PHARMACOKINETICS AND DISPOSITION A. C. FalcaÄo á M. M. FernaÂndez de Gatta M. F. Delgado Iribarnegaray á D. Santos Buelga M. J. GarcõÂa á A. Dominguez-Gil á J. M. Lanao Population pharmacokinetics of caffeine in premature neonates Received: 27 July 1996 / Accepted in revised form: 26 November 1996 Abstract Objective: To determine population pharma- cokinetic parameters of caeine in premature neonates. Methods: This population analysis was done using 145 serum concentration measurements gathered from 75 hospitalized patients during their routine clinical care. The data were analysed by use of NONMEM (mixed eects modelling) according to a one-compartment open model with either zero or ®rst-order absorption and ®rst-order elimination. The eect of a variety of develop- mental, demographic and clinical factors (gender, birth weight, current weight, gestational age, postnatal age, postconceptional age and concurrent treatment with phenobarbital and parenteral nutrition) on clear- ance and volume of distribution was investigated. For- ward selection and backward elimination regression identi®ed signi®cant covariates. Results: The ®nal pharmacostatistical model with in- ¯uential covariates were as follows: clearance (ml á h )1 )  5.81 á current weight (kg) + 1.22 á postnatal age (weeks), multiplied by 0.757 if gestational age £ 28 weeks and 0.836 if the current primary source of pa- tients' nutrition is parenteral nutrition, and volume of distribution (ml)  911 á current weight (kg). The inter- individual variability in clearance and the residual variability, expressed as coecients of variation, were 14.87% and 18.44%, respectively. Due to the lack of information on the data set we were unable to charac- terize the interindividual variability for volume of dis- tribution. Conclusion: In this study, which involved on average only two serum concentrations of caeine per patient, the use of NONMEM gave us signi®cant and consistent information about the pharmacokinetic pro®le of caf- feine when compared with available bibliographic in- formation. Additionally, parenteral nutrition and low gestational age (£ 28 weeks) may even come to be con- sidered as risk factors, and their presence may serve as an indicator of the need for periodic monitoring of caeine concentrations in premature infants. Key words Caeine, Apnoea of prematurity; neonato- logy, paediatrics, population pharmacokinetics Introduction Caeine (1,3,7-trimethylxanthine) is an alkaloid that is currently used for the treatment of idiopathic apnoea associated with prematurity [1]. The ®rst report of the chemical use of caeine in premature infants was done by Aranda et al. [2], and since then numerous other studies have con®rmed its ecacy in counteracting res- piratory problems in neonatology [3±6]. There are few data on caeine pharmacokinetic parameters and dosage schedules in premature infants [7±12], because ethical and logistic issues have limited the scope of the available studies done with traditional methodology [13, 14]. The population approach allows pooling of data and the estimation of pharmacokinetic parameters and in- terindividual variability with a limited number of sam- ples per individual. With this approach one is able to estimate the pharmacokinetic parameters of a popula- tion by using sparse data collected during routine clini- cal care rather than data collected through intensive blood sampling [15, 16]. The non-linear mixed-eects model (NONMEM) population pharmacokinetic pro- gram was used to assess information regarding the pharmacokinetic pro®le of caeine in this fragile popu- lation, which could be considered the clinical prototype for the application of this kind of data analysis [17]. The purpose of this study was to determine popula- tion pharmacokinetic parameters for neonatal patients, speci®cally those of very low birth weight, to pinpoint Eur J Clin Pharmacol (1997) 52: 211±217 Ó Springer-Verlag 1997 A.C. FalcaÄo (&) Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, P-3000 Coimbra, Portugal M.M. FernaÂndez de Gatta á M.F. Delgado Iribarnegaray D. Santos Buelga á M.J. GarcõÂa á A. Dominguez-Gil á J.M. Lanao Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Salamanca, Salamanca, Spain