Theophylline populations

T. Lee, B. Charles, P. Steer, V. Flenady, and T. Grant, Theophylline population pharmacokinetics from routine monitoring data in very premature infants with apnoea. Br J Clin Pharmacol 41 191-200 (1996). 

A serum concentration measnrement obtained 30 min after the LD, when distribution is complete, can be nsed to assess the need for and size of subsequent loading doses and for gnidance of the continnation therapy. Once a serum concentration of 10 to 15 itg/ml has been achieved by loading doses, a constant intravenous infusion is started. The required infusion rate/ o (in nig/kg/h) can then be determined based on the target steady-state serum concentration Q i rget (in Itg/nil) and the estimated theophylline population clearance Clp p (in 1/kg/h), taking any known confounding factors into account. 

While generally not of major concern, omeprazole may inhibit the metabolism of warfarin, diazepam, and phenytoin lansoprazole may decrease theophylline concentrations. Drug interactions with omeprazole are of particular concern in patients who are considered slow metabolizers, as are approximately 3% of the Caucasian population. Unfortunately, it is unclear which patients have the polymorphic gene variation that makes them slow metabolizers.17 The metabolism of esomeprazole may also be altered in patients with this polymorphic gene variation. Patients on potentially interacting drugs should be monitored for development of drug-related problems. 

Adverse reactions to drugs differ in both type and incidence in the pediatric population. Because of immature metabolic pathways, infants and children may have different metabolic patterns than adults. This at least partially explains why neonates require lower theophylline serum concentrations for the treatment of neonatal apnea and why the incidence of hepatotoxi-city following acetaminophen overdose is much lower in young children than in adults [44,45]. Antibiotic adverse effects unique to the pediatric population may... 

To follow the analysis, it is particularly important to understand the mechanism implied by the null hypothesis. Figure 6.2 will be used to describe these alleged events. A vertical scale shows theophylline clearances. Each circle (open or solid) represents a member of the population. The data form normal distributions (but these are shown turned at right angles to the usual orientation). 

More recently Brochot et al. [89] reported an extension of the isobolographic approach to interaction studies for convulsant interaction among pelloxacin, norfloxacin, and theophylline in rats. Their contribution is unique in that they started out by explaining pharmacodynamic interactions for two drugs, but then extended the approach to derive an isobol for three drug interaction. In addition they included Bayesian analysis and developed a population model with Markov chain Monte Carlo methods. 

Only few transdermal products (e.g., steroidal hormone, caffeine, theophylline, fentanyl, scopolamine, nicotine, methylphenidate) have been tested or marketed for use in the pediatric population. The development of transdermal products in pediatric doses could be very beneficial for children who are unable to tolerate oral medications. The need for several sizes of patches to cover different doses needed by different subsets of the pediatric population and to avoid accidents with cutting adult patches can be a limitation. The younger, the better permeation. Hence a compromise between topical versus transdermal efficacy and safety should be sought. 

A population PK and PK/PD analysis was performed to develop a model for the time course of theophyUine concentrations and for the time course and exposure-response of apneic episodes to treatment with theophylline (3). Results of the population pharmacokinetics of theophylline will not be presented. 

FIGURE 27.5 Final PD model predicted probability of daily episode counts. The individual points represent the final PD model predicted probability of observing the respective spell counts for every patient day ( = 4446). The probability is based on the population estimate of the Poisson mean X, given subject level covariates, postnatal age, and theophylline concentration. The line is an average probability across all subjects by postnatal day. 

C. Godfrey, The Population Pharmacokinetics and Pharmacodynamics of Theophylline in Neonates with Apnea of Prematurity. PhD Dissertation, University of Connecticut, 2001. 

E. Moore, R. Gaix, R. Banagale, and T. Grasela, The population pharmacokinetics of theophylline in neonates and young infants. / Pharmacokinet Pharmacodyn 17 47-66 (1989). 

Cystic Fibrosis. Theophylline is more rapidly eliminated in patients with cystic fibrosis than in healthy individnals. The observed theophylline clearance reaches values twice that in healthy individnals. Althongh the mechanism for this increase is unknown, clinicians should be aware of the increased dose reqnirements in this patient population and serum concentration monitoring shonld be nsed as gniding tool. In addition, the volume of distribution is also increased to approximately 0.61/kg. 

Holford, N., Hashimoto, Y., and Sheiner, L. B., Time and theophylline concentration help explain the recovery of peak flow following acute airways obstruction. Population analysis of a randomised concentration controlled trial, Clin. Pharmacokinet., 25(6) 506-515, 1993. 

Asmus, M. J. et ah. Apparent decrease in population clearance of theophylline implications for dosage, Clin. Pharmacol. Ther, 62(5) 483 89, 1997. 

Sublet JL, Pollard SJ, Kadlec GJ, Karibo JM. Non-compliance in asthmatic children a study of theophylline levels in pediatric emergency room population. Ann Allergy 1979 43 95-97. 

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