A clinical and pharmacokinetic basis for the selection and use of slow release theophylline products

In order to achieve the greatest chance for maximum benefit from theophylline in the management of chronic asthma, the serum concentration should be maintained in the therapeutic range of 10 to 20 micrograms/ml. Conventional rapid release formulations produce excessive fluctuations in serum concentrations that can result in variability in clinical response between doses. In contrast, slow release formulations have the potential to achieve relatively constant serum concentrations with 12-hour dosing intervals, thus providing around-the-clock stabilisation of the hyper-reactive airways that characterise chronic asthma. Furthermore, the decreased frequency of dosing with these formulations can improve patient compliance. However, significant differences in rate and extent of absorption exist between the available formulations. Single-dose bioavailability studies comparing a slow release product with an oral solution or plain uncoated tablet in a crossover design permit examination of the rate and extent of absorption. Comparison of a slow release product with an oral reference following multiple doses at steady-state permits examination of the extent but generally not rate of absorption. The mean fraction absorbed-time profile, calculated from a modification of the Wagner-Nelson equation, is a process-independent method of comparing rates of absorption of different products after single doses. A prospective study in 14 children with chronic asthma has demonstrated that this modified equation, when rearranged to iteratively solve for serum concentrations, can accurately predict steady-state serum concentrations for different dosing intervals in patient populations with different rates of elimination. When slow release products are compared in this manner at 8- or 12-hour dosing intervals for patients with slow elimination, clinically relevant differences between brands are not apparent. However, in patients with rapid elimination, i.e. children, cigarette smokers, and 25% of non-smoking adults, application of this method shows that only some formulations (i.e. 'Slo-Bid Gyrocaps' and 'Theo-Dur', which is also marketed under different brand names names such as 'Sustaire', 'Pulmi-Dur' and 'Theolin Retard') can maintain serum concentrations within the therapeutic range for an entire 12-hour dosing interval. More rapidly absorbed slow release products must be administered at 8-hour dosing intervals in patients with rapid elimination, despite promotional claims to the contrary. Current products promoted for once-a-day administration are clinically inadequate because of incomplete and erratic absorption, and/or excessive serum concentration fluctuations.(ABSTRACT TRUNCATED AT 400 WORDS)     

A review of clinical use of theophylline in acute asthma: factors influencing kinetic disposition and drug interactions

The clinical use of theophylline as a first line bronchodilator has declined during the last two decades. However, many therapeutic mechanisms for bronchial asthma have been discovered, and recent studies have suggested that theophylline therapy can play a beneficial role in the management of both chronic stable asthma and exacerbated disease treated in the emergency setting. In this article, the author describes the pharmacokinetics of theophylline and the major factors that influence the kinetics of the drug, such as physiopathological conditions and interactions with concomitantly administered drugs. Practical guidelines are then given on how to achieve optimal serum levels when planning theophylline therapy, including use of nomograms to decide loading and maintenance doses for nonsmoking adult asthmatic patients and adjustments for asthmatic patients with complications or on other drugs that may alter the kinetic disposition of theophylline.     

Acute and subacute toxicities of theophylline are directly reflected by its plasma concentration in dogs

The purpose of this study was to evaluate the relationship between acute and subacute toxicity and blood levels of theophylline in dogs. Theophylline was administered intravenously into dogs once (at doses of 50, 100 and 150 mg/kg) or for 4 weeks (at doses of 20, 35 and 70 mg/kg/day). In the single dose toxicity study, by increasing the dose of theophylline, plasma concentration increased and the severity of toxic symptoms were intensified. After a single dosing of theophylline, accentuated heart rate and vomiting were observed at a concentration of more than 67 micrograms/ml, and excitement, spasm and hyperpnea were observed at more than 130 micrograms/ml. Animals died after tonic convulsion at 180 micrograms/ml. In the repeated dose toxicity study, the plasma concentration of theophylline increased dependent on dosage, and was not affected by repeated dosing. Even under these conditions, the toxic symptoms were quite similar to those of the single dose, except for an additional decrease in movement, body weight reduction and myocardial lesion. These present results suggest that the severity of theophylline toxicity is dependent on its plasma concentrations rather than accumulated dosages. The blood concentration of theophylline-treated patients should be maintained within the therapeutic range in order to diminish risk.     

Characteristics of vomiting associated with acute sustained release theophylline poisoning: implications for management with oral activated charcoal

Vomiting in acute theophylline toxicity has assumed increased clinical importance since the introduction of multiple dose activated charcoal therapy. We performed a prospective study of 26 patients with acute overdose of sustained release theophylline to characterize vomiting, and its possible interference with the acceptance of activated charcoal. Twenty five of 26 patients vomited. The duration of vomiting correlated with both peak serum theophylline concentrations (p less than 0.001) and the duration of theophylline toxicity (p less than 0.001). Vomiting extended over 63% of the drug's absorptive phase (the time interval between ingestion and the peak level) and 49% of the elimination phase (the time interval between the peak level and decrease of theophylline level to less than 20 mcg/ml). Patients with peak serum theophylline concentrations less than 70 mcg/ml were able to accept larger amounts of activated charcoal than patients with serum theophylline concentrations greater than 70 mcg/ml (113 +/- 15 gms vs. 57 +/- 24 gms, p less than 0.05). Vomiting in acute sustained release theophylline toxicity is protracted, and limits the use of activated charcoal especially in patients with severe acute theophylline poisoning.     

Nocturnal asthma uncontrolled by inhaled corticosteroids: theophylline or long-acting beta2 agonists?

Asthma is an inflammatory disease of the airways that is frequently characterised by marked circadian rhythm. Nocturnal and early morning symptoms are quite common among patients with asthma. Increased mortality and decreased quality of life are associated with nocturnal asthma. Although numerous mechanisms contribute to the pathophysiology of nocturnal asthma, increasing evidence suggests the most important mechanisms relate to airway inflammation. According to international guidelines, patients with persistent asthma should receive long term daily anti-inflammatory therapy. A therapeutic trial with anti-inflammatory therapy alone (without a long-acting bronchodilator) should be assessed to determine if this therapy will eliminate nocturnal and early morning symptoms. If environmental control and low to moderate doses of inhaled corticosteroids do not eliminate nocturnal symptoms, the addition of a long-acting bronchodilator is warranted. Long-acting inhaled beta2 agonists (e.g. salmeterol, formoterol) are effective in managing nocturnal asthma that is inadequately controlled by anti-inflammatory agents. In addition, sustained release theophylline and controlled release oral beta2 agonists are effective. In patients with nocturnal symptoms despite low to high doses of inhaled corticosteroids, the addition of salmeterol has been demonstrated to be superior to doubling the inhaled corticosteroid dose. In trials comparing salmeterol with theophylline, 3 studies revealed salmeterol was superior to theophylline (as measured by e.g. morning peak expiratory flow, percent decrease in awakenings, and need for rescue salbutamol), whereas 2 studies found the therapies of equal efficacy. Studies comparing salmeterol to oral long-acting beta2 agonists reveal salmeterol to be superior to terbutaline and equivalent in efficacy to other oral agents. Microarousals unrelated to asthma are consistently increased when theophylline is compared to salmeterol in laboratory sleep studies. In addition to efficacy data, clinicians must weigh benefits and risks in choosing therapy for nocturnal asthma. Long-acting inhaled beta2 agonists are generally well tolerated. If theophylline therapy is to be used safely, clinicians must be quite familiar with numerous factors that alter clearance of this drug, and they must be prepared to use appropriate doses and monitor serum concentrations. Comparative studies using validated, disease specific quality of life instruments (e.g. Asthma Quality of Life Questionnaire) have shown long-acting inhaled beta2 agonists are preferred to other long-acting bronchodilators. Examination of costs for these therapeutic options reveals that evening only doses of long-acting oral bronchodilators are less expensive than multiple inhaled doses. However, costs of monitoring serum concentrations, risks, quality of life and otheroutcome measures must also be considered. Long-acting inhaled beta2 agonists are the agents of choice for managing nocturnal asthma in patients who are symptomatic despite anti-inflammatory agents and other standard management (e.g. environmental control). These agents offer a high degree of efficacy along with a good margin of safety and improved quality of life.     

Therapeutic monitoring of theophylline. Rationale and current status

Theophylline has been demonstrated to be a useful agent in the therapy of chronic asthma. Its use must be tempered with knowledge of its adverse effects and that these effects are related primarily to serum concentration. Accordingly, it is mandatory to monitor serum theophylline concentrations on a regular basis with any patient receiving maintenance therapy with theophylline. It is also necessary to recognise the potential side effects of theophylline therapy, and when such a patient displays symptoms of vomiting, headache or seizures, serum theophylline concentration must be checked even if a recent concentration was within the therapeutic range. The means for monitoring theophylline concentrations are now available even to the average physician who does not have immediate access to a laboratory that can provide timely serum theophylline determinations.     

Theophylline for the treatment of bronchial asthma: present status

Current Japanese asthma guidelines recommend theophylline as an additional regimen to inhaled beta-agonists (on demand use) and inhaled corticosteroids (beclomethason dipropionate 200-1200 micrograms/day or fluticason propionate 200-800 micrograms/day) for patients whose asthma is not controlled completely. Similar recommendations are made in the International Consensus Report on Diagnosis and Treatment of Asthma. Recent advances in the understanding of its actions, especially regarding the antiinflammatory and immunomodulatory effects of low doses of theophylline, encourage its appropriate use in asthma treatment. Furthermore, asthma and chronic obstructive pulmonary disease (COPD) are considerably common diseases, and the economic benefits associated with the use of a relatively inexpensive, once or twice daily oral drug (intravenous infusion, if necessary) could be of importance. But, because of its narrow therapeutic range, dosage must be individualized in order to optimize the treatment based on the measurement of theophylline concentration in serum. Theophylline is an old medication with new forms. When used effectively and safely, it can have significant clinical benefits for patients. This paper intends to review the effectiveness of theophylline--historically and contemporarily.     

Use of serum theophylline level as a guide to optimum therapy in patients with chronic obstructive lung disease

Blood and urine samples were collected simultaneously with measurements of pulmonary function at 2-hour intervals for 8 hours after oral administration of short-acting (SAT) and long-acting theophylline (LAT) preparations in 15 patients with stable chronic obstructive lung disease (COLD) on long-term maintenance theophylline therapy. The relationship between pulmonary function tests, serum theophylline level, plasma and urinary adenosine 3'5' cyclic monophosphate (cAMP) was examined. The highest forced expiratory volume in one second FEV1 was obtained with STL of 12.8 micrograms/ml +/- 5.21 SD and 9.14 micrograms/ml +/- 6.15 (P less than .05) after administration of SAT and LAT, respectively. A further increase in serum theophylline level (STL) offered no therapeutic benefit, and, in fact, was associated with a fall in FEV1 in many instances. Plasma or urinary cAMP measurements did not correlate with STL. STL at which the best pulmonary function is achieved is quite variable in patients with COLD on maintenance theophylline therapy, is frequently less than 10 micrograms/ml, and can be determined only by repeated measurements of pulmonary function at different STL. Therefore measurements of STL are of limited value in guiding treatment with theophylline.     

Differential pharmacokinetics of theophylline in elderly patients

The clinical use of theophylline as a first-line bronchodilator has declined during the last two decades. However, in many clinical settings, such as an emergency bronchial asthma attack, theophylline may have a first-line role, in combination with beta(2)-adrenoreceptor agonists and corticosteroids, for improving the asthmatic status. Furthermore, many therapeutic mechanisms of theophylline for bronchial asthma have been reported, and recent studies have suggested that theophylline therapy may have a beneficial role in the management of chronic stable asthma as well as exacerbated disease. However, theophylline has a low therapeutic index because the bronchodilation it produces has a linear relationship with logarithmic increases in serum concentration for the therapeutic range of 5-20 mg/L. Thus, the knowledge of its basic pharmacokinetics and the factors that can alter its clearance is clinically relevant for physicians. Especially when used in elderly asthmatic patients, dosage adjustment of theophylline is a requisite since the elderly have several risk factors that may increase the plasma theophylline level, such as reduced clearance, various underlying diseases and multiple coadministered drugs. After theophylline treatment has been initiated, therapeutic drug monitoring is required.     

Evaluation of the effect of nonlinear kinetics on dosage adjustments of theophylline

The pharmacokinetics of theophylline at two different dosage levels were studied in six adult volunteers. The subjects were allowed to reach steady-state serum concentrations of theophylline after 7 days of administration of a sustained-release oral product. There was a statistically significant decrease (p = 0.03) in the total body clearance (TBC) of theophylline at the higher dosage level. At a daily dose of 10.6 mg/kg/day, the mean TBC was 0.76 ml/min/kg, whereas at a dose of 15.7 mg/kg/day the TBC averaged 0.68 ml/min/kg. For two of the subjects, a linear increase in serum concentrations occurred with increasing doses. The remaining four subjects showed a saturation of the elimination processes at the higher dosage. The apparent maximum velocity (Vmax) calculated in these subjects averaged 2,923 mg/day. The mean Michaelis-Menten constant (Km) was 23.70 micrograms/ml. Computer-generated serum concentrations produced by a linear increase in doses predicted toxic concentrations of theophylline in two of the six subjects. The results suggest caution in employing a linear model for the individualization of theophylline therapy.     

Exercise, induced bronchospasm in asthmatic children as a dose-response model for theophylline

Efficacy and dose-response activity of oral theophylline were evaluated in 21 asthmatic children, using inhibition of exercise-induced bronchospasm (EIB) as a therapeutic marker. An aqueous theophylline suspension free of alcohol, sugar, and dye was found to be effective for prevention of EIB when given in usual maintenance doses of 4 to 6 mg/kg every 6 hours for 3 weeks, following single loading doses of 8 mg/kg. Pulmonary function measurements (FEV1, FEF25%-75%, PEFR) following standardized treadmill exercise stress were signifcantly improved during both acute and chronic theophylline administration compared to pre-drug control evaluations. There were no signs of developing tolerance to theophylline. The drug produced at least 50% inhibition of EIB in 16 to 21 patients treated. Individualized adjustment of maintenance dosage resulted in optimal theophylline serum concentrations of 10 to 18 microgram/ml in 17 patients. Signs of drug toxicity were observed only when serum levels exceeded 20 microgram/ml following loading doses in 6 patients. Although some children required higher maintenance dosage because of variability in theophylline pharmacokinetics, no child experienced adverse effects after dosage adjustment. Serum half-life ranged between 86 and 351 minutes (mean, 259 minutes); mean peak serum concentration of theophylline after 3 weeks of treatment was 14.9 microgram/ml.     

Steady-state pharmacokinetics of rufloxacin in elderly patients with lower respiratory tract infections.

The pharmacokinetics of rufloxacin, after repeated doses, was evaluated in 12 elderly patients with lower respiratory tract infections. Patients were given a single loading dose of 400 mg on the first day of treatment and single daily maintenance doses of 200 mg for the next 6-9 days. Serum concentrations of the drug were determined by high-performance liquid chromatography (HPLC) at regular intervals during treatment and fitted to a one-compartment open model for repeated doses. The maximum serum concentration after the first dose was 6.46 +/- 1.06 (mean +/- SEM) micrograms/ml and was reached in 4.3 +/- 0.8 h after the first administration. The elimination half-life was 28.7 +/- 4.1 h. The area under the serum levels-time curve from 0 to 24 h was 103 +/- 14 micrograms/h/ml after the first dose. On the last day of observation it increased to 155 +/- 28 micrograms/h/ml, with a mean extent of accumulation of 2.3 +/- 0.3 times. The elimination half-life was comparable to those in other studies in healthy young subjects, while plasma levels were about 80% higher. These results suggest that in elderly patients elevated drug concentrations may be reached in the serum. Although no untoward reactions related either to the drug concentration in serum or the dose have been noted with rufloxacin, this patient population should nevertheless be monitored carefully for adverse effects.     

Serum theophylline levels in asthmatic children receiving sustained-release theophylline tablets

Serum theophylline levels produced in asthmatic children by sustained-release theophylline tablets (TheoDur) were studied. Nineteen patients received for 14 days a dose of 5.5 to 13.1 mg/kg (mean 9.1 mg/kg) of amhydrous theophylline (as sustained-release TheoDur tablets) every 12 hours. Theophylline serum levels were assayed, by cation-exchange high-performance liquid chromatography, immediately before and at 4, 6 and 10 hours after the first day-five dose. Symptoms of asthma and theophylline toxicity were recorded. Mean peak-trough difference for the 6-to-10-years age group (4.5 +/- 1.6 microgram/ml) was not significantly different than that of the 11-to-17-year age group (5.2 +/- 3.2 micrograms/ml) (p greater than 0.1). Therapeutic serum theophylline levels (8 to 20 micrograms/ml) were maintained throughout a 12-hour period in 12 patients. Two patients had side effects possibly attributable to theophylline. Four patients reported asthamtic symptoms on two or more evenings; none required emergency treatment. The study suggests that sustained-release theophylline tablets administered every 12 hours can maintain therapeutic serum levels in children.     

Increased theophylline concentrations secondary to ciprofloxacin

An 82-year-old man with a history of myasthenia gravis and heart failure was admitted to the hospital with respiratory failure. Aminophylline and eventually theophylline therapy were initiated to improve respiratory status. During the hospital stay, the patient developed a resistant pseudomonal pneumonia. After failure with conventional antibiotics, ciprofloxacin was initiated because of favorable sensitivity and the planned avoidance of aminoglycoside therapy. Seventy-two hours after initiation of ciprofloxacin, the patient's theophylline level rose from a steady-state baseline of 9.8 micrograms/ml to 34.7 micrograms/ml. After the theophylline dose was reduced by approximately 67 percent, the patient's theophylline serum concentration returned to baseline (10 micrograms/ml). Until more data concerning the interaction of theophylline and ciprofloxacin are available, we recommend close monitoring of theophylline serum concentrations in patients receiving concomitant ciprofloxacin.     

Evaluation of the effect of variability in the volume of distribution of theophylline on the predictability of the iterative and the Chiou methods using computer simulations

The effect of variations in the volume of distribution on the precision of the ability of two methods--the Chiou and the iterative--to predict the total body clearance (TBC) of theophylline was evaluated utilizing computer simulations. Pharmacokinetic data [volume of distributions (V), elimination constants (k)] measured in a group of 55 adult bronchitic patients were utilized to conduct the simulations. An average V of 0.45 L/kg was utilized to calculate TBC with the Chiou and the iterative methods. Separate simulations were conducted utilizing initial (C1) serum concentrations of 2 and 10 micrograms/ml. At the C1 = 2 micrograms/ml condition, the iterative method was statistically significantly more precise (mean squared prediction error, 379.5 vs. 508.5). There were no differences when the initial serum concentration was 10 micrograms/ml under the simulated conditions. At the lower initial condition (C1 = 2) the mean prediction error was 62.3 and 54.9% for the Chiou and the iterative methods, respectively, and it ranged from 0 to 477%. It is recommended that caution be utilized when theophylline doses are individualized using these methods.     

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.     

Acute effects of short-term subcutaneous terbutaline on theophylline disposition

Summary Theophylline and subcutaneous terbutaline are frequently used concurrently in the management of acute asthma. Recent evidence demonstrating a reduction in theophylline serum concentrations during concomitant oral terbutaline therapy prompted our evaluation of subcutaneous terbutaline's effect on theophylline pharmacokinetics. Using a randomized, placebo controlled, crossover design, the disposition of a single oral theophylline dose (7 mg/kg) was studied in eight healthy, adult males before and after repeated subcutaneous administration of terbutaline (0.25 mg). Two-way analysis of variance revealed no significant difference in elimination rate constant (ke), area under the concentration-time curve (AUC), or apparent oral clearance (CL/F) of theophylline following terbutaline administration. These results indicate that subcutaneous administration of terbutaline does not alter the pharmacokinetics of single, oral doses of theophylline in adults.     

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.     

Kinetic alteration of theophylline at therapeutic doses

OBJECTIVE: To report a case of a patient diagnosed as having bronchial asthma treated with intravenous infusion of theophylline, who presented an episode of altered theophylline metabolism with a disproportionately increase in serum concentrations together with tachycardia and symptoms of intoxication. CASE SUMMARY: A 51-year-old white woman with a history of bronchial asthma was treated with intravenous infusion of theophylline in an Intensive Care Unit. Bayesian pharmacokinetic approach for dose individualization was done and linear kinetics of theophylline were observed. At therapeutic dose, an alteration of theophylline metabolism had happened, that induced a decrease on the theophylline clearance coinciding with an increase of dose. The serum concentration at this dose was 23.9 microg/ml and this was associated with symptoms compatible with intoxication by theophylline. All factors that could change theophylline elimination were analyzed. A possible drug interaction, hypothyroidism and cardiac failure were ruled out. Clinical hepatic insufficiency was not determined, but an increase of hepatic enzymes was observed. Theophylline infusion was suspended during 5 hours, the serum levels returned to therapeutic values and hepatic enzymes returned to their initial values. DISCUSSION: Episodes of anormal theophylline kinetics may occur, even with doses and serum concentrations considered to be therapeutic, especially in critically ill patients or those whose physical condition has deteriorated. This makes it necessary to carry out therapeutic drug monitoring of theophylline in this group of the population.     

Relationship between serum and saliva theophylline levels in patients with cystic fibrosis.

Theophylline levels in stimulated and unstimulated mixed saliva were compared with total and free (unbound) serum theophylline levels in 11 outpatients with cystic fibrosis (CF) who were using theophylline regularly. Stimulated saliva from CF patients predicted both total and unbound serum theophylline concentrations to within +/- 1 microgram/ml in 53.3 and 80.0%, respectively, of the samples examined. In addition, the total serum levels from CF patients could be used to predict unbound serum concentrations to within +/- 1 micrograms/ml in 100% of the cases examined. Furthermore, it was observed that prediction equations derived in a previous study with asthmatics employing identical methodology would allow both unbound and total serum theophylline levels to be predicted from saliva levels in CF patients with a degree of accuracy and precision that was approximately equal to or slightly better than the results obtained using prediction equations derived in other CF patients. These results indicate that saliva levels allow predictions of the unbound serum theophylline levels with greater accuracy and precision than they predict total serum theophylline levels. In addition, total serum levels can be used to reliably predict unbound serum levels. The use of mixed stimulated saliva is recommended as a reliable noninvasive method for monitoring unbound serum theophylline levels. The therapeutic range for saliva, which corresponds to the accepted total serum concentration range of 10-20 micrograms/ml, is approximately 5.55-11.3 micrograms/ml.