Theophylline Population Pharmacokinetics and Dosing in Children Following Congenital Heart Surgery With Cardiopulmonary Bypass

Abstract

Children undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) frequently develop acute kidney injury due to renal ischemia. Theophylline, which improves renal perfusion via adenosine receptor inhibition, is a potential targeted therapy. However, children undergoing cardiac surgery and CPB commonly have alterations in drug pharmacokinetics. To help understand optimal aminophylline (salt formulation of theophylline) dosing strategies in this population, a population-based pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM) from 71 children (median age: 5 months [90% range: 1 week – 10 years]) who underwent cardiac surgery requiring CPB and received aminophylline as part of a previous randomized controlled trial. A one-compartment model with linear elimination adequately described the pharmacokinetics of theophylline. Weight scaled via allometry was a significant predictor of clearance and volume. In addition, allometric scaled clearance increased with age implemented as a power maturation function. Compared to prior reports in non-cardiac children, theophylline clearance was markedly reduced across age. Applying the final population pharmacokinetic model, optimized empiric dosing regimens were developed via Monte Carlo simulations. Doses 50-75% lower than those recommended in non-cardiac children were needed to achieve target serum concentrations of 5-10 mg/L.

Theophylline: a review of population pharmacokinetic analyses

“…Among these, five articles were excluded because they were not written in English, not performed on humans, used duplicate data or were not able to provide sufficient information. Finally, a total of 16 articles [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] were selected for this review.…”

“…Studies with a larger sample size and longer duration of concomitant administration of theophylline and β‐agonists are needed to further confirm this interaction. Frymoyer et al . showed that theophylline clearance in all of the studied ages was lower in cardiac paediatric patients compared to non‐cardiac paediatric patients.…”

“…showed that the total CL increased by 10% per year over the age range of 1–15 years of age. Body weight was used to determine CL as a simple function or with an allometric model …”

“…Body weight was used to determine CL as a simple function 14 or with an allometric model. 24 In regard to the effect of gender on theophylline clearance, Driscoll et al 21 illustrated that there was a significant association between gender and theophylline CL and that CL in males was 25% higher than that in females. This finding was in accord with the study by Botha et al 23 The sex-related difference in theophylline clearance was due to gender-related differences that exist in the oxidative metabolism of some drugs.…”

“…Studies with a larger sample size and longer duration of concomitant administration of theophylline and b-agonists are needed to further confirm this interaction. Frymoyer et al 24 showed that theophylline 26 Normal subjects and patients 43Á1 AE 18Á6 0Á05712 0Á32 CL, total clearance; Vd, volume of distribution; GA, gestational age; PNA, post-natal age; PCA, post-conceptional age; IBW, ideal body weight; NS, not stated.…”