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DRUG INTERACTIONS |
From Vicuron Pharmaceuticals, a subsidiary of Pfizer, Inc, New York, (Dr Dowell, Dr Stogniew, Dr Krause, Dr Henkel) and Pfizer Global Research and Development, Pfizer, Inc, New York, (Dr Damle).
Address for reprints: Address for correspondence: Bharat Damle, PhD, Associate Director, Clinical Pharmacology, Pfizer Global Research & Development, 685 3rd Avenue, New York, NY 10017; e-mail: bharat.damle{at}pfizer.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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, CL, and Vss, were derived from concentration-time data. The 90% confidence intervals (CIs) of the ratios of mean pharmacokinetic parameters of anidulafungin plus tacrolimus to each drug alone were well within the 80% to 125% bioequivalence range, indicating no pharmacokinetic interaction. This ratio was 101.6 (90% CI: 92.77-111.22) for tacrolimus AUC0-
and 107.2 (90% CI: 105.1-109.4) for anidulafungin AUCss. The 2 drugs were well tolerated, and no drug-related serious adverse events were reported. Because of its lack of pharmacokinetic interaction with key immunosuppressive agents, anidulafungin is an important option for the prevention and treatment of invasive fungal infections in transplant recipients.
Key Words: anidulafungin • tacrolimus • drug interaction • pharmacokinetics • tolerability
Anidulafungin is a novel cyclic lipopeptide antifungal agent of the echinocandin class. Members of this class of antifungal agents are known to be non-competitive inhibitors of (1,3) ß-D-glucan synthase, an enzyme complex involved in the synthesis of glucan polymers in fungal cell walls. Inhibition of glucan polymer synthesis compromises cell wall integrity and causes fungal cell death. In vitro studies have shown that anidulafungin has fungicidal activity against Candida spp, including strains that are resistant to polyenes and azoles,1 and potent activity against Aspergillus spp and Pneumocystis jiroveci (P carinii f sp hominis).2,3 As a result of its potent antifungal activity, it is likely that anidulafungin will become an important treatment option in transplant recipients with suspected life-threatening fungal infections and will be used concomitantly with immunosuppressive drugs such as tacrolimus or cyclosporine.
Anidulafungin is only administered intravenously, as are the other echinocandins—namely, caspofungin and micafungin. Following intravenous administration, anidulafungin systemic exposures increase linearly with dose.4,5 Anidulafungin appears to be mainly eliminated by slow chemical degradation; approximately 90% of the administered drug is degraded, with less than 10% eliminated in the feces as intact drug.6 The half-life of elimination is approximately 1 day, allowing once-daily dosing.3,4 Using a loading dose on day 1 at twice the daily maintenance dose, steady-state plasma levels are achieved within 24 hours.4,7 In the therapeutic setting for invasive Candida infection, for example, a 200-mg loading dose is followed by 100-mg daily dose thereafter.3,4
A population pharmacokinetic model for anidulafungin, described as a 2-compartment model, estimated the volume of distribution at steady state (Vss) as 33.2 L and the clearance rate as 0.946 L/h. In the same analysis, anidulafungin showed predictable pharmacokinetics with low intersubject variability (24%); clearance was not influenced by age, weight, gender, ethnicity, and disease condition to a degree that was deemed clinically relevant.8 Furthermore, anidulafungin clearance was not influenced by the presence of P450 substrates, inducers, or inhibitors.8
Tacrolimus is a macrolide immunosuppressant used in the long-term management of allogeneic liver and kidney transplant recipients but, like other immunosuppressants, may render such patients more susceptible to serious fungal infections. Therefore, such patients will often require concomitant antifungal therapy, making it necessary to assess drug interaction. In the therapeutic setting for adult liver transplant patients, 0.10 to 0.15 mg oral tacrolimus/kg body weight is given daily. Tacrolimus is metabolized extensively by cytochrome P450, primarily by CYP3A enzyme systems.9,10 Substances or drugs known to inhibit or induce these enzymes have been shown to alter the metabolism of tacrolimus and affect its bioavailability.11-13 Tacrolimus has a narrow therapeutic window, and any medication that interferes with therapeutic concentrations of this immunosuppressant can lead to graft rejection, graft versus host disease, or serious toxicity and infection.
Drug interactions with tacrolimus have been noted for caspofungin,14 but no interaction was observed between micafungin and tacrolimus.15 This suggests the need to assess each echinocandin separately in regard to potential drug interactions with tacrolimus. In a phase I study, anidulafungin showed no clinically relevant interaction with cyclosporine.16 However, potential pharmacokinetic interactions with tacrolimus have not been investigated.
The current study was undertaken to examine the pharmacokinetics and safety of anidulafungin coadministered with tacrolimus, given the likelihood of concomitant use. The primary objective of the study was to assess the possible pharmacokinetic interaction between oral tacrolimus and intravenous anidulafungin, administered simultaneously to healthy male volunteers. The secondary objective was to assess the safety and tolerability of the 2 drugs coadministered in this manner.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Subjects. All subjects gave written informed consent before participating in the study. Thirty-six healthy volunteers were recruited, and all received at least 1 dose of each study medication. Inclusion criteria included the following: male subjects aged 18 to 55 years, a body mass index (BMI) between 18 to 30 kg/m2, and body weight >50 kg. Exclusion criteria included the following: prior recent treatment with either investigational drug, any known CYP3A4 enzyme-altering agent or any known hepatic and/or P450 enzyme-altering agent, any laboratory measurement at screening outside of the normal value range, and previous history of intolerance or hypersensitivity to the study drugs or related compounds.
Drug administration. All subjects were administered a single oral 5-mg tacrolimus capsule in the fasted state on days 1 and 13 of the study. A 200-mg intra-venous loading dose of anidulafungin was administered on day 4, with daily maintenance doses of 100 mg administered intravenously on days 5 through 13. Anidulafungin, at a concentration of 0.5 mg/mL in dextrose injection 5%, was administered as an intravenous infusion at a rate of 1 mg/min.
Pharmacokinetic Analyses
Pharmacokinetic blood sample collection. The single-dose pharmacokinetics of tacrolimus were determined when this drug was administered alone (day 1) and concurrently with anidulafungin (day 13). Blood samples for tacrolimus were collected predose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, and 72 hours postdose.
The pharmacokinetics of anidulafungin were determined at steady state when this drug was administered alone (day 10) or concurrently with tacrolimus (day 13). Blood samples were collected for anidulafungin analysis predose on days 4 and 8 and at the following time points on days 10 and 13: preinfusion, immediately postinfusion (1.67 hours), and 3, 4, 6, 8, 12, and 24 hours after the start of infusion.
Determination of plasma anidulafungin concentrations. Blood samples (6 mL) for the measurement of anidulafungin were collected at the above time intervals via venipuncture into prelabeled, sodium-heparinized tubes. The samples were centrifuged at 1500 g at 4°C for approximately 10 minutes. Resulting plasma was separated into polypropylene screw-cap tubes and frozen at -70°C until analysis for anidulafungin concentrations.
Plasma samples were assayed for anidulafungin using a validated liquid chromatography coupled to tandem-mass spectrometry (LC/MS/MS) method (XenoBiotic Laboratories, Inc, Plainsboro, NJ). Plasma aliquots (100 µL) were diluted with 300 µL of an internal standard solution (loratadine at a 400-ng/mL concentration) or 300 µL of methanol for blanks. After centrifugation at 13 000 rpm for 5 minutes, the supernatant was chromatographed on a BDS Hypersil C18 column (50 x 4.6 mm, 3 µm, Phenomenex) with an injection volume of 5 µL. The high-performance liquid chromatography (HPLC) system consisted of a Shimadzu LC-10AD pump, Shimadzu SIL-HTA autosampler, and Shimadzu SIL-HTA controller, interfaced to a PE-Sciex API 3000 tandem mass spectrometer by a turbo ion spray source operating in positive ion mode at 5000 volts and 450°C. Isocratic chromatography (flow rate 1 mL/min) was employed, using HPLC water with 25 mM ammonium formate (pH 4.0)/acetonitrile (43:57 ratio). Ions were detected in multiple-reaction monitoring (MRM) scan mode with precursor
product ion pairs of 1140.81122.8 for anidulafungin and 383.1337.1 for loratadine. Calibration was accomplished by weighted (1/x*x) linear regression of the ratio of the anidulafungin peak area to that of loratadine.
The LC/MS/MS method for anidulafungin was validated in the linear concentration range of 0.1 to 20.0 µg/mL. Overall precision for quality control samples of 0.3, 4.0, and 16.0 µg/mL, as measured by percent coefficient of variation (%CV), was 
11.37%. Overall accuracy, as measured by percent relative error (%RE), for these quality control samples was 6.13%.
Plasma quality control samples containing anidulafungin were shown to be stable after undergoing 4 freeze-thaw cycles and were stable when stored at -80°C for at least 21 months. The presence of 50 ng/mL of tacrolimus in plasma quality controls did not interfere with the anidulafungin analysis.
Determination of whole-blood tacrolimus concentrations. Blood samples (6 mL) for the analysis of tacrolimus were collected via venipuncture into prelabeled K2 EDTA tubes and stored at -20°C prior to assay. These whole-blood samples were assayed for tacrolimus using a validated LC/MS/MS method (Quest Pharmaceutical Services, Newark, Del). After thawing at room temperature, 50 µL of each sample was spiked with 50 µL of internal standard solution (ascomycin at 50 ng/mL concentration) in plastic disposable culture tubes, followed by addition of 2.0 mL of methyl t-butyl ether. The tubes were capped, shaken for 10 minutes, and centrifuged for 5 minutes at 3000 rpm. They were then placed in a dry ice/MeOH mixture to freeze the aqueous layer. The supernatant was transferred to plastic culture tubes and evaporated to dryness in a 40°C bath under a nitrogen stream, and the sample was reconstituted with 200 µL of H2O/methanol/formic acid (70:30:0.1 [v:v:v]). Subsequently, the sample was transferred to plastic autosampler vials and centrifuged for 2 minutes at 3000 rpm.
The supernatant was chromatographed on a Luna C8 column (50 x 2 mm, 5 µm, Phenomenex) with an injection volume of 20 µL. The HPLC system consisted of a Shimadzu LC-10AD pump, HTC PAL autosampler, Shimadzu DGU-14A vacuum degasser, and Shimadzu Column Switcher, interfaced to a API 4000 triple quadrupole mass spectrometer by a turbo ion spray source operating in negative ion mode at 500°C. The chromatography mobile phase was composed of 2 mM ammonium acetate in water and 100% methanol. The concentration of the latter in the gradient changed over time, as follows: 0 minutes (40%), 1.0 minutes (40%), 1.5 minutes (100%), 3.0 minutes (100%), 3.1 minutes (40%), and 4.0 minutes (40%). At the 1.0-minute time point, the column output was switched to the mass spectrometer. Ions were detected with precursorproduct ion pairs of 802.6560.3 for tacrolimus and 790.0548.3 for ascomycin. Calibration was accomplished by weighted (1/x*x) linear regression of the ratio of the peak area of tacrolimus to that of ascomycin.
The LC/MS/MS method for tacrolimus in whole blood was validated in the linear concentration range of 0.2 to 100 ng/mL. The assay was also validated to allow up to 10-fold dilution of whole-blood samples. Overall precision for quality control samples of 0.4, 20.0, and 80.0 ng/mL, as measured by %CV, was 16.4%. Overall accuracy, as measured by %RE, for these quality control samples was 5.5%.
During assay validation, whole-blood quality control samples containing tacrolimus were shown to be stable after undergoing 3 freeze-thaw cycles and were stable at -20°C for at least 7 months. The presence of 10 µg/mL anidulafungin did not interfere with the tacrolimus assay.
Pharmacokinetic parameters. Anidulafungin pharmacokinetic parameters were determined at steady state from plasma samples collected following the day 10 (anidulafungin alone) and day 13 (anidulafungin with tacrolimus) doses. Trough concentrations (Ctrough) of anidulafungin were assessed by visual examination to ensure that steady state was achieved. Single-dose pharmacokinetic parameters of tacrolimus were calculated from whole-blood samples collected following the day 1 dose (tacrolimus alone) and day 13 dose (tacrolimus with anidulafungin).
Pharmacokinetic parameters were calculated from concentration-time data by standard noncompartmental analyses using WinNonlin 4.01 (Pharsight Corp, Mountain View, Calif). Version 8.2 of the SAS statistical software package was used to provide data summary tables and listings. Maximum observed plasma concentrations (Cmax), time to Cmax (tmax), and Ctrough were obtained directly from experimental data. The area under the concentration-time curve (AUCt) was estimated using the linear trapezoidal method. For anidulafungin, AUCt was determined over the 24-hour dosing interval (AUCss). For tacrolimus, AUCt was determined from 0 to 12 hours (AUC0-12), from 0 to the time of last measurable concentration (AUC0-t), and from 0 to infinity (AUC0-). The elimination rate constant (
z) was estimated by linear regression of the linear portion of the log concentration versus time curve. AUC0- was calculated as follows:
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The terminal phase half-life (t) was calculated as ln(2)/z. Clearance of anidulafungin (CL) and apparent oral clearance of tacrolimus (CL/F) were determined as the ratios of AUCss/Dose and AUC0-/Dose, respectively. Apparent volume of distribution (Vz/F) for tacrolimus and volume at steady state (Vss) for anidulafungin were determined using standard formulas in WinNonlin.
Safety analysis. Analysis of the tolerability of tacrolimus and anidulafungin was carried out throughout the study. Safety assessments included clinical laboratory tests (hematology, serum chemistry, urinalysis), physical examination, vital signs (blood pressure, pulse, temperature), electrocardiograms, and adverse events (AEs). All clinical laboratory tests were undertaken by MDS Pharma Services Clinical Laboratory (Belfast, Northern Ireland).
Statistical analysis. The sample size for this study was based on the pharmacokinetic parameter with the largest intrasubject variability, which was the tacrolimus trough concentration. A previous study showed that this variability had a CV of 39%.17 With a total sample size 
30, the design used in this study had >80% power to reject the null hypothesis that the ratio of the test to the reference was below 0.8 and/or above 1.25 (ie, the test and reference were not equivalent). Rejection of this hypothesis would prove the alternative hypothesis that the 2 treatments were equivalent.
Pharmacokinetic and safety data were summarized using descriptive statistics. Geometric means and %CV were provided for key pharmacokinetic parameters (Cmax and AUCss for anidulafungin and Cmax, C12h, AUC0-12, AUC0-t, and AUC0- for tacrolimus). Arithmetic mean and standard deviations were provided for other pharmacokinetic parameters. The point estimate and 90% confidence intervals (CIs) for the ratios (test/reference) of natural log-normalized anidulafungin pharmacokinetic parameters (Cmax and AUCss) and natural log-normalized tacrolimus pharmacokinetic parameters (Cmax, C12h, AUC0-12, AUC0-t, and AUC0-) were calculated. No adjustments were made for multiple comparisons. Compound symmetry was assumed, and restricted maximum likelihood (REML) estimates were utilized. Least squares (LS) means and 90% CIs comparing treatment means were calculated, and the antilog was taken of the CIs to obtain adjusted LS means and CIs for the ratio. A no-effect boundary of 80% to 125% (equivalence range) was used to conclude that no clinically significant differences were present. Trough plasma concentrations collected through the dose periods were summarized for anidulafungin by collection day to ensure that steady state was attained.
All statistical analyses were performed using SAS software (version 8.2; SAS Institute, Cary, NC).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Thirty-five of the subjects received all doses of the 2 drugs and underwent all safety assessments; the remaining subject withdrew consent for study participation on day 3 for personal reasons (unrelated to safety or tolerability). All subjects received the same batches and lot numbers of tacrolimus capsules and anidulafungin solution. Two subjects had interruptions to their anidulafungin infusions due to intravenous pump malfunctions on days 10 or 13; however, these infusions were resumed and completed for all of these individuals. As these interruptions were <5 minutes in length, they were regarded as unlikely to have a significant impact on pharmacokinetic parameters when considering the 100-minute total infusion period. Another subject received only 95% of the total volume of infusion on 1 occasion due to a leaking intravenous bag. The pharmacokinetic evaluation was carried out on 36 subjects for tacrolimus and 35 for anidulafungin. All 36 subjects were included in the safety analysis.
Pharmacokinetics of anidulafungin. Steady-state concentrations of anidulafungin were achieved following the loading dose and were maintained throughout dosing with anidulafungin alone or coadministered with tacrolimus. Administration of anidulafungin alone or in combination with tacrolimus resulted in a similar mean anidulafungin Cmax (6.88 mg/L vs 7.07 mg/L, respectively) and AUCss (103.4 mg·h/L vs 110.8 mg·h/L, respectively). Maximum plasma Cmax concentrations were reached shortly after the end of infusion on day 10 and day 13 (Figure 1). Mean values were also similar for clearance (0.993 L/h vs 0.923 L/h, respectively), Vss (35.2 L vs 32.3 L, respectively), and t (25.2 vs 25.2, respectively). A summary of the pharmacokinetic parameters for anidulafungin is shown in Table I, and anidulafungin clearance data by treatment are shown in Figure 2.
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Statistical analysis of natural log-normalized plasma anidulafungin Cmax and AUCss values for comparison of anidulafungin coadministered with tacrolimus and anidulafungin alone indicated that, at steady state, the 90% CIs of the mean ratios of anidulafungin plus tacrolimus to anidulafungin alone were well within the 80% to 125% bioequivalence range.
Pharmacokinetics of tacrolimus. Administration of tacrolimus alone or together with anidulafungin resulted in similar mean tacrolimus Cmax (23.2 vs 22.5 ng/mL, respectively), C12h (3.9 vs 4.1 ng/mL, respectively), AUC0-t (229.4 vs 228.4 ng·h/mL, respectively), AUC0-12 (107.7 vs 102.6 ng·h/mL, respectively), and AUC0- (269.6 vs 270.9 ng·h/mL, respectively) values. Maximum plasma Cmax concentrations were reached shortly after the end of infusion on day 1 and day 13 (Figure 3). Mean values of CL/F (20.3 vs 19.4 L/h, respectively), Vz/F (823.3 vs 804.3 L, respectively), and t (27.8 vs 29.0 h, respectively) were also similar for tacrolimus alone and tacrolimus coadministered with anidulafungin. A summary of the pharmacokinetic parameters for tacrolimus is shown in Table II, and apparent oral clearance data are shown in Figure 4.
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Statistical analysis of natural log-normalized whole-blood tacrolimus Cmax, C12h, AUC0-12, AUC0-t, and AUC0- values for comparison of anidulafungin coadministered with tacrolimus and tacrolimus administered alone indicated that the 90% CIs of the mean ratios of anidulafungin plus tacrolimus to tacrolimus alone were well within the 80% to 125% bioequivalence range.
Safety. Coadministration of anidulafungin and tacrolimus was well tolerated by all subjects. There were no deaths, no life-threatening AEs, or any treatment-related serious AEs (SAEs). Twenty-two of the 36 subjects (61%) experienced a total of 61 treatment-emergent AEs: 11 (31%) during days 1 to 3 (tacrolimus alone), 14 (40%) during days 4 to 12 (anidulafungin alone), and 10 (29%) during days 13 to 16 (tacrolimus and anidulafungin). The most common AE was headache, which was reported a total of 10 times by 7 subjects (19%); 2 subjects reported this AE during treatment days 1 to 3, 4 subjects during treatment days 4 to 12, and 3 subjects during treatment days 13 to 16. The investigator considered 5 of the 10 headache episodes to be possibly related to the study drug. All of the headache episodes were mild in intensity and resolved without the use of concomitant medication or therapy. All remaining treatment-emergent AEs, other than laboratory abnormalities, were reported by 3 or fewer subjects each (8%); the most common of these AEs were catheter site-related reaction (3 subjects, 8%), nocturia (3 subjects, 8%), dizziness (2 subjects, 6%), pollakiuria (2 subjects, 6%), and fatigue (2 subjects, 6%). All AEs (except 1 SAE) were mild in intensity and did not result in withdrawal of treatment.
The single SAE consisted of upper extremity thrombophlebitis in the left arm on day 15, which resulted in hospitalization and the subject prematurely discontinuing the study. Because the subject had received all doses of the study drug, the relevant data obtained up to this time point were included in both the pharmacokinetic analyses and safety assessments. The independent local clinical investigator considered this SAE as unlikely related to the study drug because the intravenous infusion of anidulafungin had been administered into the subject's right arm. There were no other SAEs reported.
Eight subjects experienced slightly raised alanine aminotransferase (ALT) levels, 1 on day 12 and 7 during days 13 to 16. This elevation of ALT was categorized as an AE in 5 of the 8 subjects and was considered possibly related to the study drug. One subject experienced an ALT elevation >3 x the upper limit of normal (ULN); this subject also had concurrent total creatine phosphokinase and creatine phosphokinase MB dimer elevations outside of the respective reference ranges, possibly as a consequence of strenuous exercise on days 16 and 17. No subject experienced concurrent transaminase and bilirubin elevations above the reference ranges. No subject had clinical symptoms concurrent with elevated ALT. Three subjects (8%) experienced an increase in aspartate aminotransferase (AST) levels that was categorized as AEs; these AEs were considered possibly related to the study drug.
No hematological AEs were reported during the study, and no treatment-related trends or clinically meaningful shifts from baseline were observed. No treatment-related trends were noted in vital sign measurements, electrocardiogram parameters, or physical examination findings.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Drug interaction studies between tacrolimus and 2 prior echinocandins (caspofungin and micafungin) have been reported. In vitro studies have shown that caspofungin is not metabolized by P450 enzymes and exhibits only a minimal inhibitory effect on P-glycoprotein-mediated transport.19,20 On the other hand, caspofungin may be a substrate for organic anion transporting polypeptide (OATP1B1).20 In vivo studies in healthy volunteers have demonstrated that the tacrolimus AUC was decreased by almost 20%, and peak concentrations were decreased by 16% when caspofungin and tacrolimus were administered simultaneously.21 There was no effect of tacrolimus on the pharmacokinetics of caspofungin. For patients receiving both therapies, standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are therefore recommended.22 In another study, coadministration of cyclosporine and caspofungin resulted in an increase in plasma AUC for caspofungin of approximately 35% in healthy individuals and a transient increase in serum ALT levels.22,23 The pharmacokinetics of cyclosporine were unaffected by caspofungin. These findings have led to the recommendation that cyclosporine and caspofungin should not be administered simultaneously to patients, unless the benefits significantly outweigh the risks.22-24 It has been speculated that the mechanism of interaction between caspofungin and cyclosporine may be related to the distribution of caspofungin into tissues.25 However, the true nature of the mechanism(s) of interactions between caspofungin and tacrolimus or cyclosporine remains unclear.
Micafungin is a mild inhibitor of CYP3A metabolism in vitro but is neither an inhibitor nor a substrate for P-glycoprotein.26 Micafungin is known to increase the AUC of sirolimus, an immunosuppressant binding to the same target protein as tacrolimus, by about 21%, which necessitates monitoring of sirolimus-related toxicity and reduction of sirolimus dose if necessary.26 Steady-state administration of this echinocandin to healthy volunteers was also found to reduce the oral clearance of cyclosporine by about 20% when the 2 drugs were administered simultaneously,27 but this change was not considered to be clinically important in warranting dose modification.26 However, no alteration in the pharmacokinetics of either drug was observed when single-dose or steady-state micafungin was coadministered with tacrolimus.15 The reasons for the observed interactions between micafungin and cyclosporine or sirolimus remain unclear at the present time.
Based on in vitro studies, anidulafungin is not a substrate, inhibitor, or inducer of the cytochrome P450 isozymes involved in drug metabolism and is therefore less likely to contribute to metabolic drug interactions.6 Furthermore, this echinocandin is not metabolized by hepatocytes but is eliminated by slow chemical degradation (>90%), with only a small amount (<10%) being eliminated unchanged in the feces.28 These metabolic properties are consistent with the results of a recent open-label study, which showed that coadministration of anidulafungin and cyclosporine, a drug metabolized by the CYP3A family of cytochrome P450 enzymes, was well tolerated and did not require dosage adjustment of either drug.16
In the current study, coadministration of anidulafungin and tacrolimus to healthy volunteers did not significantly affect the pharmacokinetics of either drug. Pharmacokinetic parameters, with and without coadministration, were assessed in the same subject because intersubject variability for tacrolimus is high. There were no significant differences in any of the pharmacokinetic parameters measured for tacrolimus and anidulafungin administered alone or simultaneously. Furthermore, the 90% CIs of the mean ratios of tacrolimus coadministered with anidulafungin versus tacrolimus alone, and vice versa, were both well within the 80% to 125% bioequivalence range; this confirms that there were no significant changes in the pharmacokinetics of either drug. These results indicate that pharmacokinetic interactions are absent in the specific case of anidulafungin and tacrolimus.
The combination of anidulafungin and tacrolimus was also well tolerated in this study, with no drug-related SAEs reported and no subject requiring withdrawal of therapy for an AE. The only SAE reported during the study was a case of thrombophlebitis. The independent clinical investigator judged this event as unlikely to be related to the study drug, as it occurred contralateral to the anidulafungin administration site. Superficial thrombophlebitis has previously been reported as an uncommon adverse event in a large phase III trial (N = 601) comparing anidulafungin with fluconazole for the treatment of esophageal candidiasis. In this trial, the frequency of superficial thrombophlebitis (1.3%), which was considered to be possibly or probably related to study treatment, was identical for both anidulafungin and fluconazole.29
The design of this study incorporated daily, multiple dosing (representative of that used in the clinical setting) of anidulafungin to achieve steady-state concentrations and to maximize any potential effect on the pharmacokinetics of tacrolimus. Tacrolimus itself was administered to subjects as a single dose on 2 occasions over the 16-day study period to minimize their exposure to this potent immunosuppressive agent. This single-sequence crossover design was also chosen to mimic the clinical scenario for use of tacrolimus and anidulafungin. For instance, anidulafungin may be given to solid organ transplant patients who are already receiving immunosuppressant therapy with tacrolimus, if they develop fungal infection. For these reasons, a single-sequence crossover design was considered best suited to this study; a similar design involving single doses of 5-mg tacrolimus was used previously for assessing the drug interaction with micafungin.15 Given that tacrolimus is not a known inducer of metabolic enzymes, single-dose designs would be appropriate to assess the effect of tacrolimus on other drugs while concurrently limiting tacrolimus exposure.
The use of antifungal agents in the prevention and treatment of fungal infections in immunosuppressed patients is likely to increase as the incidence of these infections continues to rise. The results of this study support the use of anidulafungin as an antifungal therapy in this setting, by demonstrating that coadministration of anidulafungin and tacrolimus is well tolerated and can be carried out without the need for dosage adjustment of either drug. Consistent with the previous study with cyclosporine,16 anidulafungin can be administered safely and without any effect on pharmacokinetics to patients receiving tacrolimus. The lack of pharmacokinetic drug interaction with key immunosuppressive agents makes anidulafungin an attractive drug for the prevention and treatment of fungal infections in transplant recipients.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Dr Stogniew is currently at Zelos Therapeutics, Inc, West Conshohocken, Pennsylvania.
Dr Krause is currently at Delta Pharmaceutical Consulting, LLC; Dr Henkel is currently at Ception Therapeutics, Malvern, Pennsylvania.
Presented in part at the 15th European Congress of Clinical Microbiology and Infectious Diseases (2005); Copenhagen, Denmark; abstract P1113.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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