A Population Pharmacokinetic Study of Caffeine Citrate in Chinese Premature Neonates

Objective: Apnea of prematurity (AOP) is defined as an attack of apnea for at least 20 seconds, with bradycardia and cyanosis. It is a common phenomenon in the neonatal intensive care unit (NICU). Caffeine citrate, one of the methylxanthines, is used to suppress or to prevent AOP attack. This study aimed to develop a population pharmacokinetic (popPK) model for caffeine after administration to preterm neonates.

Methods: Preterm neonates, who were treated with caffeine citrate, in the NICU of West China Second University Hospital, Sichuan University during Jan, 2015 and Jun, 2017 were enrolled in this study. Serum concentration samples were obtained at 30 min, 4 h, and 12 h after the loading dose, as well as at 30 min before the first and second maintenance dose. Trough concentration samples were obtained every 7 days until caffeine citrate was stopped. All the samples were measured by high-performance liquid chromatography (HPLC). The dosing regimen of caffeine citrate, combination medications, demographic features (such as gestational age (GA), birth weight (BW), delivery pattern, and sex), and laboratory tests of liver and renal function were documented. Renal function (RF) was calculated from the ratio of predicted creatinine clearance (Schwartz1992) to predicted glomerular filtration rate (Rhodin, Anderson et al 2009). A one-compartment model with zero-order input (intravenous), or first-order input (oral), and first order elimination was used to describe the time course of caffeine concentration. Both a maturation effect and a size effect were used to account for changes in post-menstrual age (PMA week) and total body weight (TBW kg). An adult clearance (CL) of caffeine (6.55L/h/70kg) was assumed with renal CL of 1.55% of total clearance (Birkett and Miners 1991). The size effect on clearance and volume of distribution was described with an allometric model: FSIZECL = (TBW/70)^(3/4) and FSIZEV = (TBW/70)^(1/1). The maturation of caffeine renal CL was assumed to be the same as glomerular filtration rate (Rhodin, Anderson et al 2009): FMATCLR=1/(1+(PMA/47.7)^(-3.4)). The maturation of non-renal CL was expressed as: FMATCLNR=1/(1+(PMA/TM50CL)^(-HILLCL)) where TM50CL is the PMA when CL is 50% of the size standardized adult value and HILLCL is an empirical exponent. The popPK model was developed using NONMEM 7.41. Visual predictive checks (VPC) was performed for model evaluation.

Results: Concentration data (1,004 samples) were obtained from 222 (120 male) preterm neonates, with an average GA of 29.7±1.8 weeks and an average BW of 1.28±0.29 kg. Among all the maintenance doses, 32.49% (1,796/5,528) were administrated orally. The non-renal CL maturation was described by HILLCL = 1.56 while TM50CL was fixed to 300 weeks. Meanwhile, the delivery pattern was found to have effects on total CL (FMATBIRTH = 0.857 while the baby was delivered by caesarean). Thus, the model for total clearance was: CL (L/h) = 6.55 *(0.9885* FMATCLNR + 0.0115*FMATCLR*RF)*FSIZECL*0.857. The model for volume of distribution was: V (L) = 79.7*FSIZEV. For CL the between subject variability (BSV) was9.62% and for V it was 17.1%. The between occasion variability (BOV) for CL was very small (<5%).

Conclusion: As expected the clearance of caffeine in neonates was lower than adults based on size alone because of immature elimination processes. The wide variability in concentrations with a fixed dose regimen and a small BOV for CL suggest measurement of caffeine concentration would be helpful in individualizing doses to reach a safe and effective target concentration (Holford and Buclin 2012).


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