Population Pharmacokinetics and Target Attainment of Allopurinol and Oxypurinol Before, During, and After Cardiac Surgery with Cardiopulmonary Bypass in Neonates with Critical Congenital Heart Disease

Abstract

Background: The CRUCIAL trial (NCT04217421) is investigating the effect of postnatal and perioperative administration of allopurinol on postoperative brain injury in neonates with critical congenital heart disease (CCHD) undergoing cardiac surgery with cardiopulmonary bypass (CPB) shortly after birth.

Objective: This study aimed to characterize the pharmacokinetics (PK) of allopurinol and oxypurinol during the preoperative, intraoperative, and postoperative phases in this population, and to evaluate target attainment of the current dosing strategy.

Methods: Nonlinear mixed-effects modeling was used to develop population PK models in 14 neonates from the CRUCIAL trial who received up to five intravenous allopurinol administrations throughout the postnatal and perioperative periods. Target attainment was defined as achieving an allopurinol concentration >2 mg/L in at least two-thirds of the patients during the first 24 h after birth and between the start and 36 h after cardiac surgery with CPB.

Results: A two-compartment model for allopurinol was connected to a one-compartment model for oxypurinol with an auto-inhibition effect on the conversion, which best described the PK. In a typical neonate weighing 3.5 kg who underwent cardiac surgery at a postnatal age (PNA) of 5.6 days, the clearance (CL) of allopurinol and oxypurinol at birth was 0.95 L/h (95% confidence interval 0.75-1.2) and 0.21 L/h (0.17-0.27), respectively, which subsequently increased with PNA to 2.97 L/h and 0.41 L/h, respectively, before CPB. During CPB, allopurinol and oxypurinol CL decreased to 1.38 L/h (0.9-1.87) and 0.12 L/h (0.05-0.22), respectively. Post-CPB, allopurinol CL increased to 2.21 L/h (1.74-2.83), while oxypurinol CL dropped to 0.05 L/h (0.01-0.1). Target attainment was 100%, 53.8%, and 100% at 24 h postnatally, 24 h after the start of CPB, and 36 h after the end of cardiac surgery, respectively. The combined concentrations of allopurinol and oxypurinol maintained ≥ 90% inhibition of xanthine oxidase (IC90_XO) throughout the postnatal and perioperative period.

Conclusions: The minimal target concentration of allopurinol was not achieved at every predefined time interval in the CRUCIAL trial; however, the dosing strategy used was deemed adequate, since it yielded concentrations well exceeding the IC90_XO. The decreased CL of both compounds during CPB suggests influence of the hypothermia, hemofiltration, and the potential sequestration of allopurinol in the circuit. The reduced CL of oxypurinol after CPB is likely attributable to impaired kidney function.

Fig. 1

Dosing and blood sampling schedule for pharmacokinetic analysis [6]. Sample A was intended for measuring biomarkers and was excluded from the analysis. CPB cardiopulmonary bypass

Fig. 2

Allopurinol and oxypurinol concentrations versus numeral sampling time point. A description of sampling time points is provided in Fig. 1

Fig. 3

The clearance in a typical neonate (3.5 kg) over postnatal age, starting cardiac surgery with cardiopulmonary bypass at a postnatal age of 5.6 days. At birth, the clearance of allopurinol and oxypurinol was 0.95 L/h and 0.21 L/h, respectively, and increased to 2.97 L/h and 0.41 L/h before the start of CPB, respectively. During the period of cardiac surgery with CPB (shaded area), the clearance of allopurinol and oxypurinol decreased to 1.38 L/h and 0.12 L/h, respectively. After CPB, the clearance of allopurinol increased to 2.21 L/h, while clearance of oxypurinol dropped to 0.05 L/h. CPB cardiopulmonary bypass

Fig. 4

Goodness-of-fit plots of the a allopurinol and b oxypurinol final models

Fig. 5

Prediction-corrected visual predictive check of allopurinol and oxypurinol based on the final model. a Postnatal period; x-axis represents the time (in hours) after birth. b Perioperative period, including the preoperative, intraoperative and postoperative phases; x-axis represents the time (in hours) after the third dose (samples J–R). Black solid and dashed lines represent the median and 80% interval of the prediction-corrected observations; red shaded area represents the 95% CI of the median prediction; and blue shaded area represents the 95% CI of the 10th and 90th prediction intervals. Automatic binning was used, with the number of bins set to four for the postnatal period and five for the perioperative period. CI confidence interval

Fig. 6

Allopurinol plus oxypurinol concentrations over time after birth or time after the start of cardiac surgery compared with the IC90 value of 6.22 mg/L for xanthine oxidase inhibition [11]. The dotted line corresponds to 72 h after birth. IC90 90% inhibitory concentration

Fig. 7

Allopurinol and oxypurinol exposures compared with neonates with moderate-to-severe hypoxic-ischemic encephalopathy (ALBINO trial) [32]. Shaded areas represent the IQR of allopurinol and oxypurinol AUC₁₂ in neonates from the ALBINO study, in which the median (IQR) was 129 mg/L*h (93.6–161) and 42.7 mg/L*h (29.4–59.3), respectively [12]. IQR interquartile range, AUC₁₂ area under the plasma concentration-time curve from time zero to 12 h