Serum Theophylline Concentrations Research Articles

Investigation of a dosage regimen for intravenous theophylline.

A study was designed to evaluate the validity of the dosage guidelines for theophylline recommended by Hendeles and Weinberger. A total of seven asthmatic smokers and non-smokers were entered and studied. Theophylline serum concentrations were determined prior to the start of therapy and at intervals following initiation of an infusion. The mean theophylline concentration attained for all subjects was 10 micrograms/ml, however, five of the six patients completing the study did not achieve the predicted serum theophylline concentration. Further study of higher dosage designed to achieve a concentration of 12 micrograms/ml is suggested.

Components of variability in serum theophylline concentrations during maintenance therapy with a sustained release formulation.

Fifteen adult chronic asthmatic patients were studied on 6 consecutive days of the second week of treatment with a new sustained release theophylline formulation, and 8 were again studied after three months on the same dosing regimen (375 mg b.i.d.). Serum theophylline concentrations were maintained in the therapeutic range (peak - 19.7 +/- 5.0 micrograms/ml; trough - 13.0 +/- 3.2 micrograms/ml) throughout the 12 hour dosing interval, and were greater than 75% of the peak concentration over 8.6 +/- 2.9 h. A degree of drug accumulation was evident in that the 1-h and 5-h levels rose from 12.2 +/- 4.1 and 4.5 +/- 4.8 micrograms/ml during the second week to 16.9 +/- 4.6 and 18.4 +/- 4.5 micrograms/ml, respectively, at three months. Between-patient differences accounted for 61%-71% of the total variation in steady state theophylline concentrations. After accounting for differences due to sampling time and assay error, unexplained random, within-individual variability amounted to 11%-18% of the total. Quantitative estimation of these components of variability may be incorporated into dosage forecasting methods based on single determinations of serum concentration.

Pharmacokinetics of theophylline in infants with bronchiolitis.

Theophylline pharmacokinetics were studied in 12 infants (age 3 weeks-6.5 months) with bronchiolitis. 9 of the 12 patients received a single dose of aminophylline (5.0-8.5 mg/kg) whereas the remainder were at steady-state receiving multiple doses (2.5-5.0 mg/kg) of aminophylline. The dose was administered IV over 0.5-1.0 h. An HPLC method was used to measure theophylline concentrations in serum and urine. Peak serum concentrations of theophylline measured by HPLC ranged from 8.48-21.6 micrograms/ml. Total, renal and nonrenal clearance of theophylline ranged from 4.66 to 19.25, 1.07 to 5.76 and 3.59 to 16.83 ml/min/m2, respectively. Mean apparent volume of distribution and elimination half-life were 8.75 l/m2 and 11.38 h, respectively. Although no significant correlation was observed between age and theophylline kinetic parameters, clearance appeared to increase and half-life decrease with age. Our patients had a substantially lower clearance and longer half-life as compared to published data in children greater than 1 year of age. A five-fold variation in theophylline clearance demonstrates the need for monitoring theophylline serum concentration to minimize the risk of potential toxicity.

Pharmacokinetics of theophylline in patients following short-term intravenous infusion.

Serum theophylline concentrations after intravenous administration of a new short-term infusion (Euphyllin Kurzzeitinfusion) were measured in 50 out-patients with chronic obstructive airways disease (COAD). An intravenous infusion of theophylline ethylenediamine 480 mg (corresponding to approximately 350 mg anhydrous theophylline) in 50 ml isotonic solution was given in 20 min. Blood samples were taken beforehand and 25 to 30 min and 1, 3 and 6 h after starting the infusion. 86% of the patients had a one-hour serum level in he therapeutic range of 8.20 mg/l, and 2 h later, this was true of 64% of the patients. The short-term infusion was well tolerated, even in cases with unknown high pre-infusion serum levels. Pertinent pharmacokinetic parameters were determined, such as total body clearance, apparent volume of distribution, and half-life of elimination. Geometric mean an 95%-confidence limits, derived from the log-normal distribution of these parameters, were: Cl = 0.044 (0.018-0.190) l/h/kg ideal body weight, Vd = 0.451 (0.258-0.789) l/kg ideal body weight, and t 1/2(el) = 7.1 (2.6-19.1) h.

Clinical Application of Immunoprecipitation Inhibition Technique for Determination of Carbamazepine and Theophylline in Serum

The immunoprecipitation inhibition technique (i-PiT method) was used in the clinical application to determine the concentration of carbamazepine (CBZ) and theophylline (TH) in serum. Each coefficient of variation for the 3 levels of CBZ or TH was less than 9% within-run and betweenrun. The serum CBZ concentration determined by the i-PiT method was compared with that determined by high-performance liquid chromatography (HPLC). The correlation coefficient was 0.990, but serum CBZ concentration determined by the i-PiT method was about 15% higher than that determined by HPLC because of the cross reactivity in carbamazepine-10, 11-epoxide. Other antiepileptic drugs, such as phenytoin, phenobarbital and primidone, did not interfere with the i-PiT method under therapeutic condition. The serum TH concentration determined by the i-PiT method was compared with that determined by HPLC. There was good agreement between the i-PiT method and HPLC results, where the correlation coefficient was 0.994. The metabolites of TH, such as caffeine and theobromine, did not interfere with the i-PiT method under therapeutic conditions. Therefore, the i-PiT method may be useful for the serum level monitoring of patients undergoing TH therapy.

Cross validation of serum to saliva relationships of caffeine, theophylline and total methylxanthines in neonates.

We have previously described the relationships of serum and saliva concentrations of caffeine, theophylline and total methylxanthines in premature infants. We have now extended the previous studies in order to validate the previously derived relationships with new data. The new serum to saliva relationships, derived using regression and ratio models, are cross validated against the relationships from the previous data, and vice versa. A good cross validation was observed for caffeine and total methylxanthine concentrations in infants treated with caffeine. In the theophylline treatment group, theophylline concentrations did not cross validate well, whereas the total methylxanthine concentrations did. Since in vivo conversion of theophylline to caffeine and vice versa may affect the individual methylxanthine relationships, the total methylxanthine equations are recommended for predicting serum concentrations from salivary concentrations.

Effect of theophylline on thyroid status in the rat.

The effect of administration of theophylline, thyroxine (T4), or a combination of the two, for 14 days on body weight, food intake, serum concentrations of T4 and 3,5,3'-triiodothyronine (T3), and on the rate of 5'-monodieodination of T4 to T3 by hepatic and renal homogenates was evaluated. Administration of T4 (25 micrograms/kg b.w./day) increased the serum concentration of T4 and T4 5'-deiodinase activity. Administration of theophylline (191 mg/kg b.w./day) increased the serum concentration of theophylline to 28.5 micrograms/ml, increased food intake, but decreased both the concentration of T4 in serum and also T4 5'-deiodinase activity. Administration of a combination of T4 and theophylline returned T4 5'-deiodinase activity to control levels. Since the addition of only high concentrations of theophylline to incubation mixtures inhibited T4 5'-deiodinase directly, it is most likely that the effect of theophylline in vivo on the activity of the T4 5'-deiodinase enzyme is indirect and secondary to inhibition of thyroid hormone secretion.

Evaluation of a new sustained-release theophylline tablet for children.

A new, low dose sustained-release tablet of theophylline has been developed in order to facilitate a correct dose regimen in asthmatic children treated with theophylline. The formulation (Euphyllin retard mite w/groove) contains 128 mg of theophylline, and can easily be divided. The extent of bioavailability in adults is 0.91, and the peak serum concentration is reached after 8.7 h. 25 children treated with plain theophylline tablets were followed when changing to the sustained-release tablets. Compared to the plain tablets, the serum theophylline concentration before the morning dose was 29 mumol/l higher (range 12-51) when the same daily dose was given as a sustained-release preparation. The serum concentration fluctuations during one dosing interval were reduced with 13 mumol/l (0-26). Mild gastrointestinal side effects reported by the children when using the plain theophylline tablets all disappeared on changing to the sustained-release tablets.

Evaluation of the ordering of serum theophylline concentrations

The ordering of serum theophylline concentrations in a 900-bed university hospital was evaluated. Data were collected during the first week of three consecutive months from the records of adult inpatients who had serum theophylline assays performed. The appropriateness of ordering the serum theophylline determinations was evaluated on the basis of criteria including sampling at steady-state concentrations and sampling in proper relationship to the dosage schedule to represent a peak or trough concentration. A total of 113 determinations in 79 patients were reviewed. Pulmonary service patients accounted for 54 (48%) of the determinations. For the 56 concentrations ordered for patients receiving aminophylline continuous infusions, 25 (45%) of the determinations did not meet the criteria for appropriateness. For the 57 other determinations (oral theophylline products and intermittent bolus injections of aminophylline), 42 (74%) were not ordered according to the established criteria. Overall, 67 (59%) of 113 serum theophylline determinations were found to be ordered inappropriately. Corrective educational programs based on standard guidelines for ordering serum theophylline concentrations were established.

Theophylline Toxicity after the Use of Aminophylline in the Treatment of Cerebral Vasospasm

We are reporting a case of theophylline toxicity after the initiation of i.v. aminophylline and isoproterenol in the treatment of cerebral vasospasm. The dose of aminophylline (125 mg/hour) previously recommended results in a toxic serum theophylline concentration in a majority of patients if the infusion is continued for more than 24 to 48 hours. The rapid achievement of an optimal serum level is obtained with a standard loading dose of 8.0 mg/kg. The initial infusion rate should be based on calculated pharmacokinetic data. Maintenance dosing adjustments are then based on serum determinations and the presence of toxic effects.

Serum theophylline determination by fluorescence polarization immunoassay utilizing an umbelliferone derivative as a fluorescent label

We report the development of a non-radioisotopic homogeneous immunoassay to determine serum theophylline concentrations using fluorescence polarization. Theophylline is a therapeutic drug which is used in the treatment of asthma. Monitoring this drug in serum is necessary to ensure effective dosage and to avoid toxicity. The fluorescence polarization immunoassay is based on labeling the analyte with a fluorescent probe and monitoring the changes in the probe's fluorescence polarization occurring in the hapten-antibody reaction. Previous reported fluorescence polarization immunoassays invariably involved the use of fluorescein as a fluorescent label. The existence of polymorphic forms in fluorescein and the presence of contaminants in commercial preparations of fluorescein have led us to use an alternative fluorophore, namely, an umbelliferone derivative, in the polarization immunoassay. This fluoreceent probe is characterized by a high quantum yield, a large extinction coefficient, a large Stokes shift, and the absence of nonspecific interaction with normal human serum. The spectroscopic properties of this label including both the excitation and emission polarization spectra are presented, and the procedure to obtain the optimized fluorescence polarization standard curve is described. Using the polarization immunoassay technique, the theophylline concentrations of 25 clinical serum samples were determined. The values obtained correlated well with values determined by high-pressure liquid chromatography (equation of linear regression analysis y = 0.97 x + 1.33; and correlation coefficient, 0.93).

Serum concentrations of theophylline in children treated with two daily doses of a sustained-release theophylline preparation.

Over a 3-month period 22 asthmatic children were treated with a sustained-release theophylline preparation (Nuelin Retard, Riker) in twice-daily doses. During the first 2 weeks of treatment slight side-effects were observed in 14 children. Over the remaining 10-week period only four children experienced minor-side-effects. Serum theophylline levels 4 hours after tablet administration were measured three times and serum levels just before tablet administration were measured once during the observation period. The average difference between the serum levels of theophylline just before tablet administration and the corresponding serum value 4 hours afterwards was 4.2 microgram/ml. The serum values 4 hours after tablet administration showed an insignificant fall throughout the period and patient compliance was assessed as good. When the average requirements of theophylline in mg/kg found by Wyatt et al. (15) (Table 2) were used as initial doses, few dosage adjustments were necessary and no serum values were greater than 26.2 microgram/ml, but in order to avoid serum levels above 20 microgram/ml initial doses should be decreased about 10% and final adjustment made with the aid of serum theophylline measurement under steady state conditions. In children, Nuelin Retard given in two daily doses is capable of maintaining a constant therapeutic serum concentration for the whole 24-hour period.

Effect of intravenous furosemide on serum theophylline concentration

The effect of furosemide on the serum theophylline concentration (STC) was investigated in 10 patients at steady state on a continuous i.v. aminophylline infusion. A baseline STC was obtained 48 hours after the initiation of the maintenance infusion. The patients were monitored closely for the last 24 hours of the maintenance period with hourly flow records to assure the same continuous rate. Urine output was measured over four hours, then, a 40-mg dose of furosemide was administered i.v. over two minutes, and the aminophylline infusion was continued at the same rate. Urine output was measured for four hours after the furosemide dose, and then a second STC was obtained. The 40-mg furosemide i.v. bolus injection caused an average increase of 2.9 micrograms/ml in STC, with a range of 0.5--5.5 micrograms/ml. The urine volumes increased by an average of 995 ml above the baseline, with a range of 630--1377 ml. Both of the increases were significant at the p less than 0.005 level. Patients stabilized on a theophylline dosage regimen should be monitored closely during the addition or discontinuation of furosemide therapy. Furosemide has been shown to be another factor that can alter STC.U

Evaluation of “toxic” serum theophylline concentrations

The relationships between excessively high theophylline doses, the incidence of theophylline toxicity, and toxic serum theophylline concentrations in hospitalized patients were investigated. During a 24-month period, the medical records of patients whose serum theophylline content was above 20 micrograms/ml were studied. Demographic and medical information was recorded, including symptoms attributable to theophylline toxicity, and concurrent disease states and medications. A total of 3112 serum theophylline determinations were made during the study (January 1978 through December 1979); 17% were above 20 micrograms/ml. The medical records of 128 patients were available; 87 of these were studied. The patients were divided into three groups: Group 1--serum theophylline concentrations between 20 and 29.9 micrograms/ml (42 patients); Group 2--30-39.9 micrograms/ml (26 patients); Group 3--above 40 micrograms/ml (19 patients). In Group 1, 81% of the patients had at least one symptom of toxicity. In the other groups, all patients had one or more symptoms of toxicity. Tachycardia was the most common symptom. Four patients had seizures attributable to theophylline toxicity; all four had serum theophylline concentrations above 40 micrograms/ml. Of the 87 study patients, 77 (89%) had received theophylline doses above recommended guidelines. It is concluded that serum theophylline concentrations above 20 micrograms/ml result in a high incidence of toxic symptoms. Serum theophylline determinations should be obtained when treating patients with theophylline.

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.

Relationship of formulation and dosing interval to fluctuation of serum theophylline concentration in children with chronic asthma

Completeness of absorption and fluctuations in serum, theophylline concentration were examined in 14 children, 8 to 17 years of age (mean 12.4), with chronic asthma treated in variable sequence with a slow-release formulation at eight- and 12-hour intervals, and plain tablets every six hours. The total fraction absorbed for the slow-release formulation was 0.98 +/- 0.07 (mean +/- SEM) during the eight-hour and 0.99 +/- 0.04 during the 12-hour regimens. Observed fluctuations in serum concentration were closely approximated by predictions determined from absorption of single doses in adult volunteers. Available single-dose absorption data then were used to compare predicted fluctuations in serum concentration among nine formulations (18 brand names) for eight- and 12-hour dosing in an average child and adult (elimination half-lives of 3.7 and 8.2 hours, respectively). Although predicted peak concentrations were less than twice the trough for all products when given at 12-hour intervals to an average nonsmoking adult, only two of the nine formulation (both from the same manufacturer) were likely to maintain predicted fluctuations within the 10 to 20 micrograms/ml therapeutic range during 12-hour dosing intervals in an average child. Most children and those adults with rapid elimination generally will require eight-hour dosing with the other products.

Correlation of serum and saliva theophylline concentration after administration of a sustained release preparation.

The correlation between serum and saliva levels of theophylline was investigated in seven healthy volunteers after multiple dose administration of a low dose (300 mg/day) and a high dose (900 mg/day) of a sustained release theophylline preparation (Theo-Dur). Tablets were taken for five days, at 8 a. m. and 8 p. m. and a last dose was taken on Day 6 at 8 a. m. Fourteen serum and saliva samples were collected simultaneously during the dosing period and for up to 32 h after the last dose. On the 300 mg/day regimen the level in saliva was 55.3% of the serum level, with an overall variability of 6.7% and an intrasubject variability of 10.5%. After 900 mg/day, the saliva concentration was 55.5% of the serum concentration, with an overall variability of 7.6% and an intrasubject variability of 12.7%. A good correlation was found between both determinations (r = 0.99), which suggests that saliva levels could be used to monitor theophylline after administration of a sustained release tablet.

Theophylline serum protein binding in obstructive airways disease.

The percentage of theophylline bound to protein in sera obtained from patients with obstructive airways disease was determined by ultrafiltration. The bound theophylline fraction in 71 serum specimens collected from 51 patients was 60.7 +/- 10.0% (mean +/- SD) and from 30.8% to 83.2%. The correlation between unbound serum theophylline concentration and total concentration (range 0.8 to 90 mg/l) was linear (r = 0.97, p less than 0.001). Theophylline binding correlated poorly with serum albumin (r = 0.39) and total serum protein (r = 0.35), although the correlations were statistically significant (p less than 0.05), Theophylline binding in women did not differ from that in men. The extent of theophylline binding in younger patients was greater than in patients over 55 yr (64.3 +/- 8.5% and 57.0 +/- 10.4%, p less than 0.005). Variation in theophylline binding in 12 patients from whom two or more serum samples were collected was relatively small. Analysis of variance showed interpatient variation in theophylline binding (p less than 0.01) but not between sampling occasions in the same patient. The demonstrated variability in serum protein binding of theophylline should influence theophylline distribution and elimination kinetics and may be another determinant of clinical response. Patients with lower binding levels should have higher plasma levels of unbound drug after a loading dose and will need more frequent dosing.

Theophylline Absorption and Disposition in Rabbits: Oral, Intravenous, and Concentration-Dependent Kinetic Studies

Theophylline pharmacokinetics following oral and intravenous administration were studied, and the absolute bioavailability of five commercially available products was determined using the rabbit as an in vivo model. Concentration-dependent clearance studies were performed by multiple constant-rate infusion and multiple bolus dose administration of aminophylline. Theophylline pharmacokinetics following the oral adminstration of these products obeyed the one-compartment open model adequately. However, the data obtained following rapid intravenous aminophylline administration in the rabbit fit either the one-compartment model (half-life = 2.8 hr and the volume of distribution = 0.586 liter/kg) or the two-compartment model (β-phase half-life = 4.4 hr and Vd(β) = 0.708 liter/kg). There were no significant product-to-product differences in the time to peak (tmax), the rate constant of absorption (ka), or the percent of dose absorbed at 1 hr (F1); however, differences in the absolute bioavailahility (F), dose-normalized peak serum concentration (Cmax(n)), and percent of dose absorbed at 6 hr (F6) were significant. There was no evidence of concentration-dependent clearance for theophylline in the rabbit in the serum concentration range studied, but the results of the multiple constant-rate infusion study suggest that total clearance decreases at higher serum theophylline concentrations.

375 SUSTAINED RELEASE THEOPHYLLINE (SRT): A SIGNIFICANT ADVANCE IN THE TREATMENT OF CHILDHOOD ASTHMA

The efficacy and safety of an SRT preparation (Theo-DurR) was compared to regular release theophylline (RRT)(TheolairR) in the treatment of childhood asthma. We studied 34 children aged 6 - 12 years (mean 9.3 years) for 8 weeks. Both the SRT and RRT preparations were administered for 4 weeks in a randomized crossover design. Individualized theophylline dosage was determined after pre-study measurement of a time concentration curve at steady state on SRT. Mean (+SD) dosage for SRT and RRT was 22.6 ± 5.3 and 21.9 ± 5.3 mg7kg/24 hours respectively. The SRT was administered 12 hourly; the RRT 6 hourly. Expiratory flow rate and lung volumes were assessed every 2 weeks. Peak flow rates were measured at home twice daily. A diary of symptomatology including wheezing, cough, appetite, activity and side effects was kept. No difference in pulmonary function or side effects was observed between the 2 treatments. However, breakthrough wheezing was significantly more frequent (p < .01) during RRT therapy. Pill counts and serum theophylline concentration monitoring showed better compliance with SRT treatment (p < .01). Subjectively, SRT therapy was preferred by 33 of 34 families. These results demonstrate conclusively that even in young children with rapid theophylline clearance, an SRT preparation administered twice daily is effective and safe. Because of decreased wheezing, improved compliance, and greater patient acceptance, SRT has definite clinical advantage over RRT in pediatrics.