Lack of Clinically Relevant Interaction Between Desloratadine and Erythromycin
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- Banfield, C., Hunt, T., Reyderman, L. et al. Clin Pharmacokinet (2002) 41: 29. doi:10.2165/00003088-200241001-00005
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Objective: To evaluate the bioavailability, cardiac safety and tolerability of desloratadine when given in combination with the CYP3A4 inhibitor erythromycin.
Design: A randomised, 2-way crossover, placebo-controlled, third party-blind, multiple dose study.
Participants: 24 healthy volunteers (12 men, 12 women) aged 19 to 46 years.
Interventions: Oral desloratadine 7.5mg daily in combination with either placebo (n = 24) or erythromycin 500mg every 8 hours (n = 24) for 10 days. After a minimum 7-day washout period, participants crossed over to the alternative regimen.
Main outcome measures: ECG parameters.
Results: Desloratadine/erythromycin did not induce clinically or statistically significant changes in any ECG parameter. The maximum corrected QT (QTC) interval was 445 msec for both treatments. The peak plasma concentration and area under the plasma concentration-time curve from 0 to 24 hours of desloratadine were slightly increased by 1.2- and 1.1-fold by concomitant administration of erythromycin compared with desloratadine/placebo. Gastrointestinal adverse events were more frequent after desloratadine/erythromycin than desloratadine/placebo (46 s 4%), reflecting the poor gastrointestinal tolerability of erythromycin. There were no reports of syncope.
Conclusion: Combined desloratadine/erythromycin therapy was well tolerated and had no clinically relevant electrocardiographic effects at a dose that was 50% higher than the recommended dose of 5mg. Although coadministration of erythromycin slightly increased plasma concentrations of desloratadine, this change did not correlate with any prolongation of the QTC interval, and no toxicity was observed clinically.
Second-generation antihistamines were developed in an effort to reduce the sedative effects of first generation drugs and improve their antiallergic efficacy. Although second-generation compounds are less sedating than first-generation agents, serious cardiac arrhythmias have occurred with terfenadine and astemizole but not with loratadine, fexofenadine or cetirizine. The cardiotoxic effects of antihistamines are mediated via blockade of the ventricular potassium channel, resulting in a prolongation of action potential which often leads to an increase in the corrected QT (QTc) interval.[2–4] Prolongation of the QTc interval may predispose an individual to a multifocal tachyarrhythmia on the surface ECG called torsades de pointes, which can be fatal. This type of arrhythmia can emerge in otherwise healthy patients taking standard doses of terfenadine or astemizole but is more commonly associated with electrolyte imbalance, overdose, patients with hepatic or cardiac impairment, or administration of these agents in combination with one of many widely used drugs, such as erythromycin or ketoconazole.[1,6]
Erythromycin, a widely used macrolide antibiotic, is a potent inhibitor of cytochrome P450 (CYP) 3A4. Consequently, erythromycin has many clinically important interactions with other drugs that also utilise CYP3A4 for their metabolism in vivo, including terfenadine. Coadministration of erythromycin and terfenadine or astemizole can substantially increase the plasma concentrations of these antihistamines and prolong the QTc interval.[7,8] Moreover, erythromycin itself can also lengthen the QTc interval and cause torsades de pointes.[5,7] Given the potential for life-threatening arrhythmias, all new agents with antihistamine effects should be fully investigated for interactions with agents such as erythromycin.
Desloratadine is a new histamine H1 receptor antagonist. When administered once daily, desloratadine effectively reduced the symptoms of allergic rhinitis. We have studied the effect of 10 days of treatment with standard clinical doses of desloratadine and erythromycin to assess the pharmacokinetics, ECG pharmacodynamics and safety of coadministration of these 2 compounds.
The trial was a randomised, third party-blind, placebo-controlled, 2-way crossover study. 24 healthy volunteers were enrolled from the local community on the basis of previous participation in clinical studies at the centre or from unsolicited word-of-mouth advertisement. Volunteers were randomly assigned to therapy with 7.5mg desloratadine orally daily (on an empty stomach) in combination with either oral erythromycin 500mg or placebo every 8 hours for 10 days. The desloratadine dose used in this trial was 50% higher than the clinically recommended 5mg once daily dosage. After a washout period of at least 7 days, participants were crossed over to the alternative treatment. After review of the study protocol by the Institutional Review Board, all volunteers provided informed written consent, and the study was performed in accordance with the Declaration of Helsinki.
Study participants were nonsmokers (confirmed by a negative urinary cotinine test), did not use drugs of abuse (confirmed by urine screen), and had normal haematological, biochemical and urinalysis profiles. They were free of significant diseases requiring ongoing physician care and successfully completed a physical examination within clinically acceptable limits. The cardiovascular status of all participants was evaluated by a standard 12-lead ECG (25 mm/sec); normal PR, QRS, QT and QTc interval values at baseline were necessary for inclusion.
The following were exclusion criteria before study drug administration: allergy to erythromycin or antihistamines; other significant food or drug allergies; local or systemic infection within 4 weeks; use of any prescription or over-the-counter medications within 14 days [except paracetamol (acetaminophen) within 72 hours]; use of alcohol- or xanthine-containing compounds within 72 hours; use of any investigational drug within 30 days; previous narcotic or alcohol dependence; positive test results for hepatitis B surface antigen, hepatitis C antibodies or HIV antibodies; use of terfenadine or astemizole in the previous 90 days; abnormal QTc interval (>420 msec) on screening ECG; a history of syncope; and previous use of desloratadine. Pregnant or breastfeeding women were excluded, as were women unwilling to use barrier contraception during the study.
After enrolment, volunteers were confined to the study centre for 48 hours prior to the initial desloratadine dose and for each 10 days of treatment. Between treatment regimens, a washout period of at least 7 days was required. All participants received 7.5mg desloratadine once daily (at 8:00am on an empty stomach) for 10 consecutive days. According to the randomisation code, either erythromycin 500mg or placebo was administered at 8:00am, 4:00pm and midnight. All medications were swallowed whole in 1 dose with 180ml of noncarbonated water, and the mouth was checked for retained tablets to ensure compliance. Grapefruit juice was prohibited during the study.
12-lead ECGs were recorded in the supine position on day −1 at 8:00, 9:00, 9:30, 10:00 and 11:00am, noon, 1:00, 2:00, 4:00 and 6:00pm and midnight. In addition, ECGs were recorded approximately 2 hours after desloratadine administration on days 1 to 9; before the last dose of desloratadine on day 10; and at 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours thereafter. The ECGs were performed using a Hewlett Packard Pagewriter XLi. The QT interval measurement begins with the waveform recognition and beat detection and is derived from all 12 leads over the 10-second analysis period. Amplitude, duration, area and shape are derived from each waveform, creating a table of measurements. The QTc is calculated automatically from the QT measurement using Bazett’s formula. Each ECG reported ventricular rate and PR, QRS, QT and QTc intervals recorded at 25 mm/sec; a 2-minute rhythm strip reporting leads V2, I and aVF was recorded at 50 mm/sec. Each ECG was reviewed and signed off by the principal investigator, who was blinded to the treatment regimen. The value determined by the Hewlett Packard 12-lead system was noted. If the QT or QTc intervals were greater than 450 msec (the upper limit of normal value), baseline artifact or low T wave amplitude occurred, or there was more marked sinus arrhythmia, the QT/QTc intervals were verified by visual inspection and manual measurement. If the values appeared more exact by manual measurement and calculation, these were noted directly on the ECG. If further resolution of the QT/QTc intervals was required, the investigator measured the RR and QT intervals on the 50 mm/sec rhythm strips (5 msec per 0.25mm).
15ml of venous blood was collected for determination of plasma concentrations of desloratadine and its metabolite, 3-hydroxy (3-OH) desloratadine, before drug administration (0 hour) on days 7 to 9, and again on day 10 just before and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours after administration.
Whole blood was collected into heparinised tubes and centrifuged for 20 minutes at 4°C and 3000 rpm within 30 minutes of collection. Plasma was separated into 2 specimens, frozen at or below −20°C, and shipped on dry ice to PPD Pharmaco Inc. (Richmond, VA) for assay. Plasma concentrations of desloratadine and 3-OH desloratadine were determined by a validated liquid chromatographic method with tandem mass spectrometric detection (lower limit of quantitation 0.025 μg/L).
Plasma erythromycin concentrations were determined using a validated high performance liquid chromatographic mass spectrometry assay with a limit of quantitation of 20.1 μg/L (data on file, Schering-Plough).
Safety was monitored by physical examination and assessment of vital signs, laboratory parameters and ECG data at screening and 24 hours after the final dose of desloratadine and placebo. Participants were monitored continuously for adverse events and were asked to report any new symptoms experienced at any time during the 2 treatment phases.
Individual plasma concentration-time data were used to calculate pharmacokinetic parameters using model-independent methods. For desloratadine and 3-OH desloratadine, the maximum plasma concentration (Cmax) was the observed value; the minimum concentration (Cmin) was the concentration in blood samples taken prior to the administration of desloratadine (0 hour) on days 7 to 10 and on day 11 (24 hours after the last dose of desloratadine). The area under the desloratadine or 3-OH desloratadine concentration-time curve from 0 to 24 hours (AUC24h) was calculated using the linear trapezoidal method.
The primary pharmacodynamic parameters were differences between maximum baseline (day −1) ventricular rate and PR, QRS, QT and QTc intervals and maximum values at day 10. The change in each parameter from the maximum value recorded at baseline (day −1) to the maximum value recorded on day 10 (primary end-point) was analysed by a linear ANOVA model, extracting effects due to sequence, participants within sequence, period, and treatment; the 95% CI for the mean difference was determined from the model’s pooled variance. Differences between treatments were considered significant at an α level of 0.05 (2-tailed test).
Volunteers were healthy adults of either sex, aged 19 to 46 years (mean 30.5 years), with bodyweight of 50 to 89kg (mean 68 kg) and body mass index of 19 to 27 kg/m2 (mean 22.9 kg/m2). There were 12 men and 12 women, of whom 18 were White, 5 were Hispanic and 1 was Asian. All completed the study.
Steady-state pharmacokinetics were achieved by day 10 with both treatments. There was no difference in steady-state Cmin values of desloratadine over days 7 to 11 when administered with erythromycin (range 2.46 to 2.78 μg/L) or placebo (range 2.33 to 2.55 μg/L). Pharmacokinetic parameters for erythromycin were characterised by a Cmax of 2.78 μg/L and an AUC4hof 7.79 μg/L · h.
The mean plasma concentration-time curves for desloratadine and 3-OH desloratadine on day 10 during treatment with placebo or erythromycin demonstrated similar pharmacokinetics, as shown in figure 1. Coadministration of desloratadine and erythromycin resulted in 1.2- and 1.1-fold increases in Cmax and AUC of desloratadine, respectively (table I). The change in AUC was not considered significant because the corresponding CI values were within the range of 0.8 and 1.25. By this criterion, the change in Cmax was considered significant. The 1.4-fold increase observed for both Cmax and AUC of 3-OH desloratadine (table I) was considered significant.
No serious adverse events occurred during the trial, and there were no withdrawals due to an adverse event. 18 of 24 participants (75%) experienced at least 1 adverse event [desloratadine/placebo, 10/24 (42%); desloratadine/erythromycin, 15/24 (63%)]. Gastrointestinal disorders (abdominal pain, nausea, vomiting, dyspepsia or diarrhoea) occurred in 11 of 24 participants (46%) while receiving desloratadine/erythromycin and in 1 participant (4%) while receiving desloratadine/ placebo. Dizziness occurred in 11 of 24 (46%) with desloratadine/erythromycin, but in only 1 receiving desloratadine/placebo. No syncope was reported. Somnolence and concentration impairment were reported in 1 participant with desloratadine/erythromycin. There were no treatment-related changes in clinical laboratory parameters, physical examination or vital signs. No QTc values greater than 445 msec were recorded after desloratadine treatment with or without erythromycin.
Desloratadine is a new H1 receptor antagonist. In placebo-controlled clinical trials, desloratadine 5mg significantly reduced the symptoms of seasonal allergic rhinitis. Because serious cardiac arrhythmias (torsades de pointes) caused by the second generation antihistamines terfenadine and astemizole have curtailed their use worldwide, all agents with antihistamine activity must be fully evaluated for potential proarrhythmogenic effects. However, torsades de pointes is not a class effect of the second generation antihistamines: loratadine, for example, has a low incidence of cardiac adverse events.
Among the class of oral antihistamines, drug interactions with inhibitors of the CYP system are of particular clinical importance for H1 receptor antagonists that are extensively metabolised: this group includes many commonly used agents. Erythromycin increases the plasma concentrations of agents metabolised by CYP3A4, including terfenadine. In this study, the 7.5mg dose of desloratadine was used because it was the midpoint of a dose-ranging study. Coadministration of erythromycin and desloratadine (at a dose that is 50% greater than the recommended 5mg dose) led to increases in plasma concentrations of desloratadine that were probably due to concomitant erythromycin. Similar changes were observed in 3-OH desloratadine concentrations. There was no increase in the QTc interval, and all other ECG variables were also unchanged. The adverse event profiles of the 2 treatments were unremarkable. Erythromycin is associated with a high rate of gastrointestinal adverse effects and generalised malaise, as we report here. No serious adverse events occurred, and no participants discontinued treatment because of an adverse event.
Desloratadine 7.5mg daily in combination with erythromycin 500mg every 8 hours was well tolerated. There were no clinically relevant alterations in pharmacokinetic parameters of desloratadine when coadministered with erythromycin. No clinically relevant electrocardiographic changes occurred during the study, and the QTc interval was unaffected by the desloratadine/erythromycin combination as compared with desloratadine/placebo. The coadministration of erythromycin and desloratadine at a dose that was 50% higher than the recommended clinical dose did not increase the risk for eliciting cardiac arrhythmias.
Supported by a research grant from Schering-Plough Research Institute, Kenilworth, New Jersey.