Abstract
Aims
The antibiotic erythromycin is a potent inhibitor of cytochrome P450 CYP3A4 metabolism. As CYP isozymes, including CYP3A4, are involved in the metabolism of the new triazole voriconazole, this study investigated the effects of multiple-dose erythromycin or azithromycin on the steady-state pharmacokinetics of voriconazole in healthy male subjects.
Methods
In an open, randomized, parallel-group, single-centre study, 30 healthy male subjects aged 20–41 years received oral voriconazole 200 mg twice daily for 14 days plus either erythromycin (1 g twice daily on days 8–14), azithromycin (500 mg once daily on days 12–14) or placebo (twice daily on days 8–14). Only morning doses were administered on day 14. Plasma concentrations of voriconazole were measured up to 12 h postdose on days 7 and 14, and plasma pharmacokinetic parameters were calculated. Adverse events and standard laboratory test results were recorded before and throughout the study.
Results
Comparison of the voriconazole Cmax day 14/day 7 ratio for the voriconazole + erythromycin group with that of the voriconazole + placebo group yielded a ratio of 107.7% [90% confidence interval (CI) 90.6, 128.0]; for the voriconazole + azithromycin group, the ratio was 117.5% (90% CI 98.8, 139.7). Comparison of the voriconazole AUCτ day 14/day 7 ratios of the voriconazole + erythromycin and voriconazole + azithromycin groups with that of the voriconazole + placebo group showed ratios of 101.2% (90% CI 89.1, 114.8) and 107.9% (90% CI 95.1, 122.4), respectively. For voriconazole tmax, the differences between the day 14–day 7 calculations for the voriconazole + erythromycin or the voriconazole + azithromycin groups and that of the voriconazole + placebo group were −0.2 h (90% CI −0.8, 0.3) and −0.1 h (90% CI −0.7, 0.5), respectively. None of these changes was considered clinically relevant. The study drugs were well tolerated by subjects in all groups; the most common study drug-related adverse events were visual disturbances, reported in all groups, and abdominal pain, present in the voriconazole + erythromycin group.
Conclusions
Coadministration of erythromycin or azithromycin does not affect the steady-state pharmacokinetics of voriconazole in a clinically relevant manner in healthy male subjects.
Keywords: azithromycin, erythromycin, interaction, pharmacokinetics, voriconazole
Introduction
Voriconazole is a new triazole antifungal agent, developed as oral and intravenous formulations, with potent activity against a broad spectrum of clinically significant pathogens, including Aspergillus and Candida species [1–3], and emerging fungal pathogens, such as Scedosporium and Fusarium species [4, 5].
The pharmacokinetics of voriconazole have been investigated following single and multiple (10–30 days) doses in both healthy volunteers and patients [6–8]. In vitro and in vivo studies indicate that voriconazole is extensively metabolized by the cytochrome (CYP) P450 system, mainly by the polymorphically expressed CYP2C19 isoenzyme, by CYP2C9, and to a lesser extent by CYP3A4 [9].
In the clinical setting, the possibility exists for pharmacokinetic interactions between voriconazole and other agents that are also substrates for, or modulate the activity of, cytochrome P450 enzymes. Among the large number of agents that are metabolized by these enzymes, several are known to inhibit CYP3A4. For example, erythromycin, the first macrolide antibiotic, is a potent inhibitor that can result in accumulation of a variety of other CYP3A4-metabolized agents, such as carbamazepine, cyclosporin, cimetidine, terfenadine, and theophylline [10]. By contrast, the newer compound azithromycin, an azalide antibiotic derived from erythromycin, does not inhibit CYP3A4 metabolism [10] and would be unlikely to produce elevation of plasma voriconazole levels when concomitantly administered. Both compounds are widely prescribed; azithromycin, in particular, offers broad-spectrum empirical therapy for a range of mild-to-moderate, community-acquired bacterial infections in adults and children [11]. As such, erythromycin and azithromycin represent a useful and important pair of agents with which to assess the potential for clinical pharmacokinetic interactions between voriconazole and coadministered CYP3A4-metabolized agents.
The current study was conducted to investigate the effects of multiple-dose erythromycin and azithromycin on the steady-state pharmacokinetics of voriconazole.
Methods
Study population
Subjects were required to be male, aged 18–45 years, with a body mass index of between 18 and 28 according to Quetelet's Index [weight(kg)/height2(m)]. Any subject with evidence of clinically significant disease, or a history of peptic ulcers or allergies (especially drug hypersensitivity), was excluded from study entry. Subjects with clinically significant laboratory abnormalities, or for whom erythromycin or azithromycin were contraindicated, were also excluded.
Study design and drug administration
The Clinical Research Ethics Committee, Anatole France Street, Brussels, Belgium, approved the study protocol, and 30 male subjects who had given written fully informed consent had a screening visit within 3 weeks of the start of the study. Each subject received a physical examination and provided blood and urine samples for routine haematological and biochemical testing, urinalysis, and drug screening. An additional blood sample was obtained for determination of each subject's CYP2C19 genotype status. DNA isolated from whole blood was amplified using primers which specifically amplify the region containing the *2 and *3 alleles, and individual genotypes were determined by restriction fragment length polymorphism detection.
The study had an open, randomized, placebo-controlled, parallel-group, single-centre design. Subjects were randomized to one of three study drug groups: voriconazole + erythromycin, voriconazole + azithromycin, or voriconazole + placebo.
All subjects received voriconazole 200 mg (1 × 200-mg tablet) twice daily on days 1–13 and voriconazole 200 mg once daily on day 14. Each subject also received one of the following: erythromycin 1 g (2 × 500-mg film-coated tablets; Erythroforte®; Abbott Laboratories, North Chicago, IL, USA) twice daily on days 8–13, and erythromycin 1 g once daily on day 14; azithromycin 500 mg (2 × 250-mg capsules; Zithromax®; Pfizer Inc., New York, NY, USA) once daily on days 12–14 (subjects received voriconazole alone on days 8–11); or placebo (tablet) twice daily on days 8–13 and placebo once daily on day 14. Dose selection and duration of treatment with erythromycin and azithromycin were based on approved prescribing information. All study drugs were taken orally with 250 ml of water while the subject was sitting or standing. The subject was not allowed to lie down for at least 1 h after dosing, although a semirecumbent position was permitted. Study drugs were administered concomitantly at least 1 h before or at least 2 h after food, and at 12-h intervals as appropriate. A diary card was provided to record the time of the evening dose.
Each subject resided in the unit from the evening before the first dosing day until 2 h after dosing on the morning of day 1, and from the evening of day 6 until discharge on the morning of day 15. Between these periods, the subject returned each morning to the unit to be given his morning medication, and to collect his evening medication, to be self-administered at home.
No subject was allowed to take any prescribed or over-the-counter medicine throughout the study period, except for paracetamol (up to 3 g per day). Subjects were not allowed to consume caffeine or other methylxanthines or alcohol, or to undertake unaccustomed exercise, within 48 h of the start of the study drug and throughout the study drug administration period.
Measurements
Blood samples were collected prior to dosing on days 2–6 and 8–13 to determine trough voriconazole levels, and prior to dosing and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 h after dosing on days 7 and 14 in order to calculate pharmacokinetic parameters. Samples were centrifuged at 1500 g at 4 °C for 10 min within 1 h of sample collection, and plasma stored upright in screw-capped polypropylene tubes at −20 °C. Plasma samples were assayed for voriconazole using a previously validated high-performance liquid chromatography (HPLC) method [12] (BAS Analytics Ltd, Kenilworth, UK). The lower and upper limits of quantification were 10 ng ml−1 and 3000 ng ml−1, respectively. The overall imprecision of the assay was 8.6, 6.2, 7.2, and 3.4% at target voriconazole concentrations of 25, 1502, 2503, and 4800 ng ml−1, respectively. At the same concentrations, the inaccuracy of the assay was 5.6, 8.1, 2.8, and 12.0%.
A urine drug screen and alcohol breath test were performed upon admission to the unit on the evening before dosing and on the evening of day 6. A physical examination (including examination of cardiovascular and respiratory systems, abdomen and skin) and recording of supine blood pressure and pulse were performed on the evening before dosing and before the subject had left the unit on day 15. Blood and urine samples for standard laboratory safety tests were obtained before dosing on days 1 and 7, and before the subject left the unit on day 15. Additional blood samples for liver function tests were obtained before dosing on days 4, 10, and 12.
A physical examination (including an ophthalmological examination), recording of supine blood pressure and pulse, a 12-lead electrocardiogram and laboratory safety tests (haematology, clinical chemistry and urinalysis) were performed at screening and at a follow-up visit 7–10 days after the final dose was taken. Ophthalmological tests included visual acuity, visual field, direct light reflex, indirect light reflex, accommodation reflex, and eye movements.
CYP2C19 genotype is an important determinant of voriconazole plasma levels. Individuals who are homozygous poor metabolizers (PM), for example, generally have elevated plasma voriconazole levels, which might confound the determination of voriconazole–drug interactions. Therefore, each subject's CYP2C19 genotype was determined during the screening. Subjects were randomly assigned to a study drug group so that all groups included a similar proportion of homozygous poor CYP2C19 metabolizers. In addition, at the follow-up visit, CYP2C19 phenotype status was determined for subjects not previously phenotyped by collection of a blood sample 2 h after administration of a single 20-mg dose of omeprazole (Losec®; Astra, Wayne, PA, USA), a compound often used as a probe to determine CYP2C19 phenotype status [13]. Each sample was assayed for omeprazole and 5-hydroxyomeprazole using a previously validated HPLC method (Kansas City Analytical Services Inc., Shawnee, KS, USA). A log(10) omeprazole : 5-hydroxyomeprazole ratio > 1 was considered indicative of a PM phenotype.
Safety was assessed on the basis of clinical laboratory tests and adverse events reported during the study and up to 7 days after the end of study drug administration, and whenever volunteered by the subject. Adverse events were classified according to the Coding Symbol Thesaurus of Adverse Reaction Terms (COSTART). Compliance with medication was monitored by inspection of the subject's diary card and by recording of medications administered within the unit. The majority of voriconazole doses were scheduled to be taken under direct supervision at the unit.
Parameter calculations
The maximum observed plasma voriconazole concentration (Cmax) and the time to the first postdose occurrence of Cmax (tmax) were obtained directly from the recorded plasma concentration–time data. The area under the plasma concentration–time curve within a dosing interval (AUCτ) was calculated using a linear trapezoidal method. Comparisons of pharmacokinetic parameters between treatment groups were expressed as percentages, by multiplying the parameter ratios by 100.
Statistical analysis
A sample size of 30 subjects was chosen with the expectation that no more than two subjects would drop out of each study drug group, leaving at least eight evaluable subjects in each group. This sample size was considered sufficient to detect a difference of at least 30% between study drug groups in the day 14 vs. day 7 changes for AUCτ and Cmax with at least 80% power and with a significance level of 5%.
Log-transformed AUCτ and Cmax, and untransformed tmax data were subjected to an analysis of variance (anova) appropriate for the parallel-group design with repeated measures within each group. The anova model allowed for the effects of study drug group, subject, day, and day by study drug group interaction. This last term was tested against within-subject variation and formed an overall test for equality of changes from baseline between groups.
Mean pharmacokinetic parameters (geometric means for Cmax and AUCτ, and arithmetic mean for tmax) were calculated for each group on day 7 and on day 14. The mean differences, day 14–day 7, for these parameters were estimated for each treatment group, and the differences were compared between treatment groups (voriconazole + erythromycin/azithromycin vs. voriconazole + placebo). Ninety percent confidence intervals (CI) were calculated for each comparison. For Cmax and AUCτ, the ratio between antilogged treatment means and the corresponding antilogged CIs were presented.
Results
Subjects and drug administration
All 30 subjects who were screened were randomized to receive study drug (10 in each group). Subjects in the three groups were similar with respect to baseline demographic characteristics (Table 1). There were 28 Caucasian subjects, one Black, and one Asian (both in the voriconazole + azithromycin group). The minor differences in the distribution of CYP2C19 genotypes across study drug groups were considered unlikely to influence the findings of this study (and CYP2C19 genotype status was not included as a factor in the anova model as there were too few poor metabolizers in each group to enable meaningful comparisons to be made). Phenotype matched genotype for all subjects for whom phenotype was determined. All subjects completed 14 days of study drug administration, and all were assessed for pharmacokinetics and safety.
Table 1.
Baseline demographic characteristics of all randomized subjects.
| Voriconazole + erythromycin | Voriconazole + azithromycin | Voriconazole + placebo | |
|---|---|---|---|
| Number of subjects | 10 | 10 | 10 |
| Mean age, years (range) | 29 (23–41) | 28 (21–41) | 25 (20–30) |
| Mean weight, kg (range) | 80 (69–90) | 73 (60–92) | 73 (62–85) |
| Mean height, cm (range) | 181 (169–191) | 179 (158–189) | 181 (173–191) |
| CYP2C19 genotype (n) | |||
| Homozygous extensive | 9 | 8 | 5 |
| Heterozygous extensive | 0 | 1 | 4 |
| Homozygous poor | 1 | 1 | 1 |
Protocol deviations were recorded for five subjects; these were considered insufficient to exclude the subjects from the analyses and unlikely to confound the study findings.
Pharmacokinetic parameters
There was wide intersubject variability in pharmacokinetic parameters as evidenced by the coefficients of variation (CV) for Cmax and AUCτ(Table 2). Mean Cmax was similar on day 14 compared with day 7 for both the voriconazole + erythromycin and voriconazole + azithromycin groups (day 14/day 7 ratios of 94.2% and 102.8%, respectively; Tables 2 and 3). However, the mean Cmax of the voriconazole + placebo group was lower on day 14 than that on day 7 (87.5%; Table 3). Comparison of the day 14/day 7 ratio for the voriconazole + erythromycin group and that for the voriconazole + placebo group gave a ratio of 107.7% (90% CI 90.6, 128.0). Comparison of the day 14/day 7 ratio for the voriconazole + azithromycin group and that for the voriconazole + placebo group gave a ratio of 117.5% (90% CI 98.8, 139.7).
Table 2.
Summary of mean pharmacokinetic parameters for voriconazole in plasma before (day 7) and after (day 14) coadministration with erythromycin, azithromycin, or placebo.
| Voriconazole + erythromycin | Voriconazole + azithromycin | Voriconazole + placebo | ||||
|---|---|---|---|---|---|---|
| Parameter | Day 7 | Day 14 | Day 7 | Day 14 | Day 7 | Day 14 |
| Cmax (ng ml−1)* | 1779 (57) | 1676 (44) | 1819 (85) | 1870 (70) | 1866 (62) | 1633 (56) |
| AUCτ (ng·h ml−1)* | 9511 (96) | 8655 (85) | 10 734 (114) | 10 416 (115) | 10 506 (90) | 9449 (88) |
| tmax (h)† | 2.0 ± 0.6 | 1.6 ± 0.2 | 1.9 ± 0.7 | 1.7 ± 0.6 | 1.9 ± 0.5 | 1.8 ± 0.6 |
Geometric mean with coefficient of variation (%) in parentheses.
Arithmetic mean ± s.d.
Table 3.
Comparison of mean pharmacokinetic parameters for voriconazole in plasma at day 14 and at day 7, within each group and compared with placebo
| Parameter | Voriconazole + erythromycin | Voriconazole + azithromycin | Voriconazole + placebo |
|---|---|---|---|
| Mean day 14/day 7 ratio (90% CI) | |||
| Cmax | |||
| Within study drug administration | 94.2% | 102.8% | 87.5% |
| (83.4, 106.5) | (91.0, 116.2) | (77.4, 98.9) | |
| Corrected for placebo | 107.7% | 117.5% | – |
| (90.6, 128.0) | (98.8, 139.7) | ||
| AUCτ | |||
| Within study drug administration | 91.0% | 97.0% | 89.9% |
| (83.2, 99.5) | (88.7, 106.1) | (82.2, 98.4) | |
| Corrected for placebo | 101.2% | 107.9% | – |
| (89.1, 114.8) | (95.1, 122.4) | ||
| Mean day 14–day 7 difference (90% CI) | |||
| tmax (h) | |||
| Within study drug administration | −0.4 | −0.3 | −0.2 |
| (−0.8, 0.0) | (−0.7, 0.2) | (−0.6, 0.3) | |
| Corrected for placebo | −0.2 | −0.1 | – |
| (−0.8, 0.3) | (−0.7, 0.5) | ||
Mean AUCτ was lower on day 14 compared with day 7 for both the voriconazole + erythromycin and voriconazole + placebo groups (day 14/day 7 ratios of 91.0% and 89.9%, respectively; Table 3). Comparison of the day 14/day 7 ratio for the voriconazole + erythromycin group and that for the voriconazole + placebo group gave a ratio of 101.2% (90% CI 89.1, 114.8). Comparison of the day 14/day 7 ratio for the voriconazole + azithromycin group and that for the voriconazole + placebo group gave a ratio of 107.9% (90% CI 95.1, 122.4).
Mean tmax was earlier on day 14 than that for day 7 for all three groups. Comparison of the day 14–day 7 difference for the voriconazole + erythromycin group and that for the voriconazole + placebo group gave an estimated decrease in tmax of −0.2 h (90% CI −0.8, 0.3). Comparison of the day 14–day 7 difference for the voriconazole + azithromycin group and that for the voriconazole + placebo group gave an estimated decrease in tmax of −0.1 h (90% CI −0.7, 0.5).
The time course of mean plasma voriconazole concentrations from 0 to 12 h after dosing was similar for all three groups, both on day 7 and on day 14 (Figure 1). Visual inspection of the mean and individual trough plasma concentrations of voriconazole (Figure 2) suggested that steady state was achieved in most subjects by day 6. As expected, voriconazole plasma concentrations were generally highest among homozygous poor CYP2C19 metabolizers (for all groups, geometric Cmax means of 5575 ng ml−1 and 4551 ng ml−1 on days 7 and 14, respectively, n = 3) and lowest among homozygous extensive metabolizers (geometric means of 1451 ng ml−1 and 1430 ng ml−1 on days 7 and 14, respectively, n = 22). However, these differences between genotypes were not thought to influence the conclusions unduly, as the day 14 vs. day 7 comparisons were similar across genotypes. Concomitant administration of erythromycin or azithromycin with voriconazole did not appear to have a greater effect on Cmax and AUCτ for the homozygous poor CYP2C19 metabolizer in each group compared with the homozygous extensive metabolizers, although this was not subject to formal statistical analysis as there was only one homozygous poor metabolizer in each group.
Figure 1.
Mean voriconazole plasma concentration profiles (days 7 and 14).
Figure 2.
Trough voriconazole plasma concentration profiles (days 2–14).
Safety
There were no study drug discontinuations or dose reductions due to adverse events or laboratory test abnormalities. Treatment-emergent adverse events were reported by a similar number of subjects in each group (Table 4). Out of 64 adverse events, none was classified as serious, and three (luminous flashes, pruritis, and hives, one in each group) were classified as severe. Of these 64 events, 20 subjects reported 29 events, which were classified as possibly study drug-related. None of these study drug related adverse events was regarded as serious in nature, and only one (luminous flashes in the voriconazole + erythromycin group) was regarded as severe. Most adverse events resolved without treatment; five adverse events (one in the voriconazole + erythromycin group and four in the voriconazole + placebo group) were treated with concomitant medication.
Table 4.
Occurrence of adverse events and clinically significant laboratory abnormalities.
| Voriconazole + erythromycin (n = 10) | Voriconazole + azithromycin (n = 10) | Voriconazole + placebo (n = 10) | |
|---|---|---|---|
| Treatment-emergent adverse events* | |||
| Subjects with ≥1 event | 8 | 8 | 9 |
| Events | 27 | 17 | 20 |
| Study drug-related adverse events* | |||
| Subjects with ≥1 event | 8 | 7 | 5 |
| Events | 13 | 10 | 6 |
| Abdomen enlarged | 0 | 0 | 1 |
| Abdominal pain | 5 | 0 | 0 |
| Dyspepsia | 1 | 0 | 0 |
| Eructation | 2 | 0 | 0 |
| Flatulence | 1 | 1 | 0 |
| Nausea | 1 | 0 | 0 |
| Abnormal vision | 3 | 7 | 4 |
| Photophobia | 0 | 2 | 1 |
| Clinically relevant laboratory abnormalities | |||
| Subjects with ≥1 abnormality | 1 | 1 | 5 |
Includes only one count per subject per COSTART (Coding Symbols for Thesaurus of Adverse Reaction Terms) preferred term.
The most common study drug-related adverse events were abnormal vision and abdominal pain. All cases of drug-related abdominal pain were recorded in subjects in the voriconazole + erythromycin group, and all episodes occurred between days 8 and 14, the days when erythromycin was administered concomitantly with voriconazole.
Visual adverse event episodes were reported by 15 of the 30 subjects (six episodes in three voriconazole + erythromycin subjects, 15 in seven voriconazole + azithromycin subjects, and 15 in five voriconazole + placebo subjects). All visual adverse events were classified as study drug-related, and most were categorized as abnormal vision. The median duration of the visual disturbances was 15 min in the voriconazole + erythromycin group, 30 min in the voriconazole + azithromycin group, and 30 min in the voriconazole + placebo group. Most episodes of visual disturbance occurred during days 2–5 of study drug administration, with a lower rate of visual disturbances thereafter. The funduscopy and visual acuity, visual fields and external tests conducted at follow-up showed no change from baseline in any subject.
All subjects were evaluated for clinical laboratory test results. Clinically relevant results (all during study drug administration) were recorded for the following: one subject in the voriconazole + erythromycin group (ketonuria), one subject in the voriconazole + azithromycin group (elevated eosinophil count), and five subjects in the voriconazole + placebo group (two cases of haematuria, two cases of elevated monocyte count, and one case of elevated eosinophil count). An overall review of laboratory data identified no clear pattern of abnormalities related to study drugs.
Discussion
The results of this study demonstrate that coadministration of oral erythromycin or azithromycin has no clinically significant effect on the pharmacokinetics of oral, multiple-dose voriconazole in healthy male subjects.
Measurements of voriconazole pharmacokinetic para-meters before coadministration (day 7) and after coadministration (day 14) indicated some differences within subject groups, manifesting as a reduction in mean Cmax or AUCτ on day 14 compared with day 7. However, these differences were greatest with the voriconazole + placebo group, and no rationale has been established for their occurrence.
When coadministered with erythromycin, mean voriconazole Cmax and AUCτ were approximately 8% and 1% higher, respectively, when compared with administration of voriconazole with placebo. When coadministered with azithromycin, mean voriconazole Cmax and AUCτ were approximately 18% and 8% higher, respectively, when compared with administration of voriconazole with placebo. These ratios and their associated 90% CIs did not suggest any clinically relevant effect on the voriconazole exposure.
Adverse event and laboratory test data indicated that all three study drugs were well tolerated. The adverse event profiles of the erythromycin and azithromycin groups were similar to that of the placebo group. An exception was the occurrence of abdominal pain, which occurred only in the erythromycin group and is a recognized side-effect of erythromycin therapy [14]. The most common study drug-related adverse events in all three groups were visual adverse events, which were classified as abnormal vision or photophobia. These events were mild or moderate in intensity and resolved without the need for treatment.
In conclusion, the data collected in this study indicate no clinically significant effect of oral erythromycin or azithromycin on the pharmacokinetic profile of voriconazole. Accordingly, other CYP3A4 substrates metabolized by the same pathway as erythromycin and azithromycin are not expected to interact significantly with voriconazole, and are unlikely to cause any clinically relevant effect on the pharmacokinetics of voriconazole.
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