Serum/saliva correlations for theophylline in asthmatics

Theophylline levels in mixed saliva (both stimulated and unstimulated) were compared with total and free (unbound) serum theophylline levels in 28 asthmatic outpatients using theophylline regularly. Stimulated saliva predicted both total and unbound serum theophylline concentrations within +/- 1 microgram/mL in 62.5% and 92.9%, respectively, of the samples examined. In addition, the total serum levels could be used to predict unbound serum concentrations to within +/- 1 mg/L in 100% of the cases that were examined. These results indicate that saliva levels predict 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 non-invasive method for monitoring unbound serum theophylline levels. The therapeutic range for saliva, which corresponds to the accepted total serum concentration range of 10-20 mg/L, is approximately 5.6-11.3 mg/L.     

Do saliva concentrations predict plasma unbound theophylline concentrations? A problem re-examined.

On the assumption that plasma unbound drug concentrations are therapeutically active, the value of saliva concentrations in predicting plasma unbound theophylline concentrations was investigated in 25 ambulatory adults (aged 27 to 84 years) receiving theophylline (225-1350 mg aminophylline daily) for asthma or chronic bronchitis. Plasma samples from all patients were ultrafiltered, and the plasma unbound theophylline (F) concentrations were compared with the corresponding total plasma (P), citric acid stimulated saliva (S) and non-stimulated saliva (Ns) theophylline concentrations. Plasma unbound theophylline concentrations correlated significantly with P (r = 0.97) and S (r = 0.973), but less well with Ns (r = 0.883), emphasising the benefit of saliva stimulation. The ability of S to predict F theophylline concentrations was assessed using the mean ratio of 0.7297. In 92% of the patients, predicted F concentrations were within +/- 1 microgram/ml of the measured concentrations. Similarly, using the mean F/P ratio of 0.418, predicted P were within +/- 1 microgram/ml of obtained P in 84% patients, and using the mean S/P ratio of 0.568, predicted P were within +/- 1 microgram/ml of obtained P in 81%. An accuracy of +/- 1 microgram/ml in estimating F from S concentrations would be sufficient to indicate appropriate dose adjustments, and we therefore advocate the use of stimulated saliva samples for routine monitoring of theophylline therapy.     

Comparison of unbound and total serum theophylline concentrations with those of stimulated and unstimulated saliva in asthmatic children

Unstimulated saliva, citric acid stimulated saliva, and serum were collected from 31 asthmatic children taking theophylline. Salivary theophylline concentrations, and total and unbound serum theophylline concentrations were measured. The correlation coefficients between both types of saliva, and total and unbound serum theophylline were all statistically significant (p less than 0.001). The highest correlation coefficients were obtained with stimulated saliva and total serum concentrations (r = 0.98), and stimulated saliva and unbound serum (r = 0.96). The coefficients when unstimulated saliva was compared to either total or unbound serum concentrations were 0.90 and 0.89, respectively. Serum binding of theophylline averaged 58.1%. Unstimulated saliva had a higher mean theophylline concentration than stimulated saliva. The results suggest that salivary monitoring using stimulated saliva may be used to predict serum concentrations with a high degree of confidence when the saliva levels are substantially lower than, higher than, or in the middle of the therapeutic range, but there is a considerable degree of uncertainty when the salivary values are near the lower or upper end of the therapeutic range.     

Variability of the serum protein binding of theophylline in patients with asthma and cystic fibrosis.

1. The serum protein binding of theophylline was studied in 28 asthmatics and 11 patients with cystic fibrosis (CF) who were receiving the drug regularly. Peak theophylline samples were collected at 2 week intervals on four occasions in each asthmatic and on three occasions in each CF patient. The binding was measured using ultrafiltration at 37 degrees C and pH 7.4. The total and free (unbound) theophylline concentrations were measured using high-performance liquid chromatography. 2. The mean free-fractions (+/- s.d.) in asthmatics (0.50 +/- 0.03) and in CF patients (0.51 +/- 0.04) were not significantly different. The intra- and inter-subject variability in the free-fraction (fu) was relatively small in both patient groups. The binding was found to be concentration-independent at serum theophylline concentrations up to 30.9 micrograms ml-1. The effects of age, gender, serum albumin and total serum protein on the free fraction were evaluated. 3. The results indicate that the binding of theophylline is similar in the two disease states. The low degree of variability in serum theophylline binding indicates that measurements of total serum theophylline concentrations will reflect unbound serum concentrations with acceptable accuracy in both patient groups studied.     

Comparison of methods for determining unbound theophylline concentrations

In order to determine the suitability of using tears and saliva to estimate theophylline concentrations, simultaneous plasma, tear, and saliva samples were obtained in 22 adult male patients taking theophylline. Unbound theophylline concentrations were determined by equilibrium dialysis for nine of the subjects and compared with the concentrations determined in saliva and tears. The mean tear/unbound and saliva/unbound ratios were 0.94 +/- 0.12, r = 0.88, and 1.25 +/- 0.14, r = 0.91, respectively. Tear/plasma ratios ranged from 0.36 to 0.76 (mean 0.58 +/- 0.11), and tear concentrations correlated well with plasma concentrations (r = 0.94). Saliva/plasma ratios ranged from 0.52 to 1.16 (mean 0.79 +/- 0.19), and there was a positive correlation between plasma and saliva concentrations (r = 0.84). The mean tear/unbound and saliva/unbound ratio predicted the unbound concentration within 1 microgram/ml in 50 and 78% of the cases, respectively. Saliva and tears have limited clinical value in estimating the unbound concentration of theophylline.     

An evaluation of Bayesian microcomputer predictions of theophylline concentrations in newborn infants

Determination of appropriate theophylline maintenance doses in preterm infants is confounded by interpatient variability. This study evaluated the performance of an IBM PC computer program applying Bayesian regression before and during steady state in 37 preterm infants. Prior population estimates of clearance and distribution volume in preterm infants and Bayesian estimates of clearance and distribution volume based on one to three theophylline plasma concentrations were used to predict subsequent concentrations (drawn 1-17 days later). We assessed the accuracy and precision of the predictive performance of the Bayesian program with the mean prediction error and the mean absolute prediction error. The absolute prediction error (mean absolute error +/- SEM) significantly decreased with increasing feedback concentrations from 3.54 +/- 0.45 micrograms/ml (population estimates) to 2.74 +/- 0.42 (one feedback) and 2.02 +/- 0.35 micrograms/ml (two feedback concentrations). Mean prediction errors (+/- SEM) based on one to three feedbacks (-1.5 +/- 0.40 micrograms/ml) were significant improvements over population predictions (-2.63 +/- 0.72 micrograms/ml, p less than 0.05), although a small but significant average overprediction remained. Absolute prediction error was correlated with postconceptional and postnatal age when zero or one but not two feedback concentrations were available. Computer program predictions based on one measured feedback concentration were more accurate and precise than population-based predictions. Refinement of population parameters or two feedback concentrations further improved performance.     

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.     

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.     

Theophylline concentrations in serum, saliva, and cerebrospinal fluid in patients with essential tremor.

Theophylline concentrations in saliva and serum were compared in 20 patients with essential tremor. There was a strong correlation between the concentrations in saliva and serum (r = 0.9, slope of 0.48). The ratio between unbound and bound theophylline as assessed by ultrafiltration was 0.30. This ratio was similar to that between theophylline concentrations in CSF and serum. The theophylline concentration in serum was not predictable from that obtained in saliva in individual cases. Moreover, the levels in saliva were about 20% higher than the unbound concentrations of theophylline in serum.     

Evaluation of the Ames Seralyzer for therapeutic drug monitoring of theophylline

Dry reagent technology and reflectance photometry are combined in the Ames Seralyzer to offer a solid-phase plastic strip assay methodology. Light reflected from serum placed on the antibody-impregnated strip is quantitated with a two-point standard curve to display a theophylline result in 90 seconds. The accuracy and precision of the Seralyzer for serum theophylline are compared to the enzyme-multiplied immunoassay technique (Emit) which is commonly used to determine drug concentrations. Liquid calibrators (5 and 25 micrograms/ml) and liquid-spiked sera (10, 15, and 20 micrograms/ml) were measured six times daily simultaneously by both methods for twenty days. Eighty patient samples (theophylline range: 0-33 micrograms/ml) were measured twice each during the twenty days. Acceptable assay limits were established and maintained by measuring 15 micrograms/ml spiked sera prior to and during the evaluation period. All within-run and between-run means for the Seralyzer and Emit were within +/- 1 microgram/ml of the spiked value. All ranges of within-run and between-run means were within +/- 2 micrograms/ml of the spiked value. Mean between-run coefficients of variation for the Seralyzer at the 5, 10, 15, 20, and 25 micrograms/ml values were 11.5, 6.7, 4.9, 4.6, and 4.9 percent, respectively. Linear regression on the 80 patient samples gave a slope of 1.02, intercept of -0.28, and correlation of 0.984. The Seralyzer's accuracy and precision compare favorably with Emit for theophylline determinations greater than 7.5 micrograms/ml.     

Pharmacokinetics of caffeine and its demethylated metabolites in lactating adult rabbits and neonatal offspring. Predictions of breast milk to serum concentration ratios.

The purpose of this study was to assess the pharmacokinetics of caffeine and its metabolites in the lactating rabbit and suckling pup. The ability of a diffusional model to predict milk-to-serum drug concentration ratios (M/S) observed in vivo from in vitro experiments was established. The distribution into milk of caffeine, paraxanthine, theobromine, and theophylline was measured in lactating New Zealand White rabbits following an iv bolus dose of caffeine (5 mg/kg). M/S ratios were determined in vivo (M/Sobs; caffeine = 0.875 +/- 0.052; paraxanthine = 0.358 +/- 0.019; theobromine = 0.829 +/- 0.038; and theophylline = 0.412 +/- 0.054) under single dose conditions using area under the milk and serum concentration-time profiles. Predicted M/S values (M/Spred; caffeine = 0.797 +/- 0.040; paraxanthine = 0.316 +/- 0.029; theobromine = 0.692 +/- 0.062; and theophylline = 0.385 +/- 0.039) were calculated from in vitro measurements of the unbound fractions of drug in skim milk and serum (fm and fs, respectively), the skim-to-whole milk drug concentration ratio (S/W), milk and serum pH, and the pKa of the model compound. The pharmacokinetic profile of caffeine in the suckling pup following iv bolus administration (5 mg/kg) was more prolonged compared with adult rabbits. The mean systemic clearance of total caffeine (CIs) in the adults and the pups was 3.83 +/- 1.94 and 1.14 +/- 0.80 ml/min/kg, respectively. The mean unbound systemic clearance (CIs,u) for caffeine was 5.09 +/- 2.60 ml/min/kg in the adults and 1.41 +/- 0.71 ml/min/kg in the pups.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Urinary excretion of dyphylline in humans

The pharmacokinetics and urinary excretion of a single dyphylline dose were studied in five normal volunteers. The mean dyphylline half-life was 1.8 +/- 0.2 hr; the mean total body clearance rate and mean renal clearance rate were 333 +/- 62 and 276 +/- 52 ml/min, respectively; and the mean volume of distribution was 0.8 +/- 0.2 liter/kg. In the urine, 83 +/- 5% of the dose was excreted as unchanged drug, and theophylline was not detected. Dyphylline doses of 19--27 mg/kg, resulting in peak serum dyphylline concentrations of 19.3--23.5 micrograms/ml, were tolerated well by four subjects. One subject had a severe headache following a 28-mg/kg dose, associated with a peak serum dyphylline concentration of 36.4 micrograms/ml. This study confirms speculation that dyphylline is not metabolized to theophylline in vivo.     

Ability of three pharmacokinetic equations to predict steady-state serum theophylline concentrations in pediatric patients.

The pharmacokinetic equations of Chiou, Koup, and Kurland are often used in the pediatric setting to predict steady-state theophylline clearance using non-steady serum theophylline concentrations. However, these equations have not been validated or compared in a pediatric population. We evaluated the ability of these equations to predict steady-state serum theophylline concentrations in 61 children (0.21-14.3 years) who received a continuous intravenous theophylline (0.79 +/- 0.12 mg/kg/h) infusion for a minimum of five half-lives. Theophylline concentrations used in the Kurland equation were obtained 10.8 +/- 4.5 h after initiation of therapy and the time between the two concentrations used in the Chiou and Koup equations was 9.2 +/- 3.9 h. Predicted steady-state theophylline concentration values for the three methods were not different from each other (p = 0.91), nor were they different from the observed steady-state concentration values (p = 0.92). The coefficient of determination for predicted vs. observed steady-state concentrations was statistically significant (p less than 0.001) and was comparable for the three methods. There was no difference in mean bias (p = 0.78), precision (p = 0.82), or % error (p = 0.86) values for the three methods. Regardless of the method used, 75 to 82% of all predicted theophylline concentrations were within 20% of the observed steady-state value. However, on average, all methods underpredicted the clearance and hence overpredicted the serum theophylline concentration. The Kurland method did not predict steady-state concentrations any better in patients who had received theophylline prior to admission.(ABSTRACT TRUNCATED AT 250 WORDS)     

The relative predictive performance of two theophylline pharmacokinetic dosing programs

The predictive performance of 2 theophylline pharmacokinetic dosing programs (Abbott and Simkin) was evaluated using a group of 44 inpatients who had 2 serum concentrations (TSC) measured during hospitalization. Bias was assessed with the median prediction error (PE) and precision was assessed with the median absolute PE. The Abbott program was significantly less biased than the Simkin program in predicting the first TSC (PEs 0.1 and -1.3 micrograms/ml, respectively; p less than 0.05). No significant difference in bias was observed in predicting the second TSC, or in precision in predicting either the first or second TSC. Both programs exhibited small improvements in prediction precision when the first TSC was used to predict the second. Correlations of predicted versus measured TSC also improved with the second prediction. These programs may be useful in dosing theophylline; however, TSC monitoring and the application of sound clinical judgment are warranted.     

Determinants of the plasma protein binding of theophylline in health.

1 The plasma protein binding of theophylline was determined after addition of [14C]-theophylline (15 micrograms/ml) to plasma from 24 healthy drug-free volunteers and equilibrium dialysis for 2 h at 37 degrees C. 2 The percentage of drug unbound was 60.0% +/- 2.2% (s.d.) with very little variation between individuals. The binding ratio of theophylline was not significantly related to the plasma albumin or alpha 1-acid glycoprotein (AAG) concentrations but was significantly, although weakly, negatively related to the logarithm of the non-esterified fatty acid concentration (NEFA) (r = 0.443, P less than 0.05). 3 Intravenous administration of heparin (1000 units) caused a significant rise in plasma NEFA concentration and in the percentage of drug unbound in plasma after equilibrium dialysis. 4 In human serum albumin solutions, the binding ratio of theophylline was significantly related to the albumin concentration and at the albumin concentration seen in the 24 normal subjects, the percentage of drug unbound was almost identical. Addition of AAG in physiological concentrations did not enhance theophylline binding but oleic acid, and to a lesser extent palmitic acid, reduced binding significantly. 5 The percentage of theophylline unbound in plasma varied markedly with pH so that at pH7 the percentage unbound was 52% greater than at pH 8. There was no evidence of concentration dependence of binding up to 140 micrograms/ml theophylline. 6 Theophylline appears to bind almost exclusively to albumin and its plasma protein binding varies little in healthy subjects, showing no concentration-dependence over the therapeutic range of concentrations. The binding is affected by pH and by NEFA concentration, however, and these factors may be of greater importance in disease states. Caution should be employed in the use of heparin in studies of plasma protein binding of theophylline.     

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.     

Transfer of fosfomycin into human burn blister fluid and its pharmacokinetic analysis

Fosfomycin (FOM) (50 mg/kg) was administered to burned patients by intravenous bolus injection. Burn blister fluid and serum were taken during 8 hours after injection, and concentrations of FOM in burn blister fluid and serum were determined by bioassay using Proteus sp. (MB-838) as the test organism. The serum concentrations of FOM were 257 +/- 34.6 micrograms/ml at 15 minutes, 222 +/- 34.8 micrograms/ml at 30 minutes, 166 +/- 34.6 micrograms/ml at 1 hour, 114 +/- 43.9 micrograms/ml at 2 hours, 79.5 +/- 34.9 micrograms/ml at 3 hours, 63 +/- 36.4 micrograms/ml at 4 hours, 44.3 +/- 27.6 micrograms/ml at 5 hours, 29.6 +/- 20.9 micrograms/ml at 6 hours and 17.9 +/- 12.8 micrograms/ml at 8 hours after the injection. FOM concentrations in burn blister fluid were 64.4 +/- 18.1 micrograms/ml at 30 minutes, 77 +/- 26.0 micrograms/ml at 1 hour, 71.6 +/- 24.7 micrograms/ml at 2 hours, 64.8 +/- 23.6 micrograms/ml at 3 hours, 43.2 +/- 8.8 micrograms/ml at 4 hours, 24.8 +/- 7.9 micrograms/ml at 6 hours and 17.9 +/- 10.5 micrograms/ml at 8 hours after the injection. The obtained data were analysed pharmacokinetically. The serum levels were analysed by a two-compartment model, and the transfer of FOM into burn blister was analysed by a modified deconvolution method. In results, Tmax and Cmax of FOM levels in burn blister fluid were calculated as 1.3 hours and 80.9 micrograms/ml, respectively. The transfer rate constant of FOM from serum to burn blister fluid (K1) and that from burn blister fluid to serum (K2) were calculated as 0.612 hr-1 and 1.10 hr-1, respectively.     

Transfer of latamoxef into human burn blister fluid and its pharmacokinetic analysis

Latamoxef (LMOX) (50 mg/kg) was administrated intravenously to burned patients over 1 hour period. Burn blister fluid and serum were taken during 8 hours after injection, and concentrations of LMOX in burn blister fluid and serum were determined by bioassay using E. coli as a test organism. The serum concentrations of LMOX were 170.8 +/- 30.6 micrograms/ml at 30 minutes, 227.0 +/- 19.8 micrograms/ml at 1 hour, 90.3 +/- 21.4 micrograms/ml at 2 hours, 52.9 +/- 14.6 micrograms/ml at 3 hours, 38.7 +/- 13.3 micrograms/ml at 4 hours, 25.1 +/- 8.1 micrograms/ml at 5 hours, 20.5 +/- 8.1 micrograms/ml at 6 hours, 13.0 +/- 5.5 micrograms/ml (mean +/- S.D., n = 5) at 8 hours after the injection. The LMOX concentrations in burn blister fluid were 36.9 +/- 32.8 micrograms/ml at 30 minutes, 77.5 +/- 42.2 micrograms/ml at 1 hour, 85.4 +/- 19.6 micrograms/ml at 2 hours, 76.4 +/- 18.5 micrograms/ml at 3 hours, 63.5 +/- 17.8 micrograms/ml at 4 hours, 54.9 +/- 17.1 micrograms/ml at 5 hours, 34.8 +/- 10.3 micrograms/ml at 6 hours, 25.2 +/- 4.8 micrograms/ml (mean +/- S.D., n = 7) at 8 hours after the injection. The data obtained were analysed pharmacokinetically. The serum levels were analysed by two-compartment model, and the LMOX levels in burn blister fluid were analysed by the model, in which blister was considered as a small part of the peripheral compartment. In results, Tmax and Cmax of LMOX levels in burn blister fluid were calculated as 1.81 hours and 90.6 micrograms/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cimetidine inhibits theophylline clearance in patients with chronic obstructive pulmonary disease: a study using stable isotope methodology during multiple oral dose administration.

1 The effect of concurrent cimetidine administration on the disposition of theophylline was investigated in eight male patients (56-78 years) with chronic obstructive pulmonary disease (COPD). 2 The patients, who were taking oral theophylline preparations chronically (384-1020 mg/day), received a [15N], [13C]-labelled analogue of theophylline (10 mg i.v.) before and during cimetidine treatment (1200 mg/day p.o.). 3 During cimetidine treatment trough levels of theophylline increased 34% (6.4 +/- 0.8 to 8.6 +/- 1.0 micrograms/ml, P less than 0.05), half-life increased 48% (6.5 +/- 0.6 to 9.6 +/- 0.8 h, P less than 0.001), and total plasma clearance decreased 33% (3.88 +/- 0.46 to 2.59 +/- 0.33 l/h, P less than 0.001), without a significant change in volume of distribution or protein binding. 4 The effect of cimetidine on plasma levels of theophylline was maximal within 72 h. Levels returned to control values within 48 h after its discontinuation. 5 Although there was no correlation with mean plasma concentrations of cimetidine, the change in clearance of theophylline correlated with initial clearance values (r = 0.72). 6 Cimetidine reduced the plasma clearance of theophylline in patients with COPD to an extent similar to that reported in healthy volunteers.