Extended-release Theophylline Research Articles

Pharmacokinetics of a modified, compounded theophylline product in dogs

Theophylline is a commonly used bronchodilator drug for treatment of chronic canine bronchitis, but no formulations validated in dogs are currently available. An oral, modified and compounded theophylline product (MCT), which could fulfil this need, is available through a USP-compliant, veterinary compounding pharmacy; however, its pharmacokinetic properties are unknown. The aim of this study was to determine the pharmacokinetics of MCT. Plasma drug concentrations were measured in seven healthy, fed dogs after single doses of intravenous aminophylline (8.6mg/kg theophylline equivalent) and oral MCT (10mg/kg). Systemic bioavailability of the MCT was 96.2±32.9%. MCT times to maximum concentration, mean absorption time and terminal half-life were 8.85±3.63, 6.95±3.42, and 8.67±1.62hr, respectively. Based on simulations of 10mg/kg and 12-hr dosing, steady-state plasma theophylline concentrations are expected to exceed the minimum therapeutic concentration for 71.7±35.6% of the dosing interval. Overall, the MCT product investigated showed similar pharmacokinetic characteristics compared to previously validated extended-release theophylline products. An oral dose of 10mg/kg q 12hr is likely an appropriate dosage to begin therapy; however, therapeutic drug monitoring may be warranted because of inter-individual variation.

Preparation of Extended-Release Theophylline for Gastric Tube Administration Significantly Impairs Gradual Resorption

Background: Although Extended Release (ER) dosage forms are not suitable for administration via Nasogastric Tube (NGT), they are used in critically ill patients. The aim of this study is to compare pharmacokinetics of intact and crushed ER theophylline capsules and tablets. Methods: Open-label, randomized controlled trial with two parallel groups was conducted on 10 healthy volunteers. They were randomized into Theo plus® 300 (ER tablets) and Eupyllin CR N® 300 (capsules with ER pellets) group. Each group took the same drug orally twice-first prepared (for the NGT administration) by crushing and secondly as an intact dosage form. Theophylline serum levels were taken at baseline, 30 min, 60 min, 2 h, 4 h, 6 h, 9 h and 12 h after drug administration. maximum serum concentration (Cmax), time to reach Cmax (Tmax) and area under the serum concentration-time curves over 12 h (AUC12h) were calculated. Data are presented as mean ± SD. Results: Crushing increased Cmax in both Euphyllin (43.8 ± 6.5 vs. 26.5 ± 1.6 μmol/l; p<0.01) and Theoplus (45.2 ± 3.6 vs. 29.4 ± 4.8 μmol/l; p=0.013) groups. Tmax was significantly shorter after administration of crushed dosage forms in Euphyllin (0.9 ± 0.7 vs. 5.6 ± 0.9 h; p<0.001) and Theoplus (1.1 ± 0.5 vs. 9.6 ± 2.5 h; p<0.01) group. Concordantly, drug crushing augmented AUC12 h by 40% in both drugs. Conclusion: Crushing destroyed ER properties of theophylline tablets and capsules and their pharmacokinetic profiles were comparable with immediate release forms.

The neurophysiological effects ofsingle-dose theophylline in patients withchronic stroke: A double-blind, placebo-controlled, randomized cross-overstudy.

Reducing inhibitory neurotransmission with pharmacological agents is a potential approach for augmenting plasticity after stroke. Previous work in healthy subjects showed diminished intracortical inhibition after administration of theophylline. We assessed the effect of single-dose theophylline on intracortical and interhemispheric inhibition in patients with chronic stroke, in a double-blind, placebo-controlled, cross-over study. Eighteen subjects were randomly administered 300 mg of extended-release theophylline or placebo. Immediately and 5 hours following administration, transcranial magnetic stimulation was used to assess bihemispheric resting motor threshold, short-interval intracortical inhibition, long-interval intracortical inhibition, and interhemispheric inhibition. Adverse effects on cardiovascular, neurological, and motor performance outcomes were also surveilled. Change between morning and afternoon sessions were compared across conditions. One week later, patients underwent the same assessments after crossing over to the opposite experimental condition. Subjects and investigators were blinded to the experimental condition during data acquisition and analysis. For both hemispheres, changes in intracortical or interhemispheric neurophysiology were comparable under theophylline and placebo conditions. Theophylline induced no adverse neurological, cardiovascular, or motor performance effects. For both conditions and hemipsheres, the baseline level of inhibition inversely correlated with its change between sessions: less baseline inhibition (i.e. disinhibition) was associated with a strengthening in inhibition over the day, and vice versa. A single dose of theophylline is well-tolerated by patients with chronic stroke, but does not alter cortical excitability. The inverse relationship between baseline inhibition and its change suggests the existence of a homeostatic process. The lack of effect on cortical inhibition may be related to an insufficiently long exposure to theophylline, or to differential responsiveness of disinhibited neural circuitry in patients with stroke.

Performance-Based Quality Specifications: The Relationship Between Process Critical Control Parameters, Critical Quality Attributes, and Clinical Performance

The quality of pharmaceutical products is currently evaluated through a series of tests that do not explicitly communicate the clinical consequences of product variability. A previously published risk simulation platform was used to generate quantitative estimates of inefficacy and toxicity for 288 uniform lots of extended-release theophylline tablets displaying various levels of content uniformity and dissolution variability. These data were used to evaluate the univariate specifications utilized in the United States Pharmacopeia (USP) <711> and <905>. Simulation revealed that the specifications are too lenient for content uniformity, both in terms of inefficacy and toxicity, whereas the criteria for dissolution testing are too strict for inefficacy and inaccurate for toxicity. The USP tests also failed to pinpoint the clinical interaction between content uniformity and dissolution variability. Additionally, the simulation platform was used to define the underlying relationship between product quality attributes and clinical performance. Here, content uniformity and Weibull dissolution time constants were used as inputs to the design spaces, which were conditioned on quantitative estimates of inefficacy and toxicity. This methodology enhances the information content of the design space by omitting quality surrogates (e.g., dissolution, moisture content) that are utilized in current design space practices.

A New Definition of Pharmaceutical Quality: Assembly of a Risk Simulation Platform to Investigate the Impact of Manufacturing/ Product Variabcpility on Clinical Performance

The absence of a unanimous, industry-specific definition of quality is, to a certain degree, impeding the progress of ongoing efforts to "modernize" the pharmaceutical industry. This work was predicated on requests by Dr. Woodcock (FDA) to re-define pharmaceutical quality in terms of risk by linking production characteristics to clinical attributes. A risk simulation platform that integrates population statistics, drug delivery system characteristics, dosing guidelines, patient compliance estimates, production metrics, and pharmacokinetic, pharmacodynamic, and in vitro-in vivo correlation models to investigate the impact of manufacturing variability on clinical performance of a model extended-release theophylline solid oral dosage system was developed. Manufacturing was characterized by inter- and intra-batch content uniformity and dissolution variability metrics, while clinical performance was described by a probabilistic pharmacodynamic model that expressed the probability of inefficacy and toxicity as a function of plasma concentrations. Least-squares regression revealed that both patient compliance variables, percent of doses taken and dosing time variability, significantly impacted efficacy and toxicity. Additionally, intra-batch content uniformity variability elicited a significant change in risk scores for the two adverse events and, therefore, was identified as a critical quality attribute. The proposed methodology demonstrates that pharmaceutical quality can be recast to explicitly reflect clinical performance.

INFLUENCE OF BRONCHOLYTIC THERAPY ON VENTRICULAR RHYTHM DISORDERS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Aim. To evaluate effects of broncholytic therapy on ventricular rhythm disorders and high resolution electrocardiogram indices in patients with chronic obstructive pulmonary disease (COPD). Material and methods. 144 patients (54 women and 90 men; aged 47,1±1,5 y.o.) with COPD and 35 patients of control group without respiratory and cardiovascular diseases (23 men and 12 women; aged 42,4±2,8 y.o.) were examined. 24-hour ECG monitoring and high resolution ECG with time and spectral-time mapping of ventricular ECG complex were performed in patients additionally to routine examination. Results. Reduction of ventricular rhythm disorders rate was detected during therapy with extended-release theophylline or salmeterol/fluticasone in patients with moderate and severe COPD. This effect was more significant for salmeterol/fluticasone treatment. Treatment with extended-release theophylline led to increase of a number of ventricular extra systoles in patients with severe COPD. Salmeterol/fluticasone treatment did not influence number of ventricular extrasystoles. Broncholytic therapy had positive influence on processes of ventricular depolarization. It was shown by high resolution ECG indicators improvement and by late ventricular potential rate reduction. Conclusion. Salmeterol/fluticasone combination is more reasonable than extended-release theophylline for broncholytic therapy in patients with severe COPD and ventricular rhythm disorders.

Pharmacokinetics of an extended-release theophylline product in cats

To evaluate the pharmacokinetics of a brand of extended-release theophylline tablets and capsules in healthy cats. Randomized 3-way crossover study. 6 healthy cats. A single dose of aminophylline (10 mg/kg [4.5 mg/lb], IV), a 100-mg extended-release theophylline tablet, or a 125-mg extended-release theophylline capsule was administered to all cats. Plasma samples were collected via preplaced central catheters throughout a 36-hour period. Plasma samples were frozen until analyzed by use of a fluorescence polarization monoclonal immunoassay. All cats tolerated drug administration and plasma collection with no adverse effects. Peak concentrations were reached for both orally administered products between 8 and 12 hours after administration. Bioavailability was excellent. Plasma concentrations were within the human therapeutic concentration of 5 to 20 microg/mL. Daily administration of the brand of theophylline tablets and capsules used in this study at 15 mg/kg (6.8 mg/lb) and 19 mg/kg (8.6 mg/lb), respectively, maintained plasma concentrations within the desired therapeutic range in healthy cats.

Development and in vitro evaluation of extended-release theophylline matrix capsules

Polymers like cellulose (MethocelTM K100MPRCR, K15MPRCR and E4MCR) at different proportions (15-35%) were used to slow the release of theophylline (100 mg) from capsules. Volumetric method for powder filling capsules was used to prepare the capsules. Drug release from capsules was performed using apparatus 1, at 100 rpm and 900 mL of intestinal medium without enzymes (pH 7.5), at 37 °C, following the USP 28th ed. (Test 8). Dissolution profiles were compared to two batches of commercial extended-release capsules. Capsules compounded with 35% (wt/wt) of MethocelTM E4MCR showed dissolution profile according to the official especifications. Similar results were reproduced with other ten compounded batches. Commercial extended-release capsules containing theophylline pellets (100 mg) showed quick drug release when submitted to the same test, indicating that, in these conditions, the capsules did not show prolonged release. Mathematical models like zero-order, first-order and Higuchi were applied in kinetic studies of theophylline release from the compounded capsules. Polymers were efficient to control the release of theophylline in capsules involving diffusion and erosion as mechanisms, and that first-order model was the best fitted one for theophylline matrix capsules. These results support that compounded extended-release capsules can be prepared, since the drug release tests can be done.

Influence of formulation and process variables on in vitro release of theophylline from directly-compressed Eudragit matrix tablets

Extended-release theophylline (TP) matrix tablets were prepared by direct compression of drug and different pH-dependent (Eudragit L100, S100 and L100-55) and pH-independent (Eudragit RLPO and RSPO) polymer combinations. The influence of varying the polymer/polymer (w/w) ratio and the drug incorporation method (simple blend or solid dispersion) was also evaluated. Drug release, monitored using the Through Flow Cell system, markedly depended on both the kind of Eudragit polymer combinations used and their relative content in the matrix. Maintaining a constant 1:1 (w/w) drug/polymers ratio, the selection of appropriate mixtures of pH-dependent and pH-independent polymers enabled achievement of a suitable control of TP release. In particular, matrices with a 0.7:0.3 w/w mixture of Eudragit L100-Eudragit RLPO showed highly reproducible drug release profiles, with an almost zero-order kinetic, and allowed 100% released drug after 360 min. As for the effect of the drug incorporation method, simple blending was better than the solid dispersion technique, which not only did not improve the release data reproducibility, but also caused, unexpectedly, a marked slowing down in drug release rate.

Evaluation of the bioavailability and pharmacokinetics of two extended-release theophylline formulations in dogs

To evaluate the bioavailability and pharmacokinetic characteristics of 2 commercially available extended-release theophylline formulations in dogs. Randomized 3-way crossover study. 6 healthy adult dogs. A single dose of aminophylline (11 mg x kg(-1) 15 mg x lb(-1)], i.v., equivalent to 8.6 mg of theophylline/kg 13.9 mg x lb(-1) or extended-release theophylline tablets (mean dose, 15.5 mg x kg(-1) [7.04 mg x lb9-1), PO) or capsules (mean dose, 15.45 mg x kg(-1) [7.02 mg x lb(-1)], PO) was administered to all dogs. Blood samples were obtained at various times for 36 hours after dosing; plasma was separated and immediately frozen. Plasma samples were analyzed by use of fluorescence polarization immunoassay. Administration of theophylline i.v. best fit a 2-compartment model with rapid distribution followed by slow elimination. Administration of extended-release theophylline tablets and capsules best fit a 1-compartment model with an absorption phase. Mean values for plasma terminal half-life, volume of distribution, and systemic clearance were 8.4 hours, 0.546 L x kg(-1), and 0.780 mL x kg(-1) x min(1), respectively, after i.v. administration of theophylline. Systemic availability was > 80% for both oral formulations. Computer simulations predicted that extended-release theophylline tablets or capsules administered at a dosage of 10 mg x kg(-1) (4.5 mg x lb(-1)), PO, every 12 hours would maintain plasma concentrations within the desired therapeutic range of 10 to 20 microg x mL(-10. Results of these single-dose studies indicated that administration of the specific brand of extended-release theophylline tablets or capsules used in this study at a dosage of 10 mg x kg(-1), PO, every 12 hours would maintain plasma concentrations within the desired therapeutic range (10 to 20 microg x mL(-1)) in healthy dogs.

Salmeterol vs Theophylline: Sleep and Efficacy Outcomes in Patients With Nocturnal Asthma

To compare the efficacy, safety, and effects on sleep quality of salmeterol and extended-release theophylline in patients with nocturnal asthma.Randomized, double-blind, double-dummy, three-period crossover.Outpatients at a single center. Patients spent 1 night during screening and 2 nights during each study period in a sleep laboratory for completion of sleep studies.Male and female patients who were at least 18 years old with nocturnal asthma (baseline FEV1, 50 to 90% of predicted) and who required regular bronchodilator therapy. Patients on inhaled corticosteroids, cromolyn, and nedocromil were allowed into the study if their dosing remained constant throughout the study.Inhaled salmeterol (42 microg per actuation), extended-release oral theophylline (titrated to serum levels of 10 to 20 microg/mL), and placebo taken twice daily.Efficacy measurements included nocturnal spirometry, nocturnal polysomnography, sleep questionnaires, and daily measurements of lung function and symptoms. Salmeterol was superior to theophylline (p < or = 0.05) in maintaining nocturnal FEV1 levels and was superior to placebo (p < or = 0.05) in improving morning and evening peak expiratory flow (PEF) and in decreasing nighttime albuterol use. The use of salmeterol significantly increased the percentage of days and nights with no albuterol use and decreased daytime albuterol use compared with theophylline and placebo (p < or = 0.05). Sleep quality global scores significantly improved with salmeterol and placebo (p < 0.001) but not with theophylline. The effects on sleep architecture were similar across treatment groups.Salmeterol (but not theophylline) was associated with sustained improvements in morning PEF, protection from nighttime lung function deterioration, reductions in albuterol use, and improvements in patient perceptions of sleep. No differences were seen in polysomnographic measures of sleep quality.

Bioequivalence Study Between Two Extended-Release Formulations of Theophylline Using Saliva

Objective: To assess the bioequivalence between two extended-release formulations of theophylline using saliva as the biologic fluid. Design: Randomized two-way crossover design. Participants: Eight healthy, nonsmoking volunteers (7 women, 1 man) between 23 and 41 years of age took a single dose (250 mg) of two extended-release formulations of theophylline (form A, tablet; form B, capsule). Results: Significant differences were found at 2, 4, 6, and 8 hours (p &lt; 0.001), with the in vitro dissolution test between both formulations. ANOVA for AUC, maximum concentration (Cmax), average concentration, and %Cmax – 100 showed significant differences between both formulations in the in vivo trial. Conclusions: The tablet and capsule formulations of extended-release theophylline are bioinequivalent when saliva is used as the biologic fluid for performing these studies.

Clinafloxacin-Theophylline Drug Interaction

To report an apparent pharmacokinetic interaction between clinafloxacin and theophylline in a patient with chronic obstructive pulmonary disease (COPD). A patient with a history of COPD was admitted for a fracture of the right femoral neck. Admission medications included extended-release theophylline 400 mg bid. The initial serum theophylline concentration was 81.03 mumol/L (normal 55-110). A subsequent concentration was subtherapeutic (46.62 mumol/L) and the theophylline dosage was increased to 300 mg tid. Therapeutic steady-state concentrations were achieved. The patient later developed pneumonia and was enrolled in a study of nosocomial acquired pneumonia involving clinafloxacin versus ceftazidime. He was randomized to receive clinafloxacin 200 mg iv q12h. After clinafloxacin therapy was initiated, the serum theophylline concentration increased into the toxic range (155.96 mumol/L). Theophylline administration was held for 2 doses and the dosage then reduced to 200 mg tid. Serum concentrations decreased to within the therapeutic range. The fluoroquinolones have been shown to interact with the hepatic metabolism of theophylline and increase serum theophylline concentrations. The quinolone metabolite, 4-oxoquinolone, inhibits the N-demethylation of theophylline, leading to a decrease in the clearance of theophylline. The resultant rise in theophylline concentrations corresponds with the decrease in clearance and possible toxicity. In our patient, careful monitoring of theophylline concentrations and dosage adjustments resulted in the restoration of therapeutic serum concentrations. The observation of this drug interaction between clinafloxacin and theophylline suggests a need for prudent monitoring of theophylline concentrations. Dosage adjustments may be warranted when this combination of medications is used. Such action may prevent significant toxicities and prolonged hospitalization. Further controlled clinical trials in healthy volunteers are needed to substantiate the interaction between clinafloxacin and theophylline.

Conversion from Twice-to Once-Daily Extended-Release Theophylline Treatment in Patients with Reversible Airway Obstruction

This multicenter, randomized, investigator-blinded, parallel group study compared the effects of converting patients from a q12h extended-release theophylline preparation (Theo-Dur) to a q24h extended-release product (Uni-Dur). Patients (n = 133) first received open-label Theo-Dur treatment with dosage titrated to achieve peak serum theophylline concentrations of 10-20 micrograms/ml. Patients then were randomized to continue Theo-Dur (n = 64) or to convert to Uni-Dur (n = 60) with peak serum theophylline concentrations maintained in the desired range. Pulmonary function tests were performed during the open-label and blinded periods; patients maintained diaries and performed peak flow measurements before each dose of study treatment. Adverse events were recorded throughout the study. Respiratory status during blinded treatment was rated as the same or improved compared with open-label treatment by > 87% of evaluable patients and physicians, regardless of treatment group. There were no significant differences in mean peak serum theophylline concentrations at baseline, at the final evaluation, or at any point during the study. Few dosage adjustments were necessary (5/52, Uni-Dur; 9/57, Theo-Dur). There were no significant changes in pulmonary function test results or patient diary entries between the open-label and blinded periods. Headache and nausea were the most commonly reported adverse events. In conclusion, converting patients from twice- to once-daily theophylline treatment resulted in no significant changes in any measures of pulmonary function, and there were no significant differences between the groups during the blinded treatment period.

Sustained-Release Oral Delivery of Theophylline by Use of Polyvinyl Alcohol and Polyvinyl Alcohol-Methyl Acrylate Polymers

Crystalline polyvinyl alcohol (PVA) polymer and low-crystallinity polyvinyl alcohol-methyl acrylate copolymer (PVA-MA) were examined as sustained-release tablet excipients with theophylline as a model drug. By blending of different proportions of the crystalline polymer and the low-crystallinity copolymer, it was possible to affect the release characteristics of the tablets. Tablets made with crystalline PVA provided instant release of theophylline in vitro. Tablets made with a larger proportion of PVA-MA relative to PVA provided a very prolonged release profile in vitro. A formulation containing PVA-MA:PVA:theophylline in a ratio of 1:9:10 provided sustained-release profiles in vitro and in vivo in dogs. The dissolution release profile of this PVA-blend tablet formulation in vitro agreed extremely well with the percentage of bioavailable dose absorbed over time in vivo. The formulation provided a plateau of levels in plasma over 16 h. The oral bioavailability of theophylline from this formulation in dogs was approximately 80% and was equivalent to that obtained after administration of Theo-Dur, a marketed extended-release theophylline tablet from Key Pharmaceuticals.