Population pharmacokinetics of theophylline during paediatric extracorporeal membrane oxygenation

Abstract

Aims: To determine the population pharmacokinetics of theophylline during extracorporeal membrane oxygenation (ECMO) from routine monitoring data.

Methods: Retrospective data were collected from 75 term neonates and children (age range 2 days to 17 years) receiving continuous infusions of aminophylline (mean rate 9.2 +/- 2.6 micro g kg-1 min-1) during ECMO. A total of 160 plasma concentrations (range 1-8 per patient), sampled at time intervals ranging from 10 h to 432 h, were included. Population PK analysis and model building were carried out using WinNonMix Professional (Version 2.0.1). Cross-validation was used to evaluate the validity and predictive accuracy of the model.

Results: A one-compartment model with first order elimination combined with an additive error model was found to best describe the data. Of the covariables tested, bodyweight significantly influenced clearance and volume of distribution, whereas age was an important determinant of clearance, as adjudged by the differences in the -2 x log likelihood (P < 0.005) and the residual error value. The final model parameters were estimated as: clearance (l h-1) = 0.023 x bodyweight (kg) + 0.000057 x age (days) and volume of distribution (l) = 0.57 x bodyweight (kg). The interindividual variability in clearance and volume of distribution was 38% and 40%, respectively. The residual error corresponded to a standard deviation of 3.6 mg l-1. Cross-validation revealed a median (95% confidence interval) model bias of 9.4% (2.9, 16.5%) and precision of 29.5% (24.8, 36.0%).

Conclusions: The estimated clearance is significantly lower, and volume of distribution higher, than previously reported in non-ECMO patients of similar age. These differences are probably a result of the expanded circulating volume during ECMO and altered renal and hepatic physiology in this critically ill group. Large interindividual variability reflects the heterogeneous nature of patients treated on ECMO.

Figure 1

Schematic diagram of a paediatric ECMO circuit.

Figure 2

Weighted results vs. time. Weighted residuals = residual (observed - predicted) concentration divided by the square root of the observed concentration variance

Figure 3

Observed vs. individual predicted serum theophylline concentrations using the final model.

Figure 4

The worst and best time-concentration profiles predicted by the final model. Worst: •, observed; —, predicted (P); —, predicted (I). Best (two individuals): --, predicted (1); *, observed (1); --, predicted (2); •, observed (2).

Figure 4

The worst and best time-concentration profiles predicted by the final model. Worst: •, observed; —, predicted (P); —, predicted (I). Best (two individuals): --, predicted (1); *, observed (1); --, predicted (2); •, observed (2).

Figure 5

A comparison of the estimated theophylline clearances based on age determined by the present study (at 10th (○), 50th (□) and 90th () percentile weights) and a paediatric population study by Driscoll et al.[12] (▵)

Figure 6

Recirculation in a double lumen veno-venous catheter