POPULATION PHARMACOKINETICS OF CAFFEINE IN PREMATURE NEONATES

Objective: To determine population pharmacokinetic parameters of caffe ine in premature neonates. Methods: This population analysis was done using 145 serum concentration measurements gathered from 75 hospitaliz ed patients during their routine clinical care. The data were analysed by use of NONMEM (mixed effects modelling) according to a one-compart ment open model with. either zero or first-order absorption and first- order elimination. The effect of a variety of developmental, demograph ic and clinical factors (gender, birth weight, current weight, gestati onal age, postnatal age, postconceptional age and concurrent treatment with phenobarbital and parenteral nutrition) on clearance and volume of distribution was investigated. Forward selection and backward elimi nation regression identified significant covariates. Results: The fina l pharmacostatistical model with influential covariates were as follow s: clearance (ml.h(-1))= 5.81 current weight (kg) + 1.22.postnatal age (weeks), multiplied by 0.757 if gestational age less than or equal to 28 weeks and 0.836 if the current primary source of patients' nutriti on is parenteral nutrition, and volume of distribution (ml)= 911.curre nt weight (kg). The inter-individual variability in clearance and the residual variability, expressed as coefficients of variation, were 14. 87% and 18.44%, respectively. Due to the lack of information on the da ta set we were unable to characterize the interindividual variability for volume of distribution. Conclusion: In this study, which involved on average only two serum concentrations of caffeine per patient, the use of NONMEM gave us significant and consistent information about the pharmacokinetic profile of caffeine when compared with available bibl iographic information. Additionally, parenteral nutrition and low gest ational age (less than or equal to 28 weeks) may even come to be consi dered as risk factors, and their presence may serve as an indicator of the need for periodic monitoring of caffeine concentrations in premat ure infants.