Theophylline preparations are widely used in the treatment of asthma. Although most available oral preparations are well absorbed, and the dose of theophylline is often adjusted for the patients weight, the desired serum theophylline concentration is difficult to achieve. Reasons include: genetically-determined differences in individuals’ rates of hepatic metabolism; effects of disease states upon the distribution or elimination of theophylline; effects of other medications upon theophylline concentration; and, differences in the actual content of theophylline between the many marketed theophylline-containing preparations.
Since many available preparations require two, three, or even four daily doses, omission of one or more daily dose by patients may account for low serum theophylline levels in those patients. Although no available study has examined the compliance of asthma patients intake of daily prescribed medications, Kinsman et al showed an unsatisfactory compliance to PRN medications.
Therefore, the marketing of a theophylline preparation suitable for once daily oral administration may be of clinical use. Our study compares the bioavailability of a newer sustained release anhydrous theophylline suitable for once daily administration (od) to that of a currently available preparation taken twice a day (bid).
Eight adult asthmatic patients (four men, four women) were selected from the University Hospital clinic population for study. All signed informed consent. All responded to provoking agents (physical or chemical) by wheezing and reported nocturnal symptoms. None had cardiovascular, renal or hepatic disease. Six were receiving theophylline preparations prior to the study; two received “over the counter” theophylline-containing medications. Two had previously received corticosteroids. One had mild wheezing at the time of study. None smoked.
Pulmonary Function Testing
All patients had been regularly evaluated with spirometry and peak expiratory flow rates in the pulmonary clinic. These patients had serial spirometry to document reversible airways osbstruction, and met the American Thoracic Society definition of asthma. Each subject was entered into the protocol only when testing showed his maximal expiratory flow and volume to approximate his own best airway function as determined by his previous records.
We studied two treatment regimens: 1) od anhydrous theophylline (Uniphyl, Purdue Frederick Company); 2) bid anhydrous theophylline (Theo-Dur, Key Pharmaceuticals, Inc). All subjects participated in both regimens.
Patients were asked to omit all dietary xanthine derivatives for two-three days (chocolate, cola, coffee, tea). On the fourth day, patients received 800 mg Uniphyl, to be taken each evening at 8 pm. Serum theophylline was measured at 4 pm three-four days after the administration of od theophylline. The nightly dose was increased by 200 mg in those subjects whose 4 pm serum level was less than 5 μg ml. This was done repeatedly until the 5 M-g/ml concentration was attained. Steady state was defined as a level of 5 μg/ml drawn four hours before trough (8 pm). A level of 5 μg/ml was selected because it represents a minimal level which will achieve bronchodilation.
When the desired steady-state dose for each subject was established, patients were admitted to the medical service for study. Patients received pulmonary function testing, complete blood counts, and basic chemistry screening (SMA24 which includes serum albumin, globulin, alkaline phosphatase, BUN and creatinine to rule out liver or renal disease). No patient with an abnormal SMA24 result was included in the study. Intravenous cannulas were inserted for blood sampling. A 4 pm (pre-trough) sample was obtained. Between 6-8 pm, a xanthine-free hospital dinner was served. We noted conflicting reports regarding the effect of food on absorption of sustained release preparation. The former study shows “dumping” of theophylline while fasting; the latter, with food ingestion. Therefore, since patients do not eat at the same time each day, we did not adhere to a rigid time schedule for eating and taking the medication. At 8 pm each patient received OD theophylline in the dose that had already been established during the out-patient preparation described above.
Serum levels were obtained at 8 pm (time zero or trough), and again at times 2, 4, 6, 8, 10, 12, 14 and 16 hours after the administration of theophylline. Peak expiratory flow was measured at time zero and four hours after the dose.
The bid regimen was administered to the same patients 90 days after the od regimen. During the three-month (90 days) interval, patients returned to their previous out-patient therapeutic programs. For the bid regimen, the Theo-Dur dose for each patient was identical to his Uniphyl dose, but given in two divided doses. Patients were switched over to Theo-Dur from their usual medication. Three to four days later, blood levels were obtained at 4 pm.
Admission and steady state criteria were similar to the OD regimen. Serum theophylline levels were drawn at 0, 2, 4, 6, 8,10,12,14,16, 18, 20 and 24 hours after the dose of Theo-Dur.
This protocol was reviewed and approved by the institutional review board of the University of Medicine and Dentistry of New Jersey, New Jersey Medical School.
Demographic, functional, and pharmacologic data were reported as mean and standard error of the mean (SEM). Paired t statistics were used to compare data from the same subject during od and bid regimens. Pharmacokinetic data included: area under the plasma drug concentration curve (AUC) in μg/ml hour; average half life of elimination (Te) in hours; half life of absorption (Ta) in hours; mean maximum concentration, pLg/ml (Cmax); and the time at which maximum plasma concentration was achieved (Tmax). The AUC for both regimens were calculated for 24 hours by the trapezoidal rule. Data points for the od regimen extended to 16 hours. To obtain a 20-and 24-hour data point, we used the 4 pm pre-trough and the 8 pm trough levels drawn at the time of admission. Thus, we assume that the patient took his appropriate dose at 8 pm on the previous evening. Data points for absorption, elimination and maximum concentration for the bid regimen were calculated from 12 hour periods. The AUC 0-24 for the bid regimen is the combined sum (AUCq+AUCm). Bioavailability was expressed as ratio of od AUC over bid AUC. Ta, Te, Cmax and Tmax represented for the bid are from the 12-24 hour data since 0-12 and 12-24 hour values were similar (Table 3). Serum theophylline was determined by a fluorescence polarization immunoassay (FPIA-TDx theophylline systems assay).