a Department of Pharmacy Services, Clinical Pharmacology Research Center, Bassett Healthcare, 1 Atwell Road, Cooperstown, NY 13326-1394, USA; b Department of Medicine, Clinical Pharmacology Research Center, Bassett Healthcare, 1 Atwell Road, Cooperstown, NY 13326-1394, USA; c Clinical Pharmacology Research Center, Bassett Healthcare, 1 Atwell Road, Cooperstown, NY 13326-1394, USA
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Abstract |
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Introduction |
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Theophylline is a methylxanthine compound that is extensively metabolized by the CYP1A2 enzyme system and has clinically significant drug interactions with many drugs, including some macrolides (i.e. erythromycin, clarithromycin). 4,5 Although not clinically significant, a previous study demonstrated that co-administration of dirithromycin with theophylline significantly increased the clearance and decreased the area under the serum-concentration- time curve (AUC) of theophylline. 6 These findings are contrary to past macrolide- theophylline interaction studies, which have demonstrated decreased clearance and increased theophylline exposure. 5 The purpose of this study was to characterize the effect of dirithromycin on theophylline clearance and either to validate or to refute the previous anomalous findings.
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Materials and methods |
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By means of a random numbers table, subjects were randomized to receive the following regimens in random order with a 3 week washout period between the two phases: (i) a single 5 mg/kg dose of oral theophylline based on total bodyweight (TBW) given 2 h after a low-fat breakfast; (ii) 500 mg (two 250 mg tablets) of dirithromycin (Dynabac; lot no. ONE28N; Eli Lilly, Indianapolis, IN, USA) with a low-fat breakfast for 10 days plus a single dose of theophylline 2 h after the final dirithromycin dose. Theophylline doses were administered as aminophylline Oral Solution USP (lot nos 972495 and 961525; Roxane Laboratories Inc., Columbus, OH, USA), containing 90.3 mg of anhydrous theophylline per 5 mL of solution. One pre-dose (baseline) blood sample was taken, and 10 postdose blood samples were collected at 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, 4.0, 8.0, 12.0 and 24.0 h after each theophylline dose. Each 7 mL blood sample was collected, after an initial 3- 5 mL had been withdrawn and wasted, from an indwelling catheter, which was flushed with 5 mL of 0.9% sodium chloride before and after sample collection. Samples were centrifuged within 1 h of collection, and serum was transferred to storage containers and frozen at -80°C until assayed.
Theophylline samples were analysed using the Ektachem 250 Analyzer automated immunoassay
system (Johnson & Johnson Clinical Diagnostics, Rochester, NY, USA) with the Vitros
Chemistry Products theophylline slides (Johnson & Johnson Clinical Diagnostics). Each sample
was analysed in duplicate. If the difference between the two values was >15%, two more
analyses were performed. The mean of the assays was used in the analyses. The linear range of
detection for the assay was 0.1- 40.0 mg/L with a CV% of 10.
Theophylline concentration data were analysed by using the TopFit Version 2.0 computer
software.
8 This program utilizes a nonlinear least-squares regression
analysis method. Modelling of the concentration- time data was performed using
noncompartmental analysis and a weighting function of 1/y
2. Goodness of fit was determined by evaluating the
standard errors of the parameter estimates and by visual examination of the residuals. The
following pharmacokinetic parameters were obtained: area under the concentration- time curve
from zero to infinity (AUC0), total oral
clearance
(Cl/F, where F denotes bioavailability), maximum concentration of
drug in serum (Cmax), time to maximum concentration of drug in serum (Tmax), oral volume of distribution (V/F), elimination
rate
constant (k
e), and terminal elimination half-life (t½).
A pre-study power calculation using an level of 0.5, a ß level of 0.10, and an
estimated
clinical significance of 25% reduction in the treatment group found that a sample size of 12 was
necessary to find a difference. Descriptive statistics were calculated for subject demographic
parameters. Because the sample size was small the nonparametric Wilcoxon signed-rank test was
used to compare treatment phases. A value of P
0.05 was considered to be
statistically significant. Data are presented as mean ± S.D.
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Results |
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Discussion |
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A previous study 6 found that the mean Cmax concentrations of theophylline were reduced by 26% and that clearance exhibited an increase of comparable magnitude when co-administered with dirithromycin. The findings of this study are very different from what would be expected from previous macrolide-theophylline interaction reports. 5 This may be a consequence of the dichotomy that is seen with macrolide metabolism. Whereas erythromycin and clarithromycin are both known inhibitors of CYP1A2 metabolism, dirithromycin has yet to demonstrate such a propensity. 1,2,3,13,14
In the present study, administration of a standard course of dirithromycin did not significantly alter any of the pharmacokinetic parameters of a single oral dose of theophylline. These data contradict the study by Bachmann et al. 6 and could be caused by significant differences in study design involving: (i) dosing of theophylline; (ii) number of post-dose serum samples; (iii) administration of dirithromycin with food; (iv) inclusion of females; and (v) dosage form of theophylline. In the present study the patients were all dosed according to bodyweight (5 mg/kg) whereas previously all subjects received the same dose without regard to their weight. Moreover in the present study blood was drawn for 24 h after theophylline administration to characterize the elimination profile of theophylline better, whereas Bachmann et al. 6 only sampled 12 h after theophylline administration, thereby incorporating only a single elimination half-life, which could lead to errors in interpretation. The bioavailability of dirithromycin has been shown to be dramatically enhanced when administered with food. 1 In the present study dirithromycin was given with food whereas in the original study 6 dirithromycin was given on an empty stomach, which would have reduced the absorption of dirithromycin considerably. Bachmann et al. 6 did not include any females in their study, which limits its extrapolation to that population whereas the present study did include females. However, inclusion of females is unlikely to be the cause of the differences discovered. Finally, in the present study theophylline was administered as an immediate release product whereas Bachmann et al. 6 administered theophylline as a sustained release product which could have introduced period variation in bioavailability.
The differences in the two studies may or may not be the reason for the differing results. The most significant difference would be the administration of food. A similar study was also performed by Bachmann et al. 15 2 years after their original experiment and utilized patients with chronic obstructive pulmonary disease (COPD). In that study there was no statistically significant change in any of the pharmacokinetic parameters of theophylline. The only obvious change in study design between the two studies by Bachmann et al. was that dirithromycin was administered with food in the later study.
According to the present study, dirithromycin does not clinically or statistically significantly alter the pharmacokinetic parameters of or overall exposure to theophylline. Dirithromycin may be safely prescribed to patients taking theophylline, with no dosage adjustments for theophylline being required.
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Notes |
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References |
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Received 9 September 1998; accepted 28 December 1998