Serum Theophylline Concentrations Research Articles

Theophylline toxicity due to drug interaction

Acute theophylline toxicity is usually due to overdose. However, it may also be brought about by interference of its metabolism secondary to the concurrent administration of other drugs. Erythromycin is important in this regard as illustrated in the following case of a 16-year-old girl who developed theophylline toxicity while on therapy with both of these drugs. As well as the potential for theophylline toxicity, coadministration of these two drugs may result in subtherapeutic serum erythromycin concentrations. Thus, if at all possible, this practice should be avoided. If unavoidable, then serial serum theophylline concentrations should be monitored. The occurrence of this interaction is unpredictable. Thus the previous recommendation of decreasing the theophylline dosage by 25% to prevent toxicity during erythromycin therapy is irrational and should be avoided. Drug interactions should be considered in the differential diagnosis of theophylline toxicity.

Lack of theophylline assay interference from pentoxifylline and its metabolites.

Pentoxifylline, a hemorheologic agent, and its metabolites are structurally similar to theophylline and other xanthines; therefore, they have the potential to interfere with serum assays for theophylline. Any false elevation of theophylline serum concentrations could have a significant impact on drug therapy decisions. Serum was obtained from six elderly subjects who had been taking 400 mg of pentoxifylline three times daily for at least six months. A serum assay using the TDx fluorescence polarization immunoassay failed to detect any measurable amount of theophylline. Normal doses of pentoxifylline and the resulting metabolites do not appear to interfere with the TDx method of serum assay for theophylline.

Evaluation of theophylline pharmacokinetics in a pediatric population using mixed effects models.

Routine clinical pharmacokinetic data collected prospectively from pediatric patients receiving theophylline were analyzed using the NONMEM (nonlinear mixed effects model) digital computer program. A total of 314 measured serum theophylline concentrations (STCs) were obtained from 84 hospitalized patients ranging in age from 4 months to 15.2 years with the majority of patients between the ages of 1 and 8 years. Fifty-six percent were male. The race/ethnicity distribution was 71.4% Latin, 15.5% black, 11.9% Caucasian, and 1.2% (one subject) Pakistani. Of the total number of observed STCs, 16.2% reflected some degree of outpatient dosing. The pharmacokinetic model used was a one-compartment open model with either zero-order or first-order absorption and first-order elimination. Age was the most important determinant of theophylline clearance (Cl); weight was inferior to age and did not statistically improve the model (p greater than 0.005) when combined with age. Total Cl increased by 10%/year over the age range of 1 to 15 years of age. Black race and male gender were associated with higher Cl values: for a given age, Cl was 34% higher for blacks than the reference population composed of the remaining patients, and Cl for males was 25% higher than that for females. The volume of distribution (Vd) for the population was estimated to be 0.62 L/kg. The interindividual variability in Cl and Vd expressed as coefficients of variation were 19 and 28%, respectively. The residual intraindividual error variance corresponded to a standard deviation of 2.8 micrograms/ml. The STCs that represented some degree of outpatient dosing were 21% lower than those reflecting only inpatient dosing. Alternate models that include weight as a determinant of theophylline clearance are also provided. The NONMEM method of determining population pharmacokinetics is well suited to the pediatric population since it does not require a large number of STCs per patient. In this study a mean of only 3.7 STCs per patient were utilized to provide information which should prove useful in the design and adjustment of theophylline dosage regimens in children.

The population pharmacokinetics of theophylline in neonates and young infants.

The population pharmacokinetics of theophylline were evaluated using 391 theophylline serum concentration measurements from 108 neonates and young infants (postnatal age 0-26 weeks), who received theophylline for the treatment of neonatal apnea. A one-compartment pharmacokinetic model with first-order elimination was used, with intravenous aminophylline and oral theophylline administration modeled as zero-order infusions. The effect of a variety of developmental and demographic factors on clearance (CL) and volume (V) were investigated. Hypothesis testing to evaluate potentially significant factors produced a final model in which clearance was based on weight (kg) raised to an exponential power and postnatal age (weeks), with CL (ml/hr) = 17.5 (weight)1.28 + 1.17 (postnatal age). Clearance was reduced by 12% for patients receiving parenteral nutrition. Volume of distribution in this population was adequately described using only weight, with V (L) = 0.858 L/kg. Bioavailability of orally administered drug was not significantly less than unity. Interindividual variability in clearance was modest, with a coefficient of variation for clearance of 16%. An estimate of interindividual variability in volume could not be obtained. As a measure of residual variability in theophylline serum concentrations, the coefficients of variation for theophylline serum concentrations of 5.0, 10.0, and 13.0 mg/L were found to be approximately, 25, 12, and 9%, respectively. The identification of influential patient factors and the quantification of their influence on theophylline disposition allow for a priori estimates of theophylline pharmacokinetic parameters in these patients.

Bayesian derived predictions for twice daily theophylline under outpatient conditions and an assessment of optimal sampling times.

1. The accuracy of a computerised method of pharmacokinetic interpretation of a single serum theophylline concentration, employing the statistical technique of Bayesian analysis, has been evaluated for an oral slow release form of theophylline using twice daily dosing. 2. Twenty-four hour steady state serum theophylline concentration-time profiles of one Uniphyllin Continus 400 mg tablet (Napp Laboratories) every 12 h were measured in 15 patients. These profiles demonstrated a diurnal variation of theophylline absorption which was faster during the day. 3. Revised predictions of the profiles were generated by Bayesian analysis using a single serum theophylline concentration taken during a previous outpatient appointment. Comparing the predicted and measured profiles, the accuracy of the Bayesian method is considered more than adequate for clinical purposes. 4. The predictions produced by the revised estimates were statistically less biased and more precise than those derived by a theophylline algorithm using population data. 5. The mean prediction errors of the revised estimates of the day and night-peak drug concentrations were -0.55 mg l-1 and -0.21 mg l-1 whilst those of the evening and morning troughs were 1.17 mg l-1 and 0.41 mg l-1, respectively. 6. Analysis of the predictive and relative performance of the samples drawn during the profile revealed that the sample taken prior to a morning dose produced the most accurate predictions. 7. There was no statistical difference in the relative predictive performance of samples drawn up to 4 h before or 2 h after the morning dose. It is, therefore, recommended that all serum theophylline concentrations to be used in Bayesian analysis, should be drawn within this period.

Pharmacokinetic evaluation of the terfenadine-theophylline interaction

Based on results of studies of a possible terfenadine-theophylline interaction on file with Merrell Dow, Inc., a randomized, crossover study was undertaken to determine if there were a pharmacokinetic interaction between these two medications. Seventeen normal volunteers were randomized to receive theophylline or a theophylline-terfenadine combination for 14 days, followed by a 2-week washout period, with crossover to the other treatment for 14 days. Serum theophylline concentrations were measured on the last day of each treatment phase for determination of pharmacokinetic parameters. No differences were found in elimination rate constant, elimination half-life, area under the concentration-time curve, time to peak concentration, or maximum theophylline concentration. It is concluded that concomitant terfenadine therapy does not affect the pharmacokinetic profile of theophylline in healthy male volunteers.

Clinical Relevance of the Interaction of Theophylline with Diltiazem or Nifedipine

The results of previously published studies indicate that calcium channel blockers are capable of competitively inhibiting cytochrome P-450 activity in hepatic microsomes, the pathway of theophylline metabolism. In addition, case reports have suggested that theophylline serum concentrations change when a calcium channel blocker has been added to or deleted from a stable theophylline regimen. To determine the clinical relevance of this potential interaction in patients with chronic asthma, we measured a peak steady-state theophylline serum concentration in 21 subjects while receiving theophylline alone (400 to 1,500 mg/day), and again, at least seven days later, after the addition of continuous therapy with maximally tolerated doses of either diltiazem (n = 18) or nifedipine (n = 16). The diltiazem dose was increased in 120 mg/day increments, as tolerated, to a maximum of 240 to 480 mg/day, while the nifedipine dose was increased in increments of 40 mg/day, to a maximum dose of 80 to 160 mg/day. The mean +/- SEM theophylline serum concentrations were 13.6 +/- 1.4 micrograms/ml before and 14.0 +/- 1.2 micrograms/ml during concurrent diltiazem therapy, and 12.6 +/- 1.0 micrograms/ml before and 12.2 +/- 1.1 micrograms/ml during nifedipine (p greater than 0.05). With this sample size there is a 5 percent chance that we missed a 20 percent change in serum concentration (type II error). Thus, maximum tolerated doses of diltiazem or nifedipine do not impair the metabolism of theophylline to a clinically relevant degree and adjustment of theophylline dosage is not required after the addition or discontinuation of diltiazem or nifedipine. In addition, these data suggest that currently available in vitro techniques for evaluating drug interactions in the hepatocyte do not predict the clinical relevance of such an interaction in patients who might require both drugs for different therapeutic indications.

Comparison of a New Sustained-Release Theophylline Formulation (Theotrim) with a Reference Drug (Theodur) in the Steady State in Asthmatic Children

The bioequivalency of two sustained-release theophylline formulations (SRT), Theotrim and Theodur, was studied in the steady state in asthmatic children, using a double-blind crossover design. Ten children, aged 7–14 (mean 10.2) years, were treated for 2 weeks, with identical doses (mean 16 mg/kg•day) of either Theotrim or Theodur tablets. Each drug was given for 1 week in a randomized sequence. At the end of each week, a 12-hour serum theophylline concentration (STC) profile was performed and pharmacokinetic data of both drugs were compared. Peak STCs with Theotrim and Theodur were 17.1 ± 1.4 μg/ml (M ± SEM) and 16 ± 1 μg/ml (M ± SEM), respectively. Through STC were 8.9 ± 0.8 μg/ml (M ± SEM) with Theotrim compared with 9.4 ± 0.8 μg/ml (M ± SEM) with Theodur. Six patients had % fluctuation of STC < 100% with both Theotrim and Theodur, while the mean (±SEM) % fluctuation was 99(±17)% and 79(±15)% with Theotrim and Theodur, respectively. The area under the concentration curve (AUC) for 0–12 hours was 158.9 ± 13 (M ± SEM) μg/hr•ml for Theotrim, compared with 153.0 ± 10 (M ± SEM) μg/hr·ml for Theodur. The differences between all these pharmacokinetic parameters showed no statistical significance (p > 0.1). Likewise, there were no differences in the frequency of symptoms of asthma, requirement for additional bronchodilator medication, and theophylline side effects in the patients during the week of treatment with Theotrim compared with the other week when treated with Theodur. We conclude that in this group of asthmatic children, Theotrim proved to be bioequivalent to Theodur in the steady state and equally effective in the treatment of asthma.

Effect of enoxacin on theophylline neurotoxicity

Concomitant use of the bronchodilator theophylline and the antibacterial agent enoxacin has been associated with significant neurologic and other adverse effects. Enoxacin and certain other quinolones are known to inhibit the biotransformation of theophylline, thereby increasing the plasma concentrations of the bronchodilator. It was considered possible that this may not be the only interaction because theophylline as well as enoxacin are known to have neurotoxic potential. To explore the possibility of a pharmacodynamic interaction, rats pretreated orally with enoxacin or water (controls) were slowly infused i.v. with theophylline until the onset of a maximal seizure. Neither 100 nor 400 mg/kg enoxacin 1 hour before the infusion had any significant effect on the infused dose or on the concentrations of theophylline in serum, brain and cerebrospinal fluid at onset of seizures. On the other hand, 400 mg/kg enoxacin reduced the total serum clearance of a 12 mg/kg i.v. bolus dose of theophylline from 2.56±0.37 to 1.00±0.13 ml min −1kg −1 (mean±SD). It is concluded that acutely administered enoxacin in a dose sufficient to inhibit the elimination of theophylline has no direct effect on theophylline neurotoxicity in rats.

Increased transport of theophylline into gastrointestinal lumen and gastrointestinal dialysis by activated charcoal in rats with hepatic cirrhosis.

The characteristics of exsorption and/or excretion of theophylline into the small intestinal lumen in rats with hepatic cirrhosis (HC rats) induced by carbon tetrachloride were investigated by an in situ single-pass perfusion technique. The serum concentrations of theophylline after i.v. administration of aminophylline (10 mg/kg) in the HC rats were significantly higher than those in normal rats during the experimental period. Moreover, the exsorption of theophylline from blood into the intestinal lumen was significantly increased in the HC rats compared with the normal rats. Treatments with oral activated charcoal reduced the serum theophylline levels in the HC rats. Consequently, gastrointestinal dialysis by oral administration of activated charcoal may be a useful method to remove poisonous drugs from the blood in patients with hepatic failure (including cirrhosis), which decreases the systemic clearance.

Magnesium toxicity secondary to catharsis during management of theophylline poisoning

Multiple doses of oral activated charcoal are used increasingly to promote elimination of toxins that have already reached the bloodstream; this is often referred to as gastrointestinal dialysis. Cathartics usually are used in conjunction to hasten transit of the charcoal-adsorbed toxin. In the present case, a regimen of activated charcoal and magnesium citrate was used to treat a patient with theophylline poisoning. It was effective in lowering the patient's serum theophylline concentration but produced an elevated magnesium level associated with decreased responsiveness, confusion, and diminished deep tendon reflexes. Magnesium citrate may not be the optimal cathartic for use in gastrointestinal dialysis, at least in selected patients. Sorbitol has been shown to produce a more rapid catharsis without disturbing magnesium serum concentrations. Therefore, the use of sorbitol in place of magnesium citrate, at least in selected patients, may be preferred.

EFFECT OF TE-031, A NEW MACROLIDE ANTIBIOTIC, ON SERUM THEOPHYLLINE CONCENTRATION

Effect of TE-031, a new macrolide antibiotic, on theophylline kinetics was studied in asthmatic children.In the first study, 18 patients were taking sustained-release theophylline orally for 4 weeks, and TE-031 was given in a dose of 600mg/day for 7 days on the 3rd week of the study. Blood samples were collected at the same time (7:20 a.m. and 2 p.m.) on 8 days and 1 day prior to TE-031 administration, on the 3rd and 7th day after TE-031 administration and on the 7th day after the termination of TE-031. The mean serum theophylline concentration on the 7th day after administration was more significant than on other days (p<0.01).In the second study, an investigation regarding the effect of TE-031 on intravenously given theophylline was carried out in three patients. Among these patients, one of them had a significantly prolonged theophylline half-life and her clearance decreased after TE-031 administration.The results of these two studies indicate that TE-031 may affect the theophylline kinetics and its serum concentration. Patients receiving therapeutic doses of theophylline are at a considerably higher risk of theophylline toxicity if TE-031 is co-administered. Thus, it is advised to monitor theophylline concentration during administration of these two drugs together.

Dose response relation to oral theophylline in severe chronic obstructive airways disease.

To evaluate measurement of the trapped gas volume as a measure of respiratory function in patients with chronic obstructive airways disease and their response to treatment with theophylline. Patients able to produce consistent results on testing of respiratory function spent two weeks having dosage of theophylline adjusted to give individual pharmacokinetic data. This was followed by random assignment to four consecutive two month treatment periods--placebo and low, medium, and high dose, as assessed by serum concentrations of theophylline. Respiratory function and exercise performance was assessed at the end of each two month period. Chest unit in district hospital. Thirty eight patients with chronic bronchitis and moderate to severe chronic obstruction to airflow were recruited; 33 aged 53-73 years completed the study. Dosage of oral theophylline increased during two week optimisation period to 800 mg daily unless toxicity was predicted, when 400 mg was given. Targets for the steady state serum theophylline concentrations were 5-10 mg/l in the low dose period, 10-15 mg/l in the medium dose, and 15-20 mg/l in the high dose period. Respiratory function as measured by forced expiratory volume in one second, forced vital capacity, peak expiratory flow rate, slow vital capacity, and static lung volumes using helium dilution and body plethysmography from which trapped gas volume was derived. Exercise performance assessed by six minute walking test and diary cards using visual analogue scale. The forced expiratory volume in one second, forced vital capacity, and peak expiratory flow rate changed only slightly (about 13%) over the range of doses. There was a linear dose dependent fall of trapped gas volume from 1.84 l (SE 0.157) to 1.42 l (0.152), 1.05 l (0.128), and 0.67 l (0.102) during the placebo and low, medium, and high dose treatment periods. Mean walking distance increased by up to 55.6 m (20%). There was a modest improvement in dyspnoea as the dose of theophylline was increased. Side effects were mostly minor but they became more frequent as the dose was increased. The fall in trapped gas volume may reflect an improvement in peripheral ventilation (associated with treatment with theophylline) which is less apparent in the more common tests of lung function used in patients with chronic obstructive airways disease.

Effect of body weight on the volume of distribution of theophylline

The volume of distribution (Vd) of theophylline and the relevant aminophylline loading dose (LD) are usually calculated on the basis of total body weight (TBW). In obese subjects it has been suggested that lean or ideal body weight (IBW) is the best predictor. In a sample of 40 acutely ill asthmatic patients (aged 22 to 78 yr, weighing 45 to 176 kg) we measured Vd and found that (1) it increases with TBW, (2) it cannot be accurately predicted from either TBW or IBW alone by a simple regression analysis. Power functions have been usefully applied in comparing the pharmacokinetics of animal species, including humans, with different body mass. In our sample, data were best fitted by the equation Vd = 1.29 TBW 0.74, which seems to take care of lean as well as obese patients. Results were confirmed (r = 0.89 between predicted and measured values) in a second independent sample of patients (aged 26 to 77 yr, weighing 38 to 167 kg). This helps to minimize the error in obtaining the target serum concentration of theophylline when giving a LD calculated from a predicted Vd value.

Relative efficacy of phenytoin and phenobarbital for the prevention of theophylline-induced seizures in mice

We evaluated the efficacy of pretreatment with phenytoin and phenobarbital to prevent seizures in mice given convulsive doses of theophylline. The control LD50 for theophylline was determined in 48 mice by intraperitoneal injections of increasing doses without anticonvulsant treatment. Anticonvulsant effects were determined in 105 additional mice pretreated with either phenytoin 30 mg/kg (n = 35), phenobarbital 35 mg/kg (n = 30), or phenobarbital 60 mg/kg (n = 40) one hour before theophylline administration. The theophylline LD50 (95% confidence interval) was 239 mg/kg (range, 229 to 248 mg/kg) for controls, 204 mg/kg (range, 194 to 214 mg/kg) for phenytoin, 305 mg/kg (range, 288 to 323 mg/kg) for low-dose phenobarbital, and 319 mg/kg (range, 307 to 331 mg/kg) for high-dose phenobarbital. Each LD50 differed significantly from control (P less than .05). The phenobarbital groups were significantly different from phenytoin (P less than .05) but not from each other. Theophylline serum concentrations were not significantly different among groups after adjustment for different doses. The mean +/- SEM time to seizure in minutes after adjustment for theophylline dose was 23.5 +/- 4.0 minutes for controls, 5.7 +/- 7.5 minutes for phenytoin, 44.1 +/- 7.1 minutes for low-dose phenobarbital, and 63.7 +/- 6.5 minutes for high-dose phenobarbital.(ABSTRACT TRUNCATED AT 250 WORDS)

The consistency of theophylline absorption from a sustained-release formulation in asthmatic children.

Theophylline absorption was studied in asthmatic children ages 2-7 years. A bead-filled capsule of sustained-release theophylline (Slo-Bid, William H. Rorer, Inc., Fort Washington, PA) was administered in equal doses twice daily (8 AM and 8 PM) to produce serum theophylline concentrations (STCs) between 10 and 20 micrograms ml. After 7 days, blood samples were obtained every 2 hours for 24 hours. This sequence was repeated after another seven days of treatment. Elimination values were calculated after an intravenous reference dose. Slo-Bid was completely absorbed (mean +/- SD percentage of dose absorbed of 117.1 +/- 26.1 on day 1, and 104.8 +/- 16.1% on day 2), and the pattern of absorption was consistent from day to day, with maximum STCs occurring 2-6 hours after the dose, and minimum STCs at or near the time of PM dose. The percentage of fluctuation of 149.7 +/- 49.7% and 163.0 +/- 114.0% (mean +/- SD) on days 1 and 2, respectively, was slightly higher than desired, but probably was a result of rapid theophylline clearance in this group of children (119.9 +/- 25.8 ml/hr/kg). Mean residence time for absorption after AM and PM doses indicated significantly longer time for absorption (ta) after the PM doses: mean +/- SEM ta for AM doses on days 1 and 2 was 2.8 +/- 0.3 and 2.7 +/- 0.2 hours, respectively, and increased to 3.9 +/- 0.3 and 3.7 +/- 0.5 hours after PM doses on days 1 and 2, respectively (p less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac Arrhythmias during the Combined Use of Intravenous Aminophylline and Terbutaline in Status Asthmaticus

The purpose of this study was to evaluate prospectively the occurrence of cardiac arrhythmias during the combined therapy with intravenous aminophylline and terbutaline in 29 consecutive patients with status asthmaticus. The 24-hour Holter recordings were performed during continuous intravenous infusions of aminophylline (0.56 +/- 0.20 mg/kg/h) and terbutaline (0.034 +/- 0.014 microgram/kg/min). Serum theophylline concentration was 12.1 +/- 3.8 micrograms/ml and never reached the toxic level (greater than 20 micrograms/ml). Premature ventricular contractions (PVCs) were absent in 35 percent of patients and 48 percent had rare unifocal PVCs (less than 10/h). Only 17 percent of patients (five of 29) exhibited severe ventricular arrhythmias: PVCs greater than 10/h (n = 3), multifocal PVCs (n = 1); and a short run of ventricular tachycardia (n = 1). Serious supraventricular arrhythmias occurred in only 7 percent of patients (two of 29) who developed sustained runs of atrial tachycardia. These arrhythmias were always clinically well tolerated and spontaneously resolved without any antiarrhythmic treatment. We conclude that severe arrhythmias are rarely observed during combined therapy with aminophylline and terbutaline in status asthmaticus.

Fluoroquinolone Antibiotics

The newer fluoroquinolones are a major advance in antimicrobial chemotherapy. They inhibit the supercoiling activity of the DNA gyrase enzyme, thus exerting their antibacterial action on DNA and RNA synthesis, resulting in a biphasic response and killing of susceptible organisms. The newer fluoroquinolones have an extended antimicrobial spectrum compared to their older congeners, and are highly active against most Gram-negative pathogens including the Enterobacteriaceae and Pseudomonas aeruginosa. While Staphylococcus aureus and coagulase-negative staphylococci are usually susceptible to the fluoroquinolones, streptococci are generally more resistant and enterococci are resistant. All of the newer fluoroquinolones may be administered orally and most of them have been administered parenterally. They are widely distributed in the body, attaining therapeutic concentrations in most tissues. All of the fluoroquinolones have long half-lives and may be administered once or twice daily. The fluoroquinolones have proved effective in many infections, including uncomplicated or complicated urinary tract infections, respiratory tract infections, gonorrhoea, bacterial gastroenteritis, and soft tissue infections due to Gram-negative organisms. In general, success has been notable in the management of Gram-negative infections but less so with Gram-positive infections. Resistance has occurred and is proving a problem with P. aeruginosa in some cystic fibrosis patients, but as yet no plasmid-mediated resistance has developed. Cross-resistance occurs between the quinolones but only rarely with other classes of antibacterial drugs. The fluoroquinolones have an excellent safety record and their adverse effects, which include hypersensitivity reactions, dizziness, headache, gastrointestinal disturbance and minor haematological abnormalities are usually mild and transient. However, the fluoroquinolones have been found to damage juvenile weight-bearing joints in animals and are therefore only to be used with caution in children; transient arthralgia has been reported in a cystic fibrotic teenager on long term ciprofloxacin therapy. All of the fluoroquinolones except ofloxacin are associated with a variable increase in the serum concentration of theophylline, warfarin and caffeine. Thus, the fluoroquinolones are an attractive option in the management of many infections. Cost and possible resistance, however, should counsel caution in their use, and may limit them to situations where a cheaper antimicrobial of equivalent efficacy is not available.

Circadian rhythm in theophylline disposition during a constant‐rate intravenous infusion of aminophylline in the dog

The disposition of theophylline in three dogs was determined during a 48‐h constant‐rate intravenous infusion of aminophylline. A systematic fluctuation in serum theophylline concentrations was observed over a 24‐h period, which appeared to be characteristic of a circadian rhythm. Neither assay variability nor fluctuations in the infusion pump rate could account for the observed variations in the serum concentrations. It was concluded that the changes in the theophylline concentrations were the result of a circadian rhythm in theophylline disposition.

The clinical significance of food-induced changes in the absorption of theophylline from Uniphyl tablets

To determine the effects of food on the absorption of theophylline from Uniphyl tablets (a once-daily sustained-release theophylline formulation), we performed a crossover evaluation in 20 adults with asthma. After 5 days of continuous dosing (at 6 pm), all patients received their regular Uniphyl dose under specified fasting conditions, and serum theophylline concentrations were measured sequentially during the following 24 hours. The patients' next Uniphyl dose was administered immediately after ingestion of a standardized high-fat meal, and theophylline concentrations were again measured during 24 hours. Five days later, the procedure was repeated in the opposite order. The patients' mean daily theophylline dose was 890.0 ± 229.2 mg. We found relatively minor, but in some cases statistically significant, differences in pharmacokinetic parameters between food and fasting administration. When Uniphyl was administered with food, bioavailability was increased by 10% ( p < 0.01), the time of maximum concentration occurred 3 hours later ( p < 0.01), and the minimum or “trough” theophylline concentration was 0.7 mg/L greater ( p < 0.01), as compared to administration while patients were fasting. There was no evidence of “dose dumping” after either food or fasting administration of Uniphyl, and there was no significant difference in the maximum theophylline concentration attained between the two dosing conditions. There was no evidence of a difference in therapeutic efficacy between the two dosing conditions. All patients tolerated the drug well throughout the trial.