Comparative bioavailability of sustained-release and conventional tablets of hydroxyethyltheophylline in man

The comparative bioavailability of sustained-release and conventional tablets of hydroxyethyltheophylline was studied in normal subjects. In a single dose study on 7 subjects, 3 conventional tablets or 2 sustained-release tablets were administered orally after a light breakfast and blood samples taken for 6 and 12 hours respectively. With conventional tablets the mean peak concentration (8.10 +/- 0.751 microgram/ml) was reached at 3 hours and concentrations less than 5 microgram/ml were observed in 4 out of 7 subjects at 6 hours. In contrast, with sustained-release tablets of theophylline and hydroxytheophylline complex the mean peak concentration (8.90 +/- 0.88 microgram/ml) was reached at 6 hours and levels above 5 microgram/ml were observed in 4 out of 7 cases at 12 hours. Administration of 2 sustained-release tablets twice a day produced trough plasma concentrations varying between 6.9-13.8 microgram/ml, i.e. within the therapeutic range in all the 5 subjects. It is concluded that this new oral sustained-release preparation provides therapeutic plasma theophylline concentration on a 12 hourly dosage schedule.     

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.     

Relaxant effects of mefloquine on vascular smooth muscle in vitro

Summary Antacids can modify the pharmacokinetic parameters of sustained-release preparations of theophylline by changing the gastric pH. Though this has been studied with various theophylline/antacid combinations, the specific preparations investigated here have not previously been tested. The objective of the study was to assess any change in the availability of theophylline from a sustained-release preparation (SR), induced by the coadministration with an antacid.The study was designed as a double-blind randomized crossover trial in the Pneumology Departments of three general hospitals.Fifteen patients were studied. They all had stable asthma treated with theophylline and no major organ failure or gastro-intestinal lesions requiring the use of antacids. The antacide (aluminium hydroxide 800 mg and magnesium hydroxide 800 mg), or placebo, tid, was added to a stable regimen of theophylline SR bid, for 4 days, in crossover fashion.Plasma theophylline concentrations were measured before and 1,2,3,4,6,8,10,12,16 and 24 h after the morning dose of Armophylline on the fourth day of each treatment period; the maximum plasma concentration (C_max), and time to C_max (t_max) were noted, and the area under the 24-h time-concentration curve (AUC_0–24) and mean plasma concentration (C_mean) were computed. Peak expiratory flows on the same day, before and 3, 6 and 12 h after the morning dose of Armophylline were also measured.There was no change in any of the parameters studied.The addition of the antacide to theophylline, each given according to standard clinical practice, did not modify the pharmacokinetics of the latter. This result probably can not be generalized to all pairs of sustained-release theophylline-antacid preparations.     

Plasma theophylline concentrations following the oral administration of microcrystalline theophylline and a new sustained-release theophylline preparation to normal subjects

Summary Plasma theophylline concentrations have been measured in 14 normal subjects following the oral administration of a microcrystalline theophylline preparation (MT) 187.5 mg every 6 h and a sustained-release theophylline preparation (SRT) 375 mg every 12 h for 5 days. During the 5 days, blood samples were drawn before and 2 h after each morning dose with MT, and before and 4.5 h after each morning dose of SRT. On days 1 and 5, more frequent samples were taken during the dose interval. With both preparations, steady-state plasma concentrations were achieved by the third day. The trough levels were significantly higher with SRT than with MT on days 3 and 4, and the levels at 4.5 h after SRT were significantly higher than those measured 2 h after MT on days 3, 4 and 5. Over the terminal 3 days of the study, mean theophylline concentrations with SRT ranged between 11.2 and 15.5 µg/ml at measured trough and peak times, whereas the mean trough levels with MT were always below 10 µg/ml. With adjustment for the dosage differences, the mean ratio of the areas under the plasma concentration/time curves for the final dosage interval for the two formulations (AUC_SRT/AUC_MT) was 1.29±0.56, suggesting that the SRT preparation was well absorbed. The mean steady-state plasma theophylline concentrations (AUC/dose interval) on day 5 were 11.5±4.7 µg/ml with MT and 13.7±5.7 µg/ml with SRT. Nine subjects experienced a total of 35 side-effects whilst taking MT, compared with 10 subjects complaining of 23 side-effects on SRT. These results indicate that, in normal subjects, SRT 375 mg every 12 h exhibited satisfactory sustained-release properties and achieved adequate mean plasma theophylline concentrations during chronic administration. It produced higher plasma levels and a lower incidence of side-effects than the same daily dose of MT.     

Investigation of diurnal changes in the disposition of theophylline

The mechanism of observed temporal variations in plasma theophylline concentrations has been investigated. Eight healthy volunteers were given both oral and intravenous doses of theophylline (5 mg/kg) at 09.00 h and 21.00 h under controlled conditions. Regular plasma concentration measurements were made following each dose in order to determine the diurnal and nocturnal disposition of the drug. Plasma theophylline concentrations at 0.5 h following each oral dose were 6.9 +/- 0.8 micrograms/ml, a.m., and 3.9 +/- 0.6 microgram/ml, p.m. (P less than 0.05). Time to peak concentration was 1.69 +/- 0.28 h, a.m.; 2.13 +/- 0.23 h, p.m. (P less than 0.05). Values for ka were not significantly different, however. Overall bioavailability, volume of distribution and systemic clearances, calculated for the 12 h period after each dose, did not differ significantly between day and night. Diurnal variations in theophylline disposition do not appear to be the result of changes in metabolism or excretion, but may reflect minor differences in absorption.     

Prediction of optimum oral theophylline dose in patients with obstructive airways disease.

The hypothesis that a logarithmic correlation exists between the plasma theophylline concentrations 6 h after a test dose C(6) and the maintenance dose calculated to achieve a desired drug concentration during chronic oral administration (DM,CALC) was tested. A nomogram based on this relationship was evaluated as a means of predicting the optimum dose of theophylline in 14 patients with obstructive airways disease (DM,PRED). Each patient was given 5 mg/kg theophylline intravenously (i.v.) and plasma theophylline concentrations were measured for 12 h thereafter including one exactly 6 h after commencing the i.v. infusion C(6). Pharmacokinetic parameters derived from the plasma concentration-time curve were used to establish DM,CALC for a concentration of 10 micrograms/ml. DM,PRED was obtained from the nomogram using both the optimum and the actual values for C(6). Subsequently oral sustained-release theophylline was administered and the dose adjusted to establish a trough concentration of approximately 10 micrograms/ml. This dose was then corrected arithmetically, assuming a linear relationship between dose and plasma level, to represent that required to achieve a plasma concentration of exactly 10 micrograms/ml (DM,ACT). The correlation between C(6) and log DM,CALC was confirmed (r = 0.97 P less than 0.001), validating the hypothesis. DM,ACT was found to correlate significantly with DM,PRED (r = 0.90, P less than 0.01) substantiating the value of the nomogram. In nine of the 14 patients, DM,ACT corresponded satisfactorily to DM,PRED. In the remaining five, for whom DM,ACT lay outside the 95% confidence limits for the predicted dose, DM,PRED in general underestimated DM,ACT, an advantage in a drug with a low therapeutic index. The predictive error for DM,PRED was lower than that for DM,CALC, and the bias using either method was not significant. The results suggest that a single plasma theophylline assay following a test dose, and the nomogram may be useful in simplifying optimal theophylline administration.     

Prediction of maintenance oral theophylline dosage using single oral doses in patients with obstructive airways disease

This study was designed to test whether single oral doses of theophylline, rather than the specified single intravenous infusions, could be used with a nomogram designed to predict the maintenance oral dose necessary to establish plasma theophylline concentrations of 10 micrograms ml (Koup et al., 1979) in patients with obstructive airways disease. A test dose of theophylline (5 mg kg) was administered on two separate occasions as an oral elixir and as an intravenous infusion. Exactly 6 h after each test dose, plasma theophylline concentration was measured, and the result used to predict daily maintenance dose requirements. During subsequent oral administration, a sustained-release preparation was given in equally divided 12-hourly doses, and 'steady-state' concentrations were measured at trough. Nineteen patients completed the study, and on doses ranging from 4.2 to 21.1 mg kg-1 day-1, trough concentrations of 5.4 to 15.8 micrograms ml (mean 10.0 +/- 0.7 micrograms ml) were achieved. No significant differences were noted between the dose predictions made following either the oral or the intravenous test doses, and the predictive accuracy using the oral route was not compromised. This would suggest that the test dose of theophylline may be administered orally, instead of intravenously, with this nomogram without reducing its efficiency.     

Effect of an enteral nutrient formula on sustained-release theophylline absorption

The effect of an enteral nutrient formula (Osmolite) on the absorption of a single oral dose of sustained-release theophylline (Slo-bid) was studied in healthy men. In a randomized, crossover design, subjects received the enteral nutrient diet (2,400 ml/day) or food diet (F) of similar caloric, fat, carbohydrate, protein, and sodium content for 7 days. On day 6 of each diet, volunteers received a single oral dose (600 mg) of sustained-release theophylline (SRT) after fasting or with hourly oral boluses (100 ml) of enteral nutrient formula (ENF). Serial blood samples were collected for 48 h and serum concentrations were analyzed by enzyme multiplied immunoassay. Slight differences (p less than 0.01; paired t test) in Cmax (7.1 +/- 1.2 versus 8.2 +/- 1.3 mg/L) and Tmax (10.7 +/- 2.4 vs. 7.1 +/- 1.1 h) were observed between the ENF and F diets, respectively. However, areas under the curve values were similar (215 +/- 72 versus 211 +/- 70 mg h/L). This study suggests that ENF does not affect the extent of absorption of SRT when administered as a single oral dose.     

Plasma concentrations of isosorbide dinitrate after oral administration of a sustained-release formulation to human subjects

1. A peak of mean plasma concentrations of isosorbide dinitrate of 5.8 ng/ml was reached at 0.5 h after a single oral dose of 5 mg in a standard tablet formulation. Thereafter mean concentrations declined with a half-life of about 48 min. 2. A peak of mean concentrations of isosorbide dinitrate of 3.2 ng/ml was reached at 2--4 h after a single oral dose of 20mg in a sustained-realease capsule formulation (Iso Mack Retard). Thereafter mean concentrations declined by about twofold during 6 h and were still detectable at 12 h after dosing. 3. When corrected by dose/bodyweight variations, the mean area under the isosorbide dinitrate plasma concentration curve from the sustained-release capule was 76% of that from the standard tablet and this formulation-related difference in bioavailability was statistically significant (p less than 0.05). 4. The results showed that sustained-release formulation is a useful way to maintain plasma concentrations of isosorbide dinitrate for several hours.     

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.     

Serum theophylline concentrations and pulmonary function tests after administration of two sustained-release formulations containing theophylline in patients affected by chronic obstructive lung disease

We compared serum theophylline concentrations in patients treated with one of two commercially available theophylline preparations: a sustained-release aminophylline and a sustained-release theophylline. Two comparable groups of 15 out-patients with stable, chronic obstructive lung diseases were studied: one group was given sustained-release aminophylline while the other took sustained-release theophylline. Both drugs were administered orally for 7 days at a daily dose, equivalent to 12 mg/kg in terms of anhydrous theophylline. Serum theophylline concentrations were always significantly lower after treatment with sustained-release aminophylline than after treatment with sustained-release theophylline, which latter frequently caused undesirable side-effects. Moreover, patients receiving sustained-release aminophylline always showed serum theophylline concentrations lower than 10 mcg/ml. Pulmonary function tests were unaffected by the administration of either drug. We conclude that sustained-release theophylline is more effective than sustained-release aminophylline in terms of induced serum theophylline concentrations. However neither drug was suitable for the treatment of patients with chronic obstructive lung disease without other concomitant therapy.     

Bioavailability of a new sustained-release theophylline capsule in fasted and non-fasted healthy subjects: single and multiple dosing studies

Eighteen healthy, non-smoking, adult volunteers participated in single and multiple dose three-way crossover studies to evaluate a sustained-release, pellet-filled capsule of theophylline, Austyn. The effect of food on the bioavailability of the sustained-release capsule was investigated by administering 300 mg single doses of Austyn, with a high-fat meal and without food and a divided 300 mg dose of the reference product Elixophyllin elixir, given after fasting. Plasma theophylline concentrations were measured by fluorescence polarization immunoassay (FPIA) which had been validated against HPLC. The single dose study data showed that there were no significant differences (n = 18, ANOVA, p greater than 0.05) between the three regimens with respect to AUC0-infinity values (mg h l-1), (mean +/- SD); Elixophyllin fasting = 97.1 +/- 33.7, Austyn with food = 90.9 +/- 31.3, Austyn fasting = 91.2 +/- 33.8. Similarly, multiple dosing with rapid-release Nuelin tablets, Austyn capsules, and sustained-release Theo-Dur tablets demonstrated that there were no significant differences between regimens with respect to AUC0-24h, AUC0-12h, and AUC12-24h values calculated from the steady-state concentrations (5th day, 24 h sampling). However, the percentage fluctuation at steady-state over the total blood sampling period was significantly less for treatment with the sustained-release capsule. Austyn, compared with the sustained-release tablet, Theo-Dur (Austyn = 36.7 +/- 13.7 per cent, Theo-Dur = 53.1 +/- 14.1 per cent). The results of the single and multiple dose studies indicate that Austyn capsules demonstrate complete bioavailability, and good controlled release characteristics not influenced by concomitant intake of a high-fat meal and with no evidence of dose dumping.     

Patient compliance with oral theophylline therapy.

Day-to-day variations in plasma theophylline concentrations at steady-state have been assessed in 29 hospital inpatients who required theophylline for obstructive airways disease. Plasma concentrations were measured at 09.00h and 14.00h for four consecutive days in the equilibrium state in 13 patients taking 350 mg/day and 16 patients taking 700 mg/day. Analysis of variance gave 95% confidence limits for day-to-day variation of +/- 2.9 micrograms/ml at 350 mg/day and +/- 4.8 micrograms/ml at 700 mg/day. In a separate study, compliance with sustained-release theophylline therapy has been assessed in a group of 63 patients receiving the drug in general practice but not attending hospital. Compliance was estimated by comparing plasma theophylline concentrations before and after a 7-day period of measured theophylline consumption and by tablet counting. Of the 63 patients, 16 had discontinued their theophylline prior to being contacted and two did so during the first week: these were considered non-compliant. Three patients had plasma concentrations which increased by more than the day-to-day variation for their dose level during monitored intake and one other took less than 80% of his tablets. These patients were also considered non-compliant. A further four patients in whom plasma theophylline levels were zero on at least one occasion during the study were also adjudged non-compliant. Thus non-compliance with prescribed theophylline dosage occurred in 26 (41.3%) of the patients studied. In the majority of these, treatment had been discontinued and the non-compliance was gross.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of sustained-release verapamil after a single administration and at steady state

Pharmacokinetics of conventional 80 mg tablets and two types of sustained-release (SR) tablets containing 120 and 200 mg of verapamil were compared cross-over in 12 healthy volunteers. Serum concentrations of verapamil and norverapamil were analyzed both after a single oral dose and at steady state after t.i.d. administration of conventional tablets and b.i.d. administration of SR tablets. After 120 mg SR tablets serum concentrations of verapamil usually remained below 100 ng/ml for 5 days. This inadequate bioavailability was caused by very slow absorption. The relative bioavailability of verapamil in 200 mg SR tablets was 93-96% as compared to the conventional tablets. After 200 mg X 2 and 80 mg X 3, the peak serum levels were about 300 and 190 ng/ml, respectively and the trough levels 123-153 and 52-56 ng/ml, respectively. The verapamil/norverapamil ratio varied from 0.69 to 0.84 after a single dose and from 0.8 to 0.93 at steady-state. By the 4th days of treatment, the accumulation ratios ranged between 1.75-2.07 and 1.30-1.75 for verapamil and norverapamil, respectively. For each preparation studied, the apparent Cltot of verapamil was significantly reduced at steady-state. These results show that 200 mg SR verapamil tablets fulfill the basic requirements of retard preparations allowing for twice or even once daily administration.     

Acute and chronic pharmacokinetics of asymmetrical doses of slow release choline theophyllinate in asthma.

The day and night pharmacokinetics of assymetrical doses of slow release choline theophyllinate (Sabidal SR 270) were compared at day 1 and at day 4 of treatment when steady state had been achieved. Ten patients with chronic asthma were given oral choline theophyllinate 424 mg at 09.00 h and 848 mg at 21.00 h for 4 days. At regular intervals during day 1 and day 4 of treatment theophylline concentrations were measured in plasma and dried blood spots by fluorimmunoassay. Theophylline concentrations measured from dried blood spots were slightly lower than those in plasma, the difference remaining constant at all time points during day 1 and day 4 of treatment. On day 1 the mean peak plasma theophylline concentration was 5.4 +/- 1.0 (+/- s.e. mean) micrograms ml-1 4 h after the morning dose and 11.2 +/- 1.6 micrograms ml-1 4 h after the evening dose which were significantly (P less than 0.01) different. Similarly the areas under the plasma theophylline concentration-time curves at night were significantly (P less than 0.001) greater than those observed during the day. During day 4 mean peak plasma concentrations of theophylline after the morning and larger evening dose were 13.2 +/- 1.3 and 12.1 +/- 1.4 micrograms ml-1 respectively, which were not significantly different. No significant difference was observed between the areas under the plasma theophylline concentration-time curves during the day and at night. However the post-dose time to peak was significantly delayed at night (6 h) compared to the morning (2 h, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Multiple-dose pharmacokinetics of fesoterodine sustained-release in healthy Korean volunteers

Objective: Fesoterodine is a pro-drug of the active metabolite 5-hydroxymethyl tolterodine (5-HMT), a muscarinic receptor antagonist. This study aimed to evaluate the safety profile and pharmacokinetic characteristics of multiple oral doses of sustained-release fesoterodine (fesoterodine SR) in healthy Korean males. Methods: A randomized, double-blind, placebo-controlled, multiple-dose study with two oral doses (4 mg and 8 mg) was conducted in healthy Korean male participants. The study drug was administered once daily for 5 days. The plasma concentration of 5-HMT was measured up to 72 hours after the last drug administration. The CYP2D6 genotype was analyzed using polymerase chain reaction (PCR) methods to assess the effect of genetic polymorphisms on the pharmacokinetic parameters. Results: 20 participants completed the study. The mean (SD) areas under the plasma concentration-time curves during the dosing interval (AUCτ) of the 4 mg and 8 mg dose groups were 26.1 (8.0) and 64.2 (30.5) μga??h/ml and the mean peak concentrations (Cmax) were 2.6 (0.7) and 6.0 (2.0) μg/ml, respectively, at steady-state. The mean AUCτ and Cmax of 5-HMT increased in approximately the same proportion as the dose increased. Fesoterodine SR was well tolerated without any serious adverse events or abnormal clinical laboratory findings. Conclusion: Systemic 5-HMT exposure showed dose-proportional characteristics in the 4 mg to 8 mg dose range in healthy Korean males. Thus, 4 mg or 8 mg doses of fesoterodine SR taken once-daily were tolerable in healthy Korean males.     

Comparative pharmacokinetics of ketoprofen derived from single oral doses of ketoprofen capsules or a novel sustained-release pellet formulation

Nine healthy male volunteers took part in a crossover study to compare the pharmacokinetics of ketoprofen after administration of a single oral dose (200 mg) of ketoprofen as 'Orudis' capsules or encapsulated sustained-release pellets, 'Oruvail'. The mean +/- standard deviation values for highest observed plasma ketoprofen concentrations were determined by high performance liquid chromatography to be 23 +/- 11 micrograms ml-1 at 0.82 +/- 0.18 h after dosing with ketoprofen capsules and 3.5 +/- 1.0 micrograms ml-1 at 4.9 +/- 1.0 h after dosing with sustained-release pellets. The apparent ketoprofen elimination half-lives after these treatments were 3.3 +/- 1.2 h and 8.4 +/- 3.4 h, respectively. The systemic availability of ketoprofen was essentially the same after each treatment. Administration of sustained-release pellets (containing 200 mg ketoprofen) once every 24 h is predicted to produce similar average and markedly higher minimum plasma ketoprofen concentrations than are produced by ketoprofen capsules (100 mg) every 12 h, and similar minimum plasma ketoprofen concentrations to those achieved by dosing ketoprofen capsules (50 mg) every 6 h. Once-daily administration of a non-steroidal anti-inflammatory agent has an obvious therapeutic advantage over more frequent dosing. This study suggests that the sustained-release pellet formulation described herein is a suitable formulation for once-daily administration of ketoprofen.     

Pharmacokinetics of a microcrystalline theophylline preparation in patients with chronic obstructive airways disease

Summary Plasma theophylline concentrations have been measured in 9 patients with chronic obstructive airways disease following the oral administration of a microcrystalline theophylline preparation. Some measurements of FEV₁ were also made. Four patients were given 375 mg as a single dose and then subsequently 375 mg stat and 125 mg 4 times daily for 3 days, (Group I). A further 5 patients took 250 mg as a single dose and then 250 mg 4 times daily for 3 days, (Group II). In both groups, following the single dose and again after the last dose of chronic administration, blood samples were obtained at frequent intervals up to 24 h for plasma drug estimation. During the 3-day course, blood samples were drawn before and 2 h after each morning dose. In Group I patients, substantial plasma theophylline concentrations were seen only after the loading dose. Thereafter, the mean concentrations before or 2 h after the morning doese were always less than 4.0 µg/ml. Trough concentrations were usually below 2.0 µg/ml. In contrast patients in Group II achieved substantially higher plasma theophylline concentrations, with mean peak concentrations always 10 µg/ml or greater, and trough concentrations greater than 5 µg/ml on at least one occasion in every subject. The elimination half-lives after chronic administration in both groups were not significantly different from those obtained after single doses. Mean drug accumulation, measured as AUC_ss/AUC₁, was 0.87±0.07 in Group I and 0.72±0.14 in Group II, indicating that accumulation had not occurred with either regimen. The mean increase in FEV₁ 2 h after the administration of a single dose was 19.2% after 375 mg and 16.7% after 250 mg. These results indicate that the recommended dosage regimen for microcrystalline theophylline preparation (375 mg stat and 125 mg 4 times daily) produces inadequate plasma theophylline concentrations: 250 mg 4 times daily would appear to be likely to result in satisfactory theophylline levels in more patients.     

Is circadian variation in theophylline trough serum concentrations determined by time of dosing?

Ten healthy volunteers were each given two separate courses of eight doses of theophylline 200 mg as a slow release preparation at 12 hourly intervals. In the first course (regimen 1) the dose was given at 11.00 h and 23.00 h and in the second (regimen 2) at 05.00 h and 17.00 h. Sixty hours after the start of each course, four consecutive trough serum theophylline concentrations were measured. On regimen 1 the trough concentration of theophylline was 6.2 +/- 2.2 mg/l (mean +/- s.d.) at 11.00 h compared with 5.4 +/- 1.9 mg/l at 23.00 h (P less than 0.01). This circadian variation was abolished during regimen 2 when the mean theophylline concentrations were identical at 5.2 mg/l. The higher trough concentrations after the evening dose on regimen 1 and the loss of circadian variation on regimen 2 may be due to the change in sleep period in relation to the time of dosing.