The Pharmacokinetics of Theophylline in Premature Neonates During the First Few Days After Birth

Preez, M. J. Du; Botha, Julia; McFadyen, M L; Holford, Nicholas H. G.

doi:10.1097/00007691-199912000-00003

Cited by 16 publications

(18 citation statements)

References 25 publications

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“…More recently, du Preez et al [39] have evaluated theophylline pharmacokinetics in premature neonates during the first few days after birth in an attempt to identify factors that may contribute to inter-individual variability. Using a nonlinear mixed effects model, and one compartment model with first order elimination, the clearance of theophylline in this population was low, with a 56% inter-individual variability.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Treatment of Apnea of Prematurity

Bhatt‐Mehta

Schumacher

2003

Pediatric Drugs

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In the last decade, knowledge regarding the neurodevelopment and functional aspects of the respiratory centers during postnatal maturation has increased substantially. However, an increase in such knowledge has not provided a basis for change in practice. The diagnosis of apnea of prematurity (AOP) is one of exclusion. All causes of secondary apnea must be ruled out before initiating treatment for AOP. Treatment will depend on the etiology as well as effectiveness and tolerability of the treatment by the patient. The primary goal of any treatment of AOP is to prevent the frequency of apnea lasting >20 seconds, and/or those that are shorter, but associated with cyanosis and bradycardia. The clinical management of AOP is not much different today than it was two decades ago, with pharmacologic and nonpharmacologic treatment options remaining the mainstay of therapy. Methylxanthines are still the most widely used pharmacologic agents. Due to the wider therapeutic index of caffeine and ease of once daily administration, it should be the preferred agent. Doxapram, or nonpharmacologic treatment measures such as nasal continuous positive airway pressure, may be considered in infants who are unresponsive to methylxanthine treatment alone. Treatment should be continued until there is complete resolution of apnea, and for some time thereafter. The choice of method for weaning treatment remains one of individual physician preference. Discharge from hospital after apnea requires close monitoring and some infants will require home apnea monitors. The decision to provide a home apnea monitor should be individualized for each patient, depending on the effectiveness of treatment and clinical response.

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Section: Mechanism Of Actionmentioning

confidence: 99%

Treatment of Apnea of Prematurity

Bhatt‐Mehta

Schumacher

2003

Pediatric Drugs

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“…These need to be included in the mixed-effects model in some way, often involving stepwise testing. Mandema et al presented a stepwise procedure, using generalized additive models (GAM), 3 which is commonly used (for example, see references [4][5][6][7][8][9][10][11][12][13] ) and has been implemented in the program Xpose. 14 Built in a stepwise additive way, the GAM makes use of posthoc parameter estimates that are regressed on the individual covariate values.…”

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confidence: 99%

Comparison of stepwise covariate model building strategies in population pharmacokinetic-pharmacodynamic analysis

Wählby

Jonsson

Karlsson

2002

AAPS J

191

148

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The aim of this study was to compare 2 stepwise covariate model-building strategies, frequently used in the analysis of pharmacokineticpharmacodynamic (PK-PD) data using nonlinear mixedeffects models, with respect to included covariates and predictive performance. In addition, the effects of stepwise regression on the estimated covariate coefficients were assessed. Using simulated and real PK data, covariate models were built applying (1) stepwise generalized additive models (GAM) for identifying potential covariates, followed by backward elimination in the computer program NONMEM, and (2) stepwise forward inclusion and backward elimination in NONMEM. Different versions of these procedures were tried (eg, treating different study occasions as separate individuals in the GAM, or fixing a part of the parameters when the NONMEM procedure was used). The final covariate models were compared, including their ability to predict a separate data set or their performance in crossvalidation. The bias in the estimated coefficients (selection bias) was assessed. The model-building procedures performed similarly in the data sets explored. No major differences in the resulting covariate models were seen, and the predictive performances overlapped. Therefore, the choice of model-building procedure in these examples could be based on other aspects such as analystand computer-time efficiency. There was a tendency to selection bias in the estimates, although this was small relative to the overall variability in the estimates. The predictive performances of the stepwise models were also reasonably good. Thus, selection bias seems to be a minor problem in this typical PK covariate analysis.ously estimated by the use of nonlinear mixed-effects models. One of the important aims in population PK-PD modeling is the establishment of relationships between parameters and covariates (ie, patient specific variables) to explain parameter variability and facilitate dose adjustment decisions.Stepwise model building is frequently employed in population PK(-PD) covariate model building with NONMEM (the most widely used program for population PK(-PD) modeling).1 For example, 58 of 60 papers (1999-2001) related to covariate model building in NONMEM included stepwise procedures (the reference list is available from the authors). No previous comparison between covariate model building procedures has been reported in the literature. In this article we assess the performances of 2 (objective) model-building strategies that make use of stepwise procedures. In addition, we explore how the results of a (typical) covariate analysis can be affected by selection bias, a general problem in stepwise regression. The search for important covariates is not always straightforward, especially if there are large numbers of covariate-parameter relations to consider. In addition to finding the "right" (ie, true or predictive) covariate, the right functional form of the relation must be identified. This may require considerable analyst-and/or computer run-time...

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“…immaturity of the cytochrome P-450 system [27,28]. In this regard, it is notable that 8 of the 13 preterm infants treated with theophylline responded to treatment with serum levels of 28-56 Ìmol/l (5-10 Ìg/ml), and only the 5 infants with serum theophylline levels 146 Ìmol/l (8.2 Ìg/ml) exhibited reduced neutrophil functions.…”

Section: Discussionmentioning

confidence: 99%

Theophylline Alters Neutrophil Function in Preterm Infants

Mehta

Weinberger²,

Usmani³

et al. 2002

Neonatology

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Theophylline (1,3-dimethylxanthine), which is often prescribed to premature infants to treat apnea, acts, in part, by altering the metabolism of cyclic AMP. This second messenger plays a role in signal transduction mediating neutrophil functions, including respiratory burst, chemotaxis, and motility. We hypothesize that theophylline causes reduced respiratory burst activity, chemotaxis, and random motility in neutrophils. In these studies, we aim at determining the effects of theophylline on neutrophil function in vitro in cells from preterm and full-term infants and adults as well as on neutrophils obtained from premature infants receiving theophylline treatment. Neutrophils were obtained from 20 preterm infants, 16 full-term infants, and 14 adults. Chemiluminescence, chemotaxis, and random motility were measured after exposure of these cells to theophylline in vitro (0– 84 µmol/l or 0–15 µg/ml). In addition, these neutrophil activities were correlated with serum theophylline levels in 13 preterm infants receiving theophylline treatment for 72 h. Neutrophils from premature infants, term infants, and adults all displayed reduced chemiluminescence, chemotaxis, and random motility at 84 µmol/l (15 µg/ml) of theophylline in vitro. The relative reductions were greatest in cells from premature infants (p < 0.01). A level-dependent reduction in these activities was also noted in neutrophils from preterm infants with serum theophylline levels >46 µmol/l (8.2 µg/ml; p < 0.001). In contrast, lower theophylline concentrations (about 28 µmol/l or 5 µg/ml), either in vitro or in vivo, caused significant increases in neutrophil activities. Theophylline concentrations in the high therapeutic range (84 µmol/l or 15 µg/ml) cause dose-dependent reductions in neutrophil chemiluminescence, chemotaxis, and random motility. Cells from preterm infants are particularly sensitive to this effect. In contrast, theophylline concentrations in the low therapeutic range (28 µmol/l or 5 µg/ml) cause increased neutrophil activities. Altered neutrophil activity in newborns related to theophylline treatment may affect the infants’ response to infection as well as the incidence of inflammatory diseases.

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The Pharmacokinetics of Theophylline in Premature Neonates During the First Few Days After Birth

Cited by 16 publications

References 25 publications

Treatment of Apnea of Prematurity

Treatment of Apnea of Prematurity

Comparison of stepwise covariate model building strategies in population pharmacokinetic-pharmacodynamic analysis

Theophylline Alters Neutrophil Function in Preterm Infants

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