cv) of 22% and volume of distribution was 0.67 L/kg with an IIV of 18%. Residual error was 4.5 mg/L. These results were used to develop new dosage guidelines. When the new recommendations were used prospectively in a separate group of neonates, the proportion of acceptable troughs increased from 33% to 72%.
In the second study, a similar approach was used to determine the population pharmacokinetics of amikacin in children with haematological disease. Data were available from 56 children (20 male) aged 0.5 – 16 years (median 4 years), weighing 7.2 – 64 kg (median 18 kg) and with creatinine concentrations ranging from 15 – 106 m mol/L. The dose of amikacin had a median of 7.5 mg/kg 12 hourly (range 4.7 – 17.1 mg/kg) and there were 179 concentration measurements (111 peaks and 68 troughs). The initial parameter estimates were: clearance 2.36 L/h (IIV 48%); volume 5.54 L (IIV 52%); and residual error 27%. The final model was: CL (L/h) = 1.65 (1 + 0.0596 x (wt-18 kg)) x (creat/37)-0.469 and V (L) = 5.88 (1 + 0.001 x (wt-18 kg). With this model, interindividual variability could not be identified and residual error was very high (28% at 5.0 mg/L and 35% at 20 mg/L). The most likely reason for this was poor quality data.
The third example was an investigation of caffeine pharmacokinetics in 60 babies aged 1 to 100 days. Clearance was influenced by body weight, postnatal age and dexamethasone therapy, but no clinical factors were identified that influenced volume of distribution. A prospective analysis of the results in a separate group of 20 neonates found no evidence of a dexamethasone effect. A final analysis using all 80 patients found clearance (L/day) = 0.14 x weight (kg) + 0.0024 x postnatal age (days) (±20%) and volume of distribution = 0.82 L (±24%). Simulations based on these results indicated that the “standard” dosage regimen of 20 mg/kg loading dose of caffeine citrate followed by a maintenance dose of 5mg/kg/day was satisfactory.
[1] Grimsley C, Thomson AH. Population pharmacokinetics of vancomycin in neonates and young infants. Arch Dis Child 81:F221-F227, 1999.
[2] Thomson A.H. Kerr S, Wright S. Population pharmacokinetics of caffeine in neonates and young infants. Ther Drug Monit 18: 245 – 253, 1996.
Reference: PAGE 9 (2000) Abstr 88 [www.page-meeting.org/?abstract=88]
Poster: oral presentation