Pharmacokinetic evaluation of two theophylline dosing methods for infants

Kraus, D.M.; Hatzopoulos, F.K.; Reitz, S.J.; Fischer, J.H.

Therapeutic Drug Monitoring 16(3): 270-276


ISSN/ISBN: 0163-4356
PMID: 8085281
DOI: 10.1097/00007691-199408000-00019
Accession: 009178914

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Theophylline is often used in infants, yet few studies have evaluated the serum concentrations achieved with currently recommended dosing guidelines. Two theophylline dosing regimens, a postnatal age (PNA) equation and the Federal Drug Administration (FDA,) dosing guidelines, were retrospectively evaluated in a group of infants, postconceptional age (PCA) 31-96 weeks, with known theophylline clearances. Large variations in theophylline concentrations were observed for both dosing regimens. Mean +- SD projected steady-state theophylline serum concentrations. C-ss, were 17.7 +- 7.6 mu-g/ml with the PNA equation (n = 40) and 5.6 = 2.9 mu-g/ml with the FDA guidelines (n = 52). Over one-third of C-ss with the PNA equation were gt 20 mu-g/ml. Using the FDA guidelines, 40% of C-ss were lt 5 mu-g/ml. The majority of infants lt 40 weeks PCA attained projected C-ss gt 20 mu-g/ml (21.7 +- 5.1 mu-g/ml) with the PNA equation, but lt 5 mu-g/ml (4.3 +- 1.4 mu-g/ml) with FDA guidelines. An age-related bias was also observed for each dosing method. For the PNA equation, projected Cs, were significantly higher in infants lt 40 weeks versus gtoreq 40 weeks PCA (21.7 +- 5.1 versus 15.8 +- 7.9 mu-g/ml, p lt 0.01). For FDA guidelines, projected C-ss were significantly lower in infants lt 40 weeks PCA versus older infants (4.3 +- 1.4 versus 8.5 +- 4.3 mu-g/ml, p lt 0.001). Clinical application of currently accepted theophylline dosing guidelines for infants results in a high frequency of C-ss, which are potentially toxic or subtherapeutic. The wide variability and age-related bias may be attributed to using PNA as the primary basis for theophylline dosing. Since recent studies suggest PCA as the major determinant of theophylline clearance in infants, new theophylline dosing guidelines, which take into account gestational as well as PNA, need to be developed and evaluated.