Caffeine citrate treatment for extremely premature infants with apnea: Population pharmacokinetics, absolute bioavailability, and implications for therapeutic drug monitoring

Charles, Bruce G., Townsend, Sarah R., Steer, Peter A., Flenady, Vicki J., Gray, Peter H. and Shearman, Andrew (2008) Caffeine citrate treatment for extremely premature infants with apnea: Population pharmacokinetics, absolute bioavailability, and implications for therapeutic drug monitoring. Therapeutic Drug Monitoring, 30 6: 709-716.


Author Charles, Bruce G.
Townsend, Sarah R.
Steer, Peter A.
Flenady, Vicki J.
Gray, Peter H.
Shearman, Andrew
Title Caffeine citrate treatment for extremely premature infants with apnea: Population pharmacokinetics, absolute bioavailability, and implications for therapeutic drug monitoring
Journal name Therapeutic Drug Monitoring  (ERA 2012 Listed)    (ERA 2010 Rank B)   Check publisher's open access policy
Publication date 2008-12
Sub-type Article
DOI 10.1097/FTD.0b013e3181898b6f
Volume number 30
Issue number 6
ISSN 0163-4356
Start page 709
End page 716
Total pages 8
Place of publication New York : USA
Publisher Lippincott-Raven
Collection year 2009
Language eng
Subject 920111 Nervous System and Disorders
111502 Clinical Pharmacology and Therapeutics
Abstract The objective of this study was to develop a population model of the pharmacokinetics (PK) of caffeine after orogastric or intravenous administration to extremely premature neonates with apnea of prematurity who were to undergo extubation from ventilation. Infants of gestational age <30 weeks were randomly allocated to receive maintenance caffeine citrate dosing of either 5 or 20 mg/kg/d. Four blood samples were drawn at prerandomized times from each infant during caffeine treatment. Serum caffeine was assayed by enzyme-multiplied immunoassay technique. Concentration data (431 samples, median: 4 per subject) were obtained from 110 (52 male) infants of mean birth weight of 1009 g, current mean weight (WT) of 992 g, mean gestational age of 27.6 weeks, and mean postnatal age (PNA) of 12 days. Of 1022 doses given, 145 were orogastric, permitting estimation of absolute bioavailability. A 1-compartment model with first-order absorption was fitted to the data in NONMEM. Patient characteristics were screened (P < 0.01) in nested models for pharmacokinetic influence. Model stability was assessed by nonparametric bootstrapping. Clearance (CL) increased nonlinearly with increasing PNA, whereas volume of distribution (Vd) increased linearly with WT, according to the following allometric models: CL (L/h) = 0.167 (WT/70)0.75 (PNA/12)0.358; Vd (L) = 58.7 (WT/70)0.75. The mean elimination half-life was 101. Interindividual variability (IIV) of CL and Vd was 18.8 % and 22.3 %, respectively. Interoccasion variability (IOV) of CL and Vd was 35.1% and 11.1%, respectively. This study established that the elimination of caffeine was severely depressed in extremely premature infants but increased nonlinearly after birth up to age 6 weeks. Caffeine was completely absorbed, which has favorable implications for switching between intravenous and orogastric routes. The interoccasion variability about CL was twice the interindividual variability, which, among other factors, indicates that routine serum concentration monitoring of caffeine in these patients is not warranted., (C) 2008 Lippincott Williams & Wilkins, Inc.
Keyword Caffeine
Population pharmacokinetics
Preterm neonates
Bioavailability
Therapeutic drug monitoring
Q-Index Code C1
Q-Index Status Confirmed Code

 
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Created: Fri, 27 Mar 2009, 14:45:08 EST by Elizabeth Pyke on behalf of School of Pharmacy