Lack of effect of dirithromycin on theophylline pharmacokinetics in healthy volunteers

Scott A. McConnella, Anne N. Nafzigerb,c and Guy W. Amsdena,b,c,*

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


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Twelve healthy volunteers were enrolled in an open-label, randomized, crossover study. Subjects received single doses of theophylline (5 mg/kg) alone and after a 10 day course of dirithromycin (two 250 mg tablets od). The study phases were separated by a 3 week washout period. Serum samples were collected before and for 24 h after theophylline doses. Serum theophylline concentrations were measured via a validated immunoassay system and the data were modelled via non-compartmental analysis. When the control phase (i.e. no dirithromycin) was compared with the treatment phase (i.e. with dirithromycin), theophylline exposures as measured by AUC0->{infty} were not significantly different: 141.7 ± 25.9 and 136.4 ± 33.1 mg · h/L respectively (P=0.16). No significant changes in other theophylline pharmacokinetic parameters were evident. These results indicate that theophylline can be safely co-administered with dirithromycin.


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Dirithromycin is an advanced-generation macrolide antibiotic that is approved for use in respiratory tract infections. 1 Dirithromycin, unlike other macrolide antibiotics such as clarithromycin and erythromycin, is not metabolized through the hepatic cytochrome P-450 (CYP) enzyme systems. 2,3 Dirithromycin, a prodrug, is rapidly converted by non-enzymatic hydrolysis during absorption to erythromycylamine, the active compound. 1 No other metabolites have been detected and dirithromycin has no clinically significant drug interactions identified to date. 2,3

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.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This study was approved by the Institutional Review Board of the Mary Imogene Bassett Hospital. Written informed consent was obtained from each subject. Twelve volunteers meeting the following criteria were included in the study: (i) healthy as determined by medical history, physical examination, and laboratory screening (i.e. electrolytes, glucose, blood urea nitrogen, serum creatinine, urine pregnancy test for women of childbearing potential, and hepatic function tests (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase and total bilirubin)); (ii) female volunteers were either surgically sterile or had used an effective form of nonhormonal birth control for 3 months before the study and were willing to continue using it during and for 3 months after the study. Subjects were excluded from the study if they met any of the following criteria: (i) an abnormal response/value on medical history, physical examination, or laboratory screening; (ii) obesity, defined as a total bodyweight >30% above the upper limit of the ideal bodyweight for the subject's height and body frame (based on Metropolitan Life Insurance tables); (iii) exposure to drugs other than acetaminophen in the 10 days before study entry; (iv) a history of intolerance or allergy to theophylline, caffeine, dirithromycin, or erythromycin; (v) a history of smoking or the use of nicotine delivery devices within 12 months before study initiation; (vi) a history of alcohol or drug abuse; (vii) donation of blood in the 8 weeks before study initiation. Subjects were asked to abstain from caffeinated beverages, chocolate, charbroiled meats, cruciferous vegetables (e.g. broccoli, cauliflower, Brussels sprouts and cabbage), foods with a high fat content, and alcohol for 48 h before and during each study phase, as these have been shown to impact CYP1A2 drug metabolism. 7

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->{infty}), 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 {alpha} 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.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
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 References
 
Demographic parameters for the 12 subjects (eight males and four premenopausal females) are presented in Table I. Table II illustrates the mean theophylline pharmacokinetic parameters for subjects both with and without dirithromycin. Administration of dirithromycin caused no significant changes in any theophylline pharmacokinetic parameter (AUC0->{infty}, Cl/F, Cmax, T max, V/F, ke, or t½).


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Table I. Subject demographics
 

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Table II. Pharmacokinetic parameters in two treatment phasesa
 
The two drugs were relatively well tolerated. When dirithromycin and theophylline were co-administered the adverse effects reported were shakiness and jitteriness (11 subjects), headache (one subject), polyuria (one subject), and dyspepsia (one subject). When theophylline was administered alone, shakiness and jitteriness (11 subjects), headache (two subjects), and polyuria (one subject) were reported. These were all short-lived, and none of the subjects required any medical intervention. With dirithromycin alone, three subjects experienced dyspepsia that subsided a few days into dirithromycin dosing; this dissipated for all but one subject who still had symptoms on day 10 of dosing.


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Theophylline is a methylxanthine compound used for the treatment of asthma and chronic obstructive pulmonary disease. 10,11 Both of these conditions predispose patients to respiratory infections that require antibiotics, like the macrolides, for treatment. Because theophylline has a low therapeutic index and large intra-individual and inter-individual variability, monitoring of its serum concentrations is necessary to ensure efficacy and to prevent toxicity. 4,12 Interactions have been reported between theophylline and various drugs. The interactions can take one of two forms: (i) metabolic inducers that increase the clearance of theophylline, such as rifampicin and carbamazepine; (ii) metabolic inhibitors that decrease the clearance of theophylline, such as erythromycin, cimetidine, and ciprofloxacin. 5 As a result of these interactions, patients can be exposed either to low serum concentrations that are subtherapeutic and thereby lead to symptom exacerbation, or to high serum concentrations that result in toxicity.

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.


    Notes
 
* Corresponding author. Tel: +1-607-547-3399; Fax: +0-607-547-6914; E-mail: guy.amsden{at}bassett.org Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Sides, G. D., Cerimele, B. J., Black, H. R., Busch, U. & DeSante, K. A. (1993). Pharmacokinetics of dirithromycin. Journal of Antimicrobial Chemotherapy 31, Suppl. C65–75.[Abstract]

2 . Goldbert, M. J., Ring, B., DeSante, K., Cerimele, B., Hatcher, B., Sides, G. et al. (1996). Effect of dirithromycin on human CYP3A in vitro and on pharmacokinetics and pharmacodynamics of terfenadine in vivo. Journal of Clinical Pharmacology 36, 1154– 60.

3 . Lindstrom, T. D., Hanssen, B. R. & Wrighton, S. A. (1993). Cytochrome P-450 complex formation by dirithromycin and other macrolides in rat and human livers. Antimicrobial Agents and Chemotherapy 37, 265–9.[Abstract]

4 . Jennings, T. S., Nafziger, A. N., Davidson, L. & Bertino, J. (1993). Gender differences in hepatic induction and inhibition of theophylline pharmacokinetics and metabolism. Journal of Laboratory and Clinical Medicine 122, 208–16.[ISI][Medline]

5 . Kelly, H. W. (1996). Mechanisms and principles of theophylline pharmacokinetic drug interactions. In Drug Interaction and Updates Quarterly, (Hansten, P. D. & Horn, J. R., Eds), p. 497. Applied Therapeutics, Inc., Vancouver, WA.

6 . Bachmann, K., Nunlee, M., Martin, M., Sullivan, T. J., Jauregui, L., DeSante, K. et al . (1990). Changes in the steady-state pharmacokinetics of theophylline during treatment with dirithromycin. Journal of Clinical Pharmacology 30, 1001–5.[Abstract/Free Full Text]

7 . Watkins, P. B. (1992). Drug metabolism by cytochromes P450 in the liver and small bowel. Gastroenterology Clinics of North America 21, 511– 26.[ISI][Medline]

8 . Tanswell, P. & Koup, J. (1993). TopFit: a PC based pharmacokinetic/pharmacodynamic data analysis program. International Journal of Clinical Pharmacology, Therapy, and Toxicology 31, 514–20.[Medline]

9 . Cockcroft, D. W. & Gault, M. H. (1976). Prediction of creatinine clearance from serum creatinine. Nephron 16, 31–41.[ISI][Medline]

10 . Ramsdell, J. (1995). Use of theophylline in the treatment of COPD. Chest 107, Suppl, S206–9.[Free Full Text]

11 . Weinberger, M. & Hendeles, L. (1996). Theophylline in asthma. New England Journal of Medicine 334, 1380–8.[Free Full Text]

12 . Troger, U. & Meyer, F. P. (1995). Influence of endogenous and exogenous effectors on the pharmacokinetics of theophylline: focus on biotransformation. Clinical Pharmacokinetics28 , 287–314.[ISI][Medline]

13 . Larrey, D., Funck-Brentano, C., Breil, P., Vitaux, J., Theodore, C., Babany, G. et al . (1983). Effects of erythromycin on hepatic drug-metabolizing enzymes in humans. Biochemical Pharmacology 32, 1063–8.[ISI][Medline]

14 . Wrighton, S. A. & Stevens, J. C. (1992). The hepatic cytochromes P450 involved in drug metabolism. Critical Reviews in Toxicology 22, 1–21.[ISI][Medline]

15 . Bachmann, K., Jauregui, L., Sides, G. & Sullivan, T. J. (1993). Steady-state pharmacokinetics of theophylline in COPD patients treated with dirithromycin. Journal of Clinical Pharmacology 30, 861–5.

Received 9 September 1998; accepted 28 December 1998





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