A Population Pharmacodynamic Study of Apnea of Prematurity and the Effect 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 is used to suppress or to prevent AOP attacks. Based on a population pharmacokinetic (PK) model for caffeine the effect of caffeine on the hazard of AOP attacks was described.

Methods: The design of the study and the PK analysis have been described separately (Yang, Holford et al. 2019). The baseline hazard was described by a Gompertz distribution. The effect of caffeine was modelled using a sigmoid Emax model directly on the hazard of an AOP attack. Evaluated covariates included various methods of spontaneous breathing ventilation support (LFNC, HFNC, CPAP, BIPAP, BNCPAP) or mechanical ventilation (CMV, HOV). The hazard was set to 0 during mechanical ventilation. The pharmacodynamic (PD) and hazard model was developed using NONMEM 7.41. Visual predictive checks (VPC) was performed for model evaluation.


The bootstrap hazard and pharmacodynamic parameter estimates are shown in Table 1.

Table 1 Parameters of AOP hazard and pharmacodynamics of caffeine

Parameter Description Units Bootstrap average
L_LZ Baseline hazard 1/h 0.00496
B_GOM Gompertz hazard . -0.00167
CAF_EMAX Emax for caffeine effect on hazard 1/h 0.492
CAF_C50 C50 for caffeine effect on hazard mg/L 1.80
CAF_HILL Hill exponent for  effect on hazard . 2.64
GGC50 C50 with A2A receptor GG genotype mg/L 1.57


Conclusion: Caffeine suppresses AOP attacks by about 50%. The C50 suggests that a target concentration of 5 mg/L would achieve close to maximum achievable benefit.

Funding: The National Key Development Program of Clinical Specialist (neonatologist) (1311200003303); the National Science Foundation of China (81330016); the Foundation of Health and Family Planning Commission of Sichuan Province (150104, 150107).


Yang, Y., N. Holford, Z. Jiang, H. Shen, J. Shi, X. Shu, Y. Huang, J. Zhao, J. Tang and D. Mu (2019). A Population Pharmacokinetic Study of Caffeine Citrate in Chinese Premature Neonates. 20th PAGANZ.

Nick Holford