Steady-state Serum Theophylline Concentrations Research Articles

Effect of low-dose macrolide antibiotics on theophylline disposition in pediatric patients

Low-dose macrolide antibiotics are administered for the treatment of certain chronic inflammatory sinopulmonary diseases (e.g., sinusitis and panbronchiolitis). Because 14-membered ring macrolide antibiotics administered at antimicrobial doses have been suggested to elicit a significant inhibitory effect on the hepatic metabolism of theophylline, we studied whether low-dose macrolide antibiotic therapy also evokes a clinically relevant alteration in the disposition of theophylline. The steady-state serum theophylline concentration and the urinary concentrations of theophylline and its metabolites [i.e., 1-methyluric acid (1MU), 3-methylxanthine (3MX), 1, 3-dimethyluric acid (DMU), and caffeine] were examined in nine stable asthmatic children who received both theophylline and lowdose erythromycin or clarithromycin (12.3±4.5mg/kg body weight/day) and in ten children who received theophylline alone.An immunoassay and high-performance liquid chromatography with ultraviolet detection (HPLC-UV) were used for serum and urinary drug assay, respectively. Results demonstrated no significant differences in serum theophylline concentration, the metabolic clearance of theophylline to its metabolites, and the renal clearance of theophylline between the two groups. In conclusion, the administration of low-dose macrolide antibiotics for the treatment of sinopulmonary diseases would not stipulate a dosage reduction of concomitantly administered theophylline in pediatric patients

Evaluation of three theophylline dosing equations for use in infants up to one year of age

To develop appropriate theophylline dosage recommendations for infants < or = 1 year of age, we evaluated the Nassif, Hendeles, and Hatzopoulos dosing equations in 75 infants who were receiving theophylline intravenously by continuous infusion. Postnatal age ranged from 1 to 52 weeks and postconceptional age from 33 to 93.8 weeks. Using each patient's measured theophylline clearance at steady state and the dose recommended by each of the three equations, we predicted a steady-state serum theophylline concentration for the three equations. The recommended theophylline dose and resultant serum concentrations differed significantly for the three equations. The Nassif, Hendeles, and Hatzopoulos equations resulted in 78.7%, 97.3%, and 93.8%, respectively, of serum theophylline concentrations between 5 and 15 mg/L. The Hendeles and Hatzopoulos equations tended to produce concentrations between 5 and 10 mg/L in the majority of infants; the Nassif equation generally resulted in values between 10 and 20 mg/L. Four percent of the calculated serum concentrations with the Nassif equation were > 20 mg/L. When a desired concentration of 10 mg/L was used in the Hatzopoulos equation, predictions of theophylline concentrations were consistently inflated. We conclude that the Hendeles equation ((0.008 x Postnatal age in weeks) + 0.21 = mg/kg per hour or mg/kg daily = (0.2 x Postnatal age in weeks) + 5) is preferred when intravenous theophylline therapy for apnea and bradycardia or for asthma is initiated. Regardless of the equation used to estimate an initial theophylline dose in infants < or = 1 year of age, serum theophylline concentrations should be monitored within 6 to 12 hours after the start of therapy.

A prospective evaluation of elevated serum theophylline concentrations to determine if high concentrations are predictable

purpose: To evaluate prospectively whether serum theophylline concentrations of 25 mg/L and greater were predictable (and presumably preventable) by use of basic pharmacokinetic calculations. design: Prospective study. patients: Fifty-five patients with a serum theophylline concentration of at least 25.0 mg/L were evaluated initially and if subsequent elevated theophylline concentrations occurred. interventions: The predicted steady-state serum theophylline concentration was calculated from the dosage rate divided by the predicted clearance to determine how many elevated concentrations (greater than 20 mg/L) were predictable. Predicted clearances were 0.04 L/kg/hour for normal subjects less than 70 years of age and 0.02 L/kg/hour for patients with congestive heart failure, chronic obstrucive pulmonary disease, or liver disease. Estimated clearances were determined and compared with predicted clearances. If patients did not have steady-state concentrations, additional calculations were made. main results: From 6,368 consecutive theophylline determinations, 69 (1.08%) samples from 55 patients were 25 mg/L or higher. Predictably high concentrations occurred in 23 of 33 (69.7%) fully evaluable cases. These concentrations occurred because of a failure to consider decreased elimination clearance from congestive heart failure, chronic obstructive pulmonary disease, or hepatic disease. Five fatalities occurred, and in two cases, theophylline appeared to contribute to the patient's death. Three other patients experienced syncope. The predicted elimination clearance of theophylline of 0.02 L/kg/hour was too high in eight patients over 70 years old with cardiac or pulmonary disease. Nursing and pharmacy oversights were identified as three patients were given two theophylline products simultaneously. conclusions: Most elevated theophylline concentrations are predictable (and preventable) by basic pharmacokinetic calculations. Patients experiencing elevated theophylline concentrations often had comorbid conditions and were greater than 60 years of age. The dosage rate of theophylline (mg/hour) can be estimated from predicted clearance (L/kg/hour) times desired steady-state serum concentration (mg/L).

Nifedipine alters serum theophylline levels in asthmatic patients with hypertension

The effect of nifedipine on serum theophylline levels in 13 female hypertensive patients having asthma on theophylline therapy has been investigated. Administration of a slow release theophylline product in a dose of 200 mg bidaily for 15 days provided a steady-state through serum theophylline concentration (11.2 +/- 2.7 micrograms/ml). After this period, 10 mg bidaily nifedipine was added to therapy and trough serum theophylline levels, pulmonary function tests and blood pressure measurements have been performed following 15 and 45 days of simultaneous use of theophylline and nifedipine. No change has been observed in serum theophylline level after 15 days of simultaneous use, however after 45 days, serum theophylline level was significantly lower (7.3 +/- 1 micrograms/ml). There were no changes in clinical responsiveness of either of these drugs.

Evaluation of Three Theophylline Dosing Methods in Pediatric Patients

Three methods used for individualizing theophylline dosing were prospectively evaluated in 34 pediatric patients to compare the methods' ability to accurately predict steady-state serum theophylline concentrations (STCs) from non-steady-state data. Methods evaluated included a Bayesian weighted sum of squares regression program, an algebraic method developed by Chiou, and a commonly used population-based pediatric dosing algorithm. An expanded retrospective evaluation was also done to further compare the Bayesian and Chiou methods. Patients (aged 1-11 y) admitted to the hospital for acute bronchospasm refractory to inhaled beta agonists and with physician's orders to receive intravenous aminophylline were eligible for participation. Study patients received a 6-mg/kg loading dose aminophylline, followed by a 0.8-1.0 mg/kg/h constant aminophylline infusion. STCs were obtained 0.5 and 5.5 hours postinfusion. Subjects were randomized to one of three dosing method groups (Bayesian, Chiou, or pediatric algorithm). Doses were calculated using the assigned method to attain a target steady-state STC. Predictions from each dosing method were compared with actual serum concentrations for bias and precision. Additionally, analysis of fit-to-the-line-of-identity for predicted versus observed STCs was evaluated for each method. Precision of methods was also compared with regard to their ability to predict within 20 percent of their observed steady-state STC. Results from the prospective evaluation showed no significant difference between the three methods tested. Predicted STCs fell within 20 percent of their observed steady-state concentrations for 18 percent (2/11) of patients in the algorithm group, and 45 percent (5/11) of patients in the Chiou group and 17 percent (2/12) of the patients in the Bayesian group met this criterion. Retrospective analysis of all 34 patients demonstrated that the Bayesian and Chiou methods had similar bias and precision and no statistical difference was found between them. The results from this evaluation suggest that the pediatric dosing algorithm is equivalent in predictive bias and precision to the Bayesian and Chiou methods as well as in its ability to identify doses that result in steady-state STCs within 20 percent of their target values. Given the relative inaccuracy of these methods, cautious use of these techniques is recommended when evaluating non-steady-state STCs obtained from children during the acute stages of reactive airway disease.

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.

Dose-dependent kinetics of theophylline

This article reviews the background and current status of knowledge regarding the nonlinear kinetics of theophylline. The metabolic and renal mechanisms of nonlinearity and their significance with respect to single and multiple doses of theophylline are reviewed. Major implications of nonlinearity in theophylline kinetics with respect to bioavailability studies, predictions of steady-state serum theophylline concentrations, and dosage adjustments at steady state are presented in detail.

Conversion from intravenous to sustained-release oral theophylline in pediatric patients with asthma.

A method for converting pediatric patients from intravenous aminophylline to sustained-release oral theophylline was evaluated in eight asthmatic children. The administration of Theo-Dur tablets two hours before discontinuation of a continuous intravenous aminophylline infusion resulted in a peak rise of 5.6 +/- 3.0 micrograms/ml over steady-state serum theophylline concentrations. This method of conversion is acceptable in children with equivalent oral and intravenous doses of theophylline and serum theophylline concentrations less than 15 micrograms/ml. Children with steady-state theophylline concentrations greater than 15 micrograms/ml are likely to develop concentrations exceeding the therapeutic range using this conversion method.

The effect of phenobarbital on theophylline disposition in children with asthma

The disposition of theophylline was examined in seven children with asthma on two occasions before and on one occasion after chronic phenobarbital dosing (2 mg/kg/day). There was little intrapatient variability in apparent theophylline clearance between the two baseline assessments (0.081 versus 0.073 L/hr/kg). After 19 days of phenobarbital therapy, there was a significant increase in apparent theophylline clearance (0.104 versus 0.077 L/hr/kg), accompanied by a 30% decrease in the mean steady-state serum theophylline concentration (12.0 versus 8.4 μg/ml). The inducing effect of phenobarbital on theophylline metabolism may require theophylline dosage adjustment in patients with asthma who receive both drugs concurrently to maintain a given average steady-state theophylline concentration.

Rapid estimation of serum theophylline clearance in children with acute asthma.

Serum theophylline clearance was estimated prior to reaching steady state in 29 asthmatic children, aged 1-14 years, using methods described by Chiou et al. and Vozeh et al. Comparison of the estimated clearance by the Vozeh method (0.094 +/- 0.005 L/kg/h) did not differ significantly from that estimated by the Chiou method (0.094 +/- 0.005 L/kg/h). Neither estimate of serum theophylline clearance differed significantly from the calculated clearance at steady state (0.092 +/- 0.006 L/kg/h). Linear correlations between predicted and observed serum theophylline clearances were found for both the Chiou (p = 0.002, r = 0.54) and Vozeh (p = 0.02, r = 0.49) methods. Estimates of the steady-state serum theophylline concentrations by the Vozeh method (10.32 +/- 0.56 mg/L) and the Chiou method (10.28 +/- 0.52 mg/L) did not differ significantly from each other or from the observed steady-state serum theophylline concentration (10.54 +/- 0.48 mg/L). A linear correlation between predicted and observed serum theophylline concentrations was found for both the Chiou (p = 0.02, r = 0.43) and Vozeh (p = 0.001, r = 0.57) methods. These results suggest that either method of estimating serum theophylline clearance can be used to rapidly individualize therapy in children with acute asthma.

Dose-dependent kinetics of theophylline in adults with pulmonary diseases.

The incidence of dose-dependent pharmacokinetics of theophylline was retrospectively investigated in adults with pulmonary disease receiving continuous aminophylline infusions. Twenty-one of 180 successive admissions to medical intensive care units with a diagnosis of chronic obstructive pulmonary disease, asthma, or respiratory failure met the criteria of two steady-state serum theophylline concentrations on two different doses. Of these, 14 patients continued to smoke, whereas 7 had never smoked or had stopped greater than 1 year prior to admission. No statistical difference existed between the mean systemic clearances of theophylline at the two different doses, using either total body weight or ideal body weight. Only 1 of the 21 patients met the criteria for dose dependency of a greater than or equal to 50% reduction in clearance with dosage increase. Six of eight subjects with decreased clearance on the higher dose were nonsmokers. In contrast, all nine with augmented clearance following dosage increase were smokers. Four were considered to have proportional changes. In general, nonsmoking patients tended to have greater changes in serum theophylline concentration than in dosage. Conversely, smoking patients demonstrated smaller changes in concentration. The relationship of smoking status and dose-dependent theophylline elimination is discussed.

Theophylline

This study was undertaken to evaluate a method of prospectively estimating appropriate aminophylline infusion rates in acutely ill, hospitalized patients with bronchospasm. Steady-state serum theophylline concentrations (Css), clearances (Cl), and half-lives (t1/2) were estimated by the Chiou method using serum concetrantions obtained 1 and 6 h after the start of a constant-rate intravenous aminophylline infusion in 10 male patients averaging 57 years of age. Using an enzyme-multiplied immunoassay (EMIT) system for theophylline analysis, pharmacokinetic estimations were excellent for Css (r = 0.9103, p less than 0.01) and Cl (r = 0.9750, p less than 0.01). The mean estimation errors were 9.4% (range 0.8-21.5) for Css and 12.3% (range 1.3-28.0) for Cl. There was no correlation between patient age and Cl. This method is useful for rapidly individualizing aminophylline therapy in patients with acute bronchospasm.

The Effects of Cimetidine on Theophylline Pharmacokinetics at Steady State

The effects of cimetidine on the pharmacokinetics of theophylline were studied in seven healthy subjects at steady state after oral dosing. Aminophylline (200 mg) was administered every six hours for three days (A), then aminophylline (200 mg) and cimetidine (300 mg) were administered every six hours for seven days (A-C). Multiple serum theophylline determinations were made after the last dose on each regimen using an enzyme immunoassay. Cimetidine decreased the apparent total body clearance of theophylline an average of 29 percent (range: 18-47 percent) from 39.5 +/- 11.7 to 28.1 +/- 3.4 ml/hr/kg (p less than 0.02). There was no significant change in the volume of distribution; however, the terminal half-life increased from 7.3 +/- 1.5 to 10.1 +/- 2.1 hr (p less than 0.01) during A and A-C, respectively. The increase in the average steady state serum theophylline concentration of 34 percent (range: 23-87 percent) observed in our subjects may have important clinical implications.

Conversion from intravenous to oral dosing using sustained-release theophylline tablets.

Theophylline total body clearance was determined in asthmatic patients, from steady-state serum theophylline concentrations, measured during a constant-rate, intravenous aminophylline infusion. Theo-Dur dosing rates were calculated from the product of theophylline total body clearance and the desired steady-state theophylline concentration. After stopping the aminophylline infusion, oral doses of Theo-Dur were given every 12 hours. Blood samples were obtained 1, 3, 6,9, and 12 hours after the first oral dose and 12 hours after the second oral dose. Patients were evaluated for compliance and theophylline toxicity after receiving Theo-Dur for one week. Total body clearances and theophylline dosing rates varied more than threefold. The difference between the intravenous steady-state serum concentration and the average oral serum concentration was 1.2 micrograms/ml in patients with similar oral and intravenous dosing rates. The difference between peak and trough serum theophylline concentrations after the first oral dose averaged 7.8 micrograms/ml. Eight of nine patients evaluated after leaving the hospital were compliant, as determined from a tablet count during a clinic visit. Serum theophylline concentrations, determined 12 hours after the last Theo-Dur dose, averaged 10.4 micrograms/ml for the compliant patients.

Effect of erythromycin on theophylline clearance in asthmatic children

Fifteen asthmatic children (mean age = 14.5 years) who required daily theophylline therapy were studied for effect of erythromycin ethyl-succinate on theophylline clearance. After a one week course of EES, there was 25.8 +/- 18.4% reduction in theophylline clearance rate (P less than 0.001), and a concomitant elevation in steady-state serum theophylline concentration of 40.0 +/- 35.3% (P less than 0.01). Three subjects reached serum theophylline concentrations greater than 20 micrograms/ml. Patients receiving therapeutic doses of theophylline are at considerable risk of theophylline toxicity if EES is co-administered.

Rapid prediction of steady-state serum theophylline concentration in patients treated with intravenous aminophylline.

In 15 acutely ill asthmatics the steady-state serum theophylline concentration was predicted by the method of Chiou et al. using two serum concentration measurements obtained 1 and 5 h after starting a continuous infusion of aminophylline. Two theophylline assays with different precision characteristics were compared. With a precise HPLC-assay the prediction was excellent: prediction error (predicted minus measured concentration) = -0.22 +/- 1.97 mg/l (mean +/- SD); r = 0.922. When the theophylline concentration was determined by a rapid enzyme immunoassay of lower precision, but convenient for clinical use, the prediction was less accurate (prediction error = 0.58 +/- 3.88, r = 0.852). However, it was still clearly superior to dosing recommendations based on the population average of theophylline clearance, even after taking into consideration the effect of smoking, congestive heart failure and cirrhosis (prediction error = 3.62 +/- 13.36, r = 0.560). As employed in this study, the method may be useful in helping the physician to choose the optimal dose in severely ill asthmatics.

Dose-dependent elimination kinetics of theophylline.

There are an increasing number of clinical and experimental studies appearing in the literature suggesting that the elimination kinetics of theophylline may be dose-dependent in man. Evidence of nonlinearity includes observations that steady-state serum theophylline concentrations may increase disproportionately with increases in dose and that the elimination half-life of theophylline after multiple doses is longer than after single doses. Theophylline is apparently eliminated by parallel Michaelis-Menten and first-order kinetics. Although no specific studies of theophylline metabolism have been carried out to determine the causes of nonlinearity, it would appear that 1-demethylation of theophylline is a potentially saturable metabolic pathway. Dietary methylxanthines or their metabolites may influence the rate of elimination of theophylline and contribute to the causes of nonlinearity. Until the elimination kinetics of theophylline have been studied in more detail as a function of dose, it would seem prudent to increase doses of theophylline cautiously to minimise the risks of adverse side effects which might be associated with unexpected accumulation of theophylline.

Reliability of theophylline clearance in determining chronic oral dosage regimens

Predicted and approximated mean serum theophylline concentrations were compared to assess the feasibility of using theophylline clearance, calculated from the intravenous steady-state serum theophylline concentration, to determine appropriate oral dosage requirements. Ten patients with reversible airway disease (age 7 to 64 years) received theophylline (as Aminophylline USP) by constant i.v. infusion. Theophylline clearance was calculated for each patient from steady-state serum theophylline concentrations determined from blood samples obtained after a least 48 hours of constant theophylline infusion. Aminophylline USP tablets were then adminstered orally. Blood levels measured at peak and trough times following oral theophylline administration were used to calculate an approximate mean serum theophylline concentration. The relationship between predicted and approximated mean serum theophylline concentrations was calculated and analyzed by orthogonal least square regression line. Serum theophylline concentrations ranged from 5.1 microgram/ml to 20.1 microgram/ml, and clearances ranged from 0.03 liter/kg/hr to 0.09 liter/kg/hr. During oral therapy, the maximum concentration ranged from 10.4 microgram/ml to 23.8 microgram/ml, while the minimum ranged from 6.5 microgram/ml to 15.2 microgram/ml. The difference between predicted and approximated mean serum concentrations was within +/-1.6 micrograms/ml in all cases. The study indicates that the theophylline clearance calculated from i.v. infusion data can be used to determine appropriate oral dosage requirements.