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Safety and Pharmacokinetics of Coadministered Voriconazole and Anidulafungin

From Vicuron Pharmaceuticals, King of Prussia, Pennsylvania (Dr Dowell, Dr Schranz); and Pfizer Inc, New York, New York (Dr Baruch, Dr Foster).

Address for reprints: James A. Dowell, Vicuron Pharmaceuticals, 455 South Gulph Road, Suite 310, King of Prussia, PA 19406.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
There is considerable interest in combining echinocandin and triazole antifungal agents for treatment of invasive fungal infections; however, information is needed regarding the tolerability and potential for pharmacokinetic interactions. Anidulafungin is a semisynthetic echinocandin, and voriconazole is an extended-spectrum triazole. In a random sequence, 17 subjects received anidulafungin with placebo, voriconazole with placebo, and anidulafungin with voriconazole. Anidulafungin was administered intravenously: 200 mg on day 1, then 100 mg/d on days 2 through 4. Voriconazole was administered orally: 400 mg every 12 hours on day 1, then 200 mg every 12 hours on days 2 to 4. No dose-limiting toxicities or serious adverse events occurred, and all adverse events were mild and consistent with the known safety profiles of both drugs. Pharmacokinetic parameters were not affected by coadministration. The geometric mean ratio (90% confidence interval) of the combination/drug alone for AUC_SS was 97.4% (94.9-99.9), 97.4% (92.1-103.0), and 94.4% (87.0-102.5) for anidulafungin, voriconazole, and the voriconazole metabolite, respectively.

Key Words: Anidulafungin • voriconazole • drug interaction

Anidulafungin is a cyclic lipopeptide antifungal agent of the echinocandin class, being developed for treatment of invasive and esophageal candidiasis and invasive aspergillosis.^4,5 Echinocandins are non-competitive inhibitors of (1,3)-ß-D-glucan synthase, a fungus-specific enzyme involved in the synthesis of glucan. Inhibition of glucan synthesis compromises cell wall integrity, resulting in fungal cell death.⁶ The in vitro activity of anidulafungin includes Candida and Aspergillus, including strains resistant to azoles and amphotericin B.^5,7,8 The elimination of anidulafungin is primarily due to nonenzymatic chemical degradation of the parent compound to inactive peptidic degradants.⁹ Anidulafungin, therefore, is believed to have a limited potential to be involved in competitive pharmacokinetic interactions.

Voriconazole is a broad-spectrum triazole antifungal agent that is approved for the treatment of acute invasive aspergillosis, candidemia, and certain invasive Candida infections in nonneutropenic patients, esophageal candidiasis, and as salvage therapy for serious fungal infections caused by Scedosporium apiospermum and Fusarium species.^10-13 Voriconazole exhibits broad-spectrum in vitro activity and is fungicidal against Aspergillus species and fungistatic for yeasts.^{8,10,12,14,15} Voriconazole is highly bioavailable when given orally.^16-18 In vitro studies have shown that voriconazole and its major metabolite, voriconazole N-oxide, are metabolized by cytochrome P450 enzymes, specifically CYP2C19, CYP2C9, and CYP3A4.¹⁹ Although the potency of voriconazole inhibition of CYP3A4 was found to be significantly less than that of both ketoconazole and itraconazole, there is still a potential for voriconazole and its major metabolite to interact with drugs metabolized by cytochrome P450 enzymes. Pharmacokinetic interactions have been observed in clinical studies between voriconazole and some of the drugs that are considered substrates, inhibitors, or inducers of CYP2C19, CYP2C9, or CYP3A4.^12,20-23

Because of their different and potentially synergistic mechanisms of action, it is likely that anidulafungin and voriconazole will be studied in the future as combination therapy for the treatment of serious fungal infections. A clinical trial was conducted in healthy male subjects to evaluate safety, tolerability, and the pharmacokinetics of coadministered anidulafungin and voriconazole.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Study Design
The study was designed as a blinded, randomized, multiple-dose, crossover, pharmacokinetic interaction study in healthy male subjects. A total of 18 subjects were to be enrolled, with the intent of at least 14 subjects completing all study medications and assessments. The study was conducted at a single center and included 3 study periods for each subject. Subjects received each of 3 regimens in separate study periods. The 3 regimens were received by subjects in a random sequence and included intravenous (IV) anidulafungin with an oral placebo, voriconazole with an IV placebo, and IV anidulafungin with oral voriconazole. Study periods were separated by a washout of 11 or more days. Anidulafungin was given as a 200-mg IV infusion on day 1 followed by 100-mg IV infusions daily on days 2 to 4. The infusion was prepared in 5% dextrose injection, USP, to a concentration of 0.5 mg/mL and infused at a rate of 1 mg/min. Voriconazole was administered orally as 400 mg every 12 hours on day 1, then 200 mg every 12 hours on days 2 to 4. Subjects were confined to the clinic for the first 4 days of each study period, received standardized moderate-fat meals while on the study, and were required to abstain from food at least 1 hour before and after oral voriconazole administration. The morning doses of voriconazole were administered 2 hours after the start of the coadministered IV infusion (anidulafungin or placebo). The investigator, subjects, study sponsors, and analysts were blinded to the regimens.

All subjects provided written informed consent. The study was approved by the Institutional Review Board, MDS Pharma Services, and was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization, Good Clinical Practices, and the Food and Drug Administration regulations (21 CFR, parts 50 and 56) for the protection of the rights and welfare of human subjects participating in biomedical research.

Selection of Subjects
The study enrolled healthy male subjects between the ages of 18 and 45 years who were able to sign voluntary informed consent forms. Subjects were to have a body mass index (BMI) of 18 to 30 kg/m² and a body weight of greater than 50 kg. Exclusion criteria included any evidence or history of clinically significant medical abnormalities, positive tests for hepatitis B or C, a positive test for drugs of abuse, history of drug or alcohol abuse, history or evidence of habitual use of tobacco or nicotine-containing products within 3 months of the study, or recent use of prescription or nonprescription drugs, vitamins, or dietary supplements.

Blood Sampling Procedure
Blood samples (7 mL each) were drawn and plasma was obtained to characterize the pharmacokinetics of anidulafungin, voriconazole, and the N-oxide metabolite of voriconazole at steady state (day 4 of each study period). Blood samples were collected at 0.5, 1.67, 2.25, 2.5, 3, 3.5, 4, 6, 8, 10, 14, and 24 hours following the start of the day 4 IV infusion. Samples were also obtained to measure trough concentrations of each drug on days 2, 3, and 4 of each study period to ensure achievement of steady-state concentrations. Whole-blood samples were centrifuged at approximately 1700g for 10 minutes at 4°C within 15 minutes of the blood draw. Plasma was collected for assay of anidulafungin, voriconazole, and voriconazole N-oxide metabolite. Plasma samples were stored in labeled screw-capped polypropylene tubes at approximately -70°C until assayed.

Bioanalytical Procedures
A validated liquid-chromatography-tandem mass spectrometry (LC-MS/MS) analytical method was used for the determination of anidulafungin in human plasma at MDS Pharma Services (Montreal, Canada). For each sample, a 100 µL aliquot of plasma was pipetted into a 1.5-mL Eppendorf conical tube. A total of 300 µL of internal standard working solution (efavirenz) was added and vortexed. Samples were centrifuged at 16000g for 5 minutes. A total of 200 µL of supernatant was transferred into injection vials (Waters, Milford, Mass). Samples were injected using an Alliance 2690 Autosampler (Waters) with a BDS Hypersil C18 (50 x 4.6 mm, 3.0 µm) analytical column using a mobile phase of 57:43 acetonitrile/25 mM ammonium formate, pH 4.0. A Perkin Elmer Sciex API 3000 LC-MS/MS with a Turbo Ionspray source was used to analyze the eluate from the chromatographic column. The analytes were detected using selected reaction monitoring in positive ion mode. The mass transitions monitored for anidulafungin were m/z 1141 1122. The calibration range (without dilution) of the assay was 0.1 to 20 mg/L. The interday assay precision for the anidulafungin assay, as measured by the percentage coefficient of variation (%CV) of the quality control samples prepared at concentrations of 0.300, 4.00, and 16.0 mg/L, was less than or equal to 12.5%. The assay accuracy, as measured by the mean determined concentration for each of the quality controls and expressed as a percentage of the theoretical concentration, ranged from 94.4% to 110%.

Plasma samples were analyzed for voriconazole and the N-oxide metabolite of voriconazole at PPD Development (Richmond, Va) using a validated assay. A 100-µL sample aliquot was acidified with 500 µL of 20 mM ammonium formate, pH 3, and fortified with 20 µL working solution of a chemically related internal standard. Analytes were isolated through solid-phase extraction using a 96-well Varian Bond Elute Matrix C₁₈ extraction plate. A portion of the solid-phase extraction eluate was diluted 4-fold to a final extract composition of 1:1 methanol/20 mM ammonium acetate, pH 4.0. The final extract was analyzed via high-performance liquid chromatography on a Phenomenex Luna C₁₈ (2) (2 x 50 mm, 50 µm) analytical column using a mobile phase of 70:30 methanol/20 mM ammonium acetate (pH 4.0), with MS/MS detection using a Perkin Elmer Sciex API 3000 with a Turbo Ionspray source operating in positive ion mode. The mass transitions monitored were m/z 350.3 281.2 for voriconazole and m/z 366.2 223.9 for voriconazole N-oxide. The calibration range of the assays (without dilution) was 0.01 to 2.5 mg/L for voriconazole and 0.02 to 5 mg/L for the N-oxide metabolite. For both voriconazole and its metabolite, the interday assay precision, as measured by the %CV for 3 levels of quality controls, was less than or equal to 11.2%. The mean assay accuracy ranged from 95.3% to 99.9% for voriconazole and from 101% to 104% for the N-oxide metabolite.

Assay validations for all analytes included long-term and freeze/thaw stability that was adequate to meet the needs of this study. In addition, interference testing was performed on all assays and showed no assay interference between voriconazole, voriconazole N-oxide metabolite, and anidulafungin.

Safety Monitoring
Safety and tolerability were monitored before, during, and after each study period with laboratory tests, physical examinations that included vital signs (sitting blood pressure, pulse rate, and body temperature), electrocardiograms (ECGs), and adverse event monitoring. Subjects were queried about possible adverse events and symptoms daily, and any recorded adverse event was classified by severity and relationship to study drug.

Pharmacokinetic Analysis
The pharmacokinetic parameters for anidulafungin, voriconazole, and the N-oxide metabolite of voriconazole were estimated by noncompartmental methods using WinNonlin (version 4.0; Pharsight Corporation, Mountain View, Calif). Parameters were determined for the drugs administered alone and in combination. The pharmacokinetic parameters included the maximum observed plasma concentration (C_max) and area under the plasma concentration versus time curve at steady state (AUC_ss). AUC_ss was calculated using the linear trapezoidal rule applied to the steady-state (day 4) concentrations through the dosing period. The dosing period for anidulafungin was 24 hours, while the dosing period for voriconazole and the voriconazole N-oxide metabolite was 12 hours. In addition, using standard noncompartmental techniques and relationships, the terminal half-life (), total body clearance (CL), and volume of distribution at steady state (V_SS) were determined for anidulafungin.²⁴

Statistical Analysis
Safety and pharmacokinetic parameters were summarized by drug regimen: anidulafungin administered alone, voriconazole administered alone, and anidulafungin administered with voriconazole. Statistical comparisons of pharmacokinetic parameters were made for each analyte using a 2 one-sided tests procedure, comparing drug administered alone (reference) to drug administered in combination (test). The statistical analyses of the pharmacokinetic parameters were performed using PROC MIXED of SAS, version 8.2, on natural log-transformed pharmacokinetic parameters C_max and AUC_SS. The natural log-transformed anidulafungin pharmacokinetic parameters CL, V_SS, and were also statistically analyzed. The statistical model included treatment, period, sequence, and subject (sequence), with subject (sequence) as a random effect. The least squares means and the 90% confidence intervals for the parameter ratios (administered in combination/administered alone) were calculated. No effect boundaries of 80% to 125% (equivalence range) were used to determine whether clinically significant differences were present.

View larger version (16K): [in this window] [in a new window]   Figure 1. Steady-state plasma concentration-time profile of anidulafungin (mean ± standard deviation) following administration of anidulafungin alone or in combination with voriconazole. Data time points are slightly offset for ease of reading.

View larger version (9K): [in this window] [in a new window]   Figure 2. Anidulafungin trough concentrations in plasma (mean ± standard deviation) following administration of anidulafungin alone or in combination with voriconazole.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Subjects
Eighteen healthy male subjects were enrolled, of whom 17 completed all 3 study periods. Subjects were 20 to 40 years of age, with a median age of 28 years. Subject BMI ranged from 22 to 30 kg/m², with a median BMI of 25 kg/m². Most of the subjects in the study were Hispanic (n = 16), and the remainder were white (n = 2). One subject completed the first 2 study periods and was dropped from the study for non-study-related reasons. This subject did not complete a regimen of anidulafungin administered alone. Data for all 18 subjects participating in the study were included in the safety assessment. Data for all 18 subjects were included in the statistical analyses of voriconazole and voriconazole N-oxide metabolite pharmacokinetic parameters, and data from 17 subjects were included in the statistical analyses of anidulafungin pharmacokinetic parameters.

Pharmacokinetics of Anidulafungin
Steady-state concentrations of anidulafungin in plasma following administration of anidulafungin alone or in combination with voriconazole are shown in Figure 1. Steady-state anidulafungin concentrations, attained as trough levels of anidulafungin in plasma, were consistent on days 2 through 4 (Figure 2). Steady-state anidulafungin pharmacokinetic parameters are shown in Table I. There were no significant differences in the pharmacokinetic parameters when subjects received anidulafungin alone or in combination with voriconazole. The geometric mean ratio of the compared treatments was nearly unity. The 90% confidence intervals for the ratios are also shown in Table I. These intervals were within the 80% to 125% bioequivalence range used to detect clinically significant differences. Individual anidulafungin C_max and AUC_SS values are plotted by drug regimen in Figure 3. There were no trends of increasing or decreasing concentrations or exposures.

View larger version (16K): [in this window] [in a new window]   Figure 3. Individual anidulafungin Cmax and AUCSS parameters following administration of anidulafungin alone or in combination with voriconazole.

Pharmacokinetics of Voriconazole and Voriconazole N-oxide Metabolite
Figure 4 shows the steady-state concentrations of voriconazole in plasma following administration of voriconazole alone or in combination with anidulafungin. Voriconazole trough levels were consistent on days 2 through 4 as shown in Figure 5, indicating attainment of steady-state concentrations. The steady-state concentration-time profiles of the voriconazole N-oxide metabolite are shown in Figure 6. Steady-state voriconazole and voriconazole N-oxide metabolite pharmacokinetic parameters are shown in Tables II and III, respectively. There were no significant differences in the pharmacokinetic parameters when subjects received voriconazole alone or in combination with anidulafungin. The geometric mean ratio of the compared treatments was nearly unity. The 90% confidence intervals for the voriconazole and the voriconazole N-oxide metabolite ratios are also shown in Tables II and III, and these intervals were within the 80% to 125% bioequivalence range used to detect clinically significant differences. Individual voriconazole C_max and AUC_SS values are plotted by drug regimen in Figure 7. Individual voriconazole N-oxide metabolite pharmacokinetic parameters are plotted by drug regimen in Figure 8. There were no trends of increasing or decreasing concentrations or exposures.

View larger version (16K): [in this window] [in a new window]   Figure 4. Steady-state plasma concentration-time profile of voriconazole (mean ± standard deviation) following administration of voriconazole alone or in combination with anidulafungin. Data time points are slightly offset for ease of reading.

View larger version (9K): [in this window] [in a new window]   Figure 5. Voriconazole trough concentrations in plasma (mean ± standard deviation) following administration of voriconazole alone or in combination with anidulafungin.

View larger version (15K): [in this window] [in a new window]   Figure 6. Steady-state plasma concentration-time profile of voriconazole N-oxide metabolite (mean ± standard deviation) following administration of voriconazole alone or in combination with anidulafungin. Data time points are slightly offset for ease of reading.

View larger version (18K): [in this window] [in a new window]   Figure 7. Individual voriconazole Cmax and AUCSS parameters following administration of voriconazole alone or in combination with anidulafungin.

View larger version (18K): [in this window] [in a new window]   Figure 8. Individual voriconazole N-oxide metabolite Cmax and AUCSS parameters following administration of voriconazole alone or in combination with anidulafungin.

Safety and Tolerability
Overall, all regimens were well tolerated by all subjects. There were no serious adverse events or deaths in this study. All adverse events were mild in intensity. Fifteen of the 18 subjects (83%) experienced some type of adverse event during this trial, 7 subjects (41%) during administration of anidulafungin alone, 11 subjects (61%) during administration of voriconazole alone, and 12 subjects (67%) during coadministration of both drugs. One subject was dropped from the study after the second study period due to pharyngolaryngeal pain unrelated to study drugs that was later diagnosed as tonsillitis.

All drug-related adverse events are presented by study regimen in Table IV. For anidulafungin administered with an oral placebo, the most frequently reported drug-related adverse event was injection site reaction. These adverse events included bruising, erythema, pain, and swelling at the sites of injection. One subject also reported a headache following administration of anidulafungin alone. During the administration of voriconazole administered with an IV placebo, drug-related adverse events were dizziness, injection site reactions, headache, visual disturbance, and nausea. For the drug combination, drug-related adverse events were injection site reaction, photophobia, visual disturbance, headache, and blurred vision.

There were no adverse events related to electrocardiogram (ECG) results or vital signs across all study regimens. Mean ECG and vital sign parameters remained within their respective reference ranges throughout the study trial. Overall, no trends were observed in individual parameters.

Laboratory Measurements
There were no clinically significant changes in individual laboratory parameters for any subject receiving the drug combination. Mean laboratory values remained within reference ranges, with no marked change from baseline noted across any of the regimens. One subject exhibited a clinically significant potassium value approximately 72 hours following administration of voriconazole alone (5.7 mEq/L; increase of 1.8 mEq/L). The potassium level returned to reference range (3.8-5 mEq/L) at baseline of the next study period and remained within reference range throughout the remainder of the study. None of the remaining individual serum chemistry abnormalities was clinically significant, and there were no adverse events related to serum chemistry. There were no notable trends or shifts in hematology values. One subject exhibited a clinically significant monocyte count 2 weeks following the anidulafungin alone regimen (13.9%; increase of 2.1%). Another subject exhibited a clinically significant white blood cell count 2 weeks after the start of voriconazole alone (12.7 thou/µL; increase of 3.7 x 10³/µL). None of the remaining individual hematology abnormalities were considered clinically significant, and there were no adverse events related to hematology. Overall, no trends were observed in individual laboratory parameters.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The present study compared the safety and pharmacokinetics of anidulafungin and voriconazole administered alone to those of coadministered compounds. The study design was robust, using multiple doses and a crossover comparison of regimens. The dosages used for both drugs in this study are typical of those used in other clinical studies. An anidulafungin dose of 100 mg/d is being studied for treatment of invasive fungal infections, and 200 mg every 12 hours is the recommended dose of oral voriconazole for treatment of serious fungal infections. A loading dose regimen was used for both drugs in this study, and these regimens were effective in attaining steady-state concentrations following the first day of drug administration. The study sample size was based on the pharmacokinetic assessments and was sufficient to show any clinically significant differences. A post hoc analysis of statistical power confirmed the adequacy of this sample size. The power for each of the pharmacokinetic comparisons presented in this study was at least 94%.

The steady-state anidulafungin, voriconazole, and voriconazole N-oxide metabolite pharmacokinetic parameters observed in this study are consistent with the parameters observed in other trials. A previous examination of potential drug interactions between anidulafungin and cyclosporine in healthy volunteers had similar pharmacokinetic parameters.²⁵ Anidulafungin pharmacokinetic parameters were also similar to those reported in patients.²⁶ The pharmacokinetics of voriconazole and its N-oxide metabolite has been studied in healthy volunteers and patients using a similar regimen as the present study and showed pharmacokinetic parameters similar to those observed in this study.^12,17,22,23

Concentrations and exposures of all analytes as measured by steady-state C_max and AUC_SS were closely comparable when the drug was administered alone compared to administration in combination. There was no indication of induction or inhibition of any of the analytes with the coadministration. In addition to C_max and AUC_SS, the study design permitted estimates of CL, V_SS, and for anidulafungin. These anidulafungin pharmacokinetic parameters were unaffected by coadministered voriconazole.

The lack of any pharmacokinetic interaction was originally suggested by the different elimination pathways of anidulafungin and voriconazole, and this hypothesis is confirmed by the data from this trial. Anidulafungin is nonenzymatically degraded in the body, while voriconazole is metabolized by hepatic cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. The results of this study, however, cannot be readily extrapolated to other antifungal combinations. Caspofungin, another echinocandin, is subject to biotransformation by metabolism and has been shown to interact clinically with other drugs metabolized by cytochrome P450 enzymes.²⁷ Voriconazole has an inhibition potency for CYP3A4 that is significantly less than that of ketoconazole or itraconazole, other azole antifungals.

The adverse events in the current study were similar to those experienced in past studies of anidulafungin and voriconazole. Infusion-associated adverse events (site pain, bruising, swelling, and erythema) were observed in the study but were comparable in rate and severity for anidulafungin and the IV placebo. Visual disturbances were experienced by subjects in this study and occurred following the administration of either voriconazole alone or coadministration of anidulafungin and voriconazole. Photophobia was observed only during the administration of anidulafungin with voriconazole, and dizziness was observed only during the administration of voriconazole alone. Although there were some small differences in drug-related adverse events across the 3 regimens, the numbers of events were small, and the rates were consistent with the adverse events reported in other healthy subject and patient trials.^{11-13,16,17,28} As with previous studies, these events were mild and resolved within hours after drug administration. No trends in clinical laboratory values, vital signs, ECG parameters, or physical examination findings were noted in this study with the use of the anidulafungin-voriconazole combination.

In conclusion, the coadministration of intravenous anidulafungin and oral voriconazole appeared to be well tolerated in this study. These 2 drugs may be administered together in future clinical studies to examine the efficacy of the combination for the treatment of serious fungal infections without concern for clinically significant pharmacokinetic interactions.

	ACKNOWLEDGEMENTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The authors wish to thank Jeanine Napoli-Bortel, Dr Jeff Wilson, Kay Clark, and Dr Mark Allison for their assistance in managing and overseeing the operations of the study. This study was jointly funded by Vicuron Pharmaceuticals and Pfizer Inc.

DOI: 10.1177/0091270005281234

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TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

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