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Assessment of the Safety and Pharmacokinetics of Anidulafungin When Administered With Cyclosporine

From Vicuron Pharmaceuticals, Inc, King of Prussia, Pennsylvania (Dr Dowell, Dr Stogniew, Dr Krause, Dr Henkel) and MDS Pharma Services, Phoenix, Arizona (Dr Weston).

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

	ABSTRACT

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Anidulafungin is a novel antifungal agent of the echinocandin class that is intended for the treatment of invasive fungal disease. It is likely that anidulafungin will be coadministered with cyclosporine. In vitro studies and clinical studies were performed to evaluate the effect of anidulafungin on cyclosporine metabolism and to investigate the safety and pharmacokinetics of anidulafungin when concomitantly administered with cyclosporine. The potential for anidulafungin to inhibit the metabolism of cyclosporine was evaluated by pooled human hepatic microsomal protein fractions in vitro, incubating ³H-cyclosporine with different concentrations of anidulafungin. The safety of coadministration and the effects of cyclosporine on the pharmacokinetics of anidulafungin were assessed in a multiple-dose, open-label clinical study of 12 healthy volunteers. Subjects received a 200-mg intravenous loading dose of anidulafungin, followed by a daily 100-mg intravenous maintenance dose on days 2 through 8. An oral solution of cyclosporine (Neoral oral solution; 100 mg/mL) 1.25 mg/kg was also administered to subjects twice daily on days 5 through 8. In the in vitro study, the addition of anidulafungin had no effect on cyclosporine metabolism by human hepatic microsomal protein fractions. In the clinical study, no dose-limiting toxicities or serious adverse events occurred. A small increase in anidulafungin concentrations and drug exposure (22%) was observed after 4 days of dosing with cyclosporine and was not considered to be clinically relevant. The results support the concomitant use of anidulafungin and cyclosporine without the need for dosage adjustments of either drug.

Key Words: Cyclosporine • anidulafungin • drug interactions • drug safety • pharmacokinetics

The echinocandins are a novel class of antifungal agents that inhibit the enzyme ß-(1,3)-D-glucan synthase, disrupting cell wall glucan formation.² ß-(1,3)-glucan is responsible for the structural integrity of the fungal cell wall. Cross-links between glucan and chitin provide additional cell wall rigidity.³ Inhibition of glucan synthesis results in osmotic fragility and cell death. Anidulafungin is an echinocandin that has unique properties compared to other parenteral antifungal agents and has demonstrated activity against Candida spp., Aspergillus spp., and Pneumocystis carinii.^4,5 In vitro studies have shown that anidulafungin is fungicidal against Candida spp., including strains resistant to polyenes and azoles.⁶ A large in vitro surveillance study of Candida albicans bloodstream isolates showed that the activity of anidulafungin was 8- to 16-fold better than that of the marketed echinocandin caspofungin (Cancidas; Merck & Co, Whitehouse Station, NJ).⁷

The long-term management of organ transplant recipients involves medications such as cyclosporine, tacrolimus, or sirolimus for the prevention of graft rejection. Drugs that affect the disposition of these medications can lead to graft rejection, graft versus host disease,^8,9 and renal, hepatic, or neurological toxicity.¹⁰ It is important to have treatments that lack significant drug interactions when treating this population for serious fungal infections.¹¹

In a labeling warning, coadministration of cyclosporine and caspofungin is not recommended unless the potential benefit outweighs the potential risk to the patient.¹² A single day of treatment with cyclosporine was found to increase the area under the plasma concentration-time curve (AUC) of caspofungin by approximately 35% in healthy subject studies. Caspofungin did not alter the pharmacokinetics of cyclosporine. Changes in the pharmacokinetics were accompanied by transient elevations of alanine aminotransferase (ALT) exceeding 2 to 3 times the upper limit of normal. These elevations in ALT were also coupled, to a lesser magnitude, with parallel increases in aspartate aminotransferase (AST). This prompted the evaluation of the concomitant administration of cyclosporine and anidulafungin.

Anidulafungin has a low potential to be involved in pharmacokinetic drug interactions.¹³ It is not metabolized by hepatocytes and is not a clinically relevant substrate, inhibitor, or inducer of cytochrome P450 isoenzymes commonly involved in drug-drug interactions.

Anidulafungin is eliminated by slow chemical degradation to a ring-opened product that is further degraded. Human studies have shown that most of the drug is chemically degraded with the remainder, <10% of the dose, excreted intact in feces.¹⁴ In addition, anidulafungin and its degradation products are not excreted into urine; therefore, the drug is unlikely to be involved in drug-drug interactions due to competitive renal elimination.

The pharmacokinetic properties of anidulafungin determined from multiple-dose clinical studies indicate that it has a predictable and dose-proportional plasma concentration and exposure profile.^15,16 The drug is rapidly and widely distributed with a steady-state volume of distribution (V_ss) of 30 to 50 L. The peak plasma concentrations (C_max) occur at or immediately after the end of the infusion. Steady state is achieved after the first dose when a loading dose of twice the maintenance dose is used. The plasma clearance (CL) and half-life (t_1/2) of anidulafungin are dose independent. Plasma CL is approximately 1 L/h, and the t_1/2 of the drug is about 1 day, reflecting chemical degradation. The pharmacokinetics of anidulafungin in patients treated for fungal infections (50-100 mg/d) are similar to those observed in healthy subjects.¹⁶ In addition, low intersubject and intrasubject variability have been observed in patient and healthy subject studies.^15,16

	METHODS

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In Vitro Study
The potential for anidulafungin to inhibit the metabolism of cyclosporine was evaluated using pooled human hepatic microsomal protein fractions (HHMPF), [³H]-cyclosporine, and 5 different concentrations of anidulafungin. [³H]-Cyclosporine (2 mg/L) was incubated with 1 mg/mL of HHMPF and 1.5, 4.5, 9, 15, and 30 mg/L of anidulafungin. Incubations were conducted for 0, 15, 30, and 45 minutes. Ketoconazole (10 µM), a known inhibitor of the cytochrome P450 isoenzyme CYP3A4, was used as a positive control in this experiment. The incubations were conducted at 37°C in 50 mM potassium phosphate buffer (pH 7.4) containing 1 mM ethylenediaminetetraacetic acid (EDTA) and a nicotinamide adenine dinucleotide phosphate (NADPH)–generating system. At the end of each incubation period, the samples were centrifuged, and the resulting supernatants were analyzed by high-performance liquid chromatography (HPLC) for cyclosporine and its metabolites. Additional 45-minute inhibition experiments were conducted with cyclosporine alone and HHMPF.

Clinical Study
Study design. Healthy adult volunteers were enrolled in an open-label study. Volunteers received a 200-mg intravenous loading dose of anidulafungin (Vicuron Pharmaceuticals) on day 1, followed by a daily 100-mg intravenous maintenance dose given on days 2 to 8. Anidulafungin infusions were administered at a rate of 1 mg/min. On days 5 to 8, an oral solution of cyclosporine (1.25 mg/kg) (Neoral oral solution for microemulsion; Novartis Pharma AG, Basel, Switzerland) was given twice daily.

A predose screening assessment was conducted within 21 days prior to admission to the clinical sites. Routine blood chemistry tests, hematology, physical examinations, and vital signs were performed beginning with the predose screening period and through to study follow-up (day 14). Safety was evaluated by the daily solicitation and recording of adverse events, as well as from the results of routine clinical laboratory tests, vital signs, and physical examinations.

Subjects. A total of 12 female and male volunteers were enrolled in this study. Eligibility for study participation was determined on the basis of a prestudy medical history, physical examination, vital signs, and clinical laboratory test results. Subjects were prohibited from using prescription and over-the-counter medications or alcohol throughout the study and for 30 days after the last dose of study medication. Women of childbearing potential, as well as male volunteers, were required to practice an effective birth control method during the study and for 30 days following their last dose of anidulafungin.

All subjects provided written informed consent. The study was approved by the institutional review board at 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 Code of Federal Regulations parts 50 and 56) for the protection of the rights and welfare of human subjects participating in biomedical research.

Pharmacokinetic blood sample collection. Blood samples for the determination of trough anidulafungin levels were obtained 24 hours after each dose of anidulafungin. On days 4 and 8, blood samples were obtained to characterize the steady-state pharmacokinetic profile of anidulafungin in the absence and presence of cyclosporine, respectively. On both days 4 and 8 of the study, blood samples were obtained prior to the anidulafungin dose and 1, 1.75, 1.92, 2.17, 2.67, 3.17, 5.17, 7.67, 11.67, 18.67, and 24 hours after the start of the infusion. Whole-blood samples for the determination of trough concentrations of cyclosporine were also obtained on days 5 to 8 prior to each morning dose of cyclosporine and again 24 hours after the last morning cyclosporine dose.

Determination of plasma anidulafungin concentrations. Blood samples (10 mL each) were collected into heparinized tubes at the above specified time intervals. The samples were centrifuged at 1500g 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 aliquots (100 µL) were diluted with 300 µL of an internal standard solution (efavirenz). After centrifugation, the supernatant was chromatographed on a BDS Hypersil C18 column (50 x 4.6 mm, 3.0 µm). The assay demonstrated acceptable accuracy and precision throughout the study. The overall accuracy for the quality control solutions was between 86.5% and 104.3%, with a precision of less than or equal to 10.3%.

Determination of blood cyclosporine concentrations. Whole-blood samples (10 mL) were collected into tubes containing EDTA. These samples were frozen until analyzed for cyclosporine concentrations. Prior to analysis, these samples were acidified and extracted with methyl-tert-butyl ether. The extract was washed with aqueous base, evaporated to dryness, and reconstituted in mobile phase. The reconstituted samples were then washed with hexane and injected onto a liquid chromatography/tandem mass spectrometry (LC-MS/MS) system equipped with a Turbo Ion Spray interface. Cyclosporine D was used as the internal standard. The overall accuracy for the quality control solutions was between 93.3% and 106.8%, with a precision of less than or equal to 9.1%.

Pharmacokinetic analysis. Daily plasma trough concentrations (C_trough) were statistically summarized across all subjects for each study day. On days 4 and 8, more extensive pharmacokinetic sampling was performed to determine the daily peak concentrations (C_max), the area under the steady-state concentration-time curve (AUC_ss), and the clearance (CL) for anidulafungin. Anidulafungin pharmacokinetic parameters were estimated using noncompartmental methods using WinNonlin pharmacokinetic software (version 4.1, Pharsight Corporation, Mountain View, Calif). The C_max values were obtained directly from the observed data. The AUC_ss was calculated using the linear trapezoidal rule, and the CL was calculated as dose/AUC_ss.

Statistical analysis. Statistical analyses were performed using WinNonlin and SAS software (version 8.1, SAS Institute, Cary, NC). Summary statistics are reported for all pharmacokinetic parameters by treatment period (day 4 vs day 8). The day 4 pharmacokinetic parameters (anidulafungin alone) were treated as the reference values. Differences between anidulafungin pharmacokinetic parameters in the absence and presence of cyclosporine for days 4 and 8 were evaluated using the Student t test for paired data. Natural log-transformed parameters were used in the statistical testing. Differences were also examined by constructing a 90% confidence interval about the geometric mean ratio and comparing the interval to the 80% to 125% bioequivalence range.¹⁷ Geometric least squared means were determined by linear mixed-effects modeling. Trough concentrations were evaluated using repeated-measures analysis of variance (ANOVA) with a P < .05 for significance.

	RESULTS

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In Vitro Study
The radiopurity of [³H]-cyclosporine was 98%. Complete inhibition of cyclosporine metabolism was observed in the presence of 10 µM ketoconazole. No metabolism of cyclosporine was observed in the absence of HHMPF. In the presence of 1 mg/mL of HHMPF, approximately 15% of the initial cyclosporine was metabolized at the end of the 45-minute incubation period, resulting in 3 distinct metabolites. These metabolites accounted for 6%, 2%, and 1% of radioactivity. These results were replicated when varying concentrations of anidulafungin were incubated with cyclosporine and HHMPF. Anidulafungin, at concentrations up to 30 mg/L, had no inhibitory effect on the in vitro metabolism of cyclosporine by HHMPF. These results indicate that coadministration of anidulafungin and cyclosporine is unlikely to have any effect on the metabolism of cyclosporine.

Clinical Study
Demography. The mean age (± SD) of the study subjects was 35.3 (± 10.3) years (range, 18-50 years). The mean weight (± SD) of subjects was 78.0 (± 20.0) kg (range, 53-115 kg). Of the subjects, 75% were female (n = 9). The ethnic background of the study population was 58% white (n = 7), 25% Hispanic (n = 3), and 17% black (n = 2).

Subject accountability. Twelve subjects (100%) were enrolled in this study, all of whom received study drug. All subjects were included in the analyses of safety, tolerability, and pharmacokinetics. One subject (8%) had study drug prematurely discontinued by the investigator on day 6 due to mild elevations in ALT and AST. All subsequent study procedures were completed for this subject. Eleven subjects (92%) completed all aspects of this study.

Safety. The coadministration of anidulafungin and cyclosporine was well tolerated by all subjects. There were no severe or life-threatening adverse events reported by any subject. The adverse events reported during administration of anidulafungin alone were similar to those reported during anidulafungin and cyclosporine coadministration. All reported adverse events were categorized by the investigator as mild or moderate in the degree of severity. The most common drug-related adverse event reported during administration of anidulafungin alone included headache, injection site erythema (5 subjects each), abdominal pain (4 subjects), and injection site pain (3 subjects). During concomitant administration of anidulafungin and cyclosporine, the most commonly reported drug-related adverse events were abdominal pain (4 subjects) and nausea (4 subjects). All other adverse events that occurred during either treatment condition occurred in 3 subjects (diarrhea, abnormal liver function tests, and dizziness).

One subject was discontinued prematurely from the study by the investigator due to a mild increase in hepatic transaminase levels on day 6 (ALT 88 U/L, AST 72 U/L), which was reported as possibly related to study drug administration. Study drugs were discontinued after the first dose of cyclosporine on day 6; however, subsequent study procedures and follow-up were completed for this subject. The elevated hepatic transaminase levels in this subject were reversible. In addition, follow-up study procedures on day 14 identified a subject whose laboratory studies remained normal during the administration of study medications but were elevated after being discharged from the clinical pharmacology unit on day 14 (ALT 163 U/L, AST 115 U/L).

Pharmacokinetics. Anidulafungin concentrations achieved steady state following the first day of drug administration using the 2:1 loading dose regimen. Cyclosporine trough concentrations were still increasing by day 8 but appeared to be approaching steady-state levels. The mean cyclosporine C_trough was 60.5 µg/L.

Pharmacokinetic parameters for anidulafungin on days 4 and 8 are presented in Table I. A comparison of the mean (± SD) plasma anidulafungin concentrations during the treatment periods, with (day 8) and without (day 4) concomitant administration of cyclosporine, is shown in Figure 1. The C_max for anidulafungin on days 4 and 8 were not significantly different and were 7.5 mg/L and 8.1 mg/L, respectively. Individual observations of C_max are shown in Figure 2. The mean AUC_ss and C_trough of anidulafungin increased after concomitant administration of cyclosporine. In the presence of cyclosporine, the mean anidulafungin AUC_ss on day 8 of 127.6 mg·h/L was 22% higher (P < .05) compared with the AUC_ss of 104.5 mg·h/L reported on day 4 in the absence of cyclosporine. Increases were small but consistent across individuals, as shown in Figure 3. The mean C_trough for anidulafungin when administered alone was 2.8 mg/L. In the presence of cyclosporine, the plasma anidulafungin trough concentration (4.0 mg/L) was 43% higher (P < .05). The clearance (CL) of anidulafungin was decreased by 16% between days 4 and 8 (P < .05).

View larger version (13K): [in this window] [in a new window]   Figure 1. Mean (SD) plasma anidulafungin concentrations without (day 4) and with (day 8) concomitant administration of cyclosporine.

View larger version (14K): [in this window] [in a new window]   Figure 2. Individual observations of anidulafungin maximum concentration (Cmax) without (day 4) and with (day 8) concomitant administration of cyclosporine.

View larger version (15K): [in this window] [in a new window]   Figure 3. Individual estimates of anidulafungin area under the plasma concentration-time curve at steady-state (AUCss) without (day 4) and with (day 8) concomitant administration of cyclosporine.

The geometric least squared means, corresponding day 8/day 4 ratios, and 90% confidence intervals about the geometric mean ratio were calculated for anidulafungin exposure parameters (C_max and AUC_ss) and are shown in Table II. The 90% confidence interval falls within the 80% to 125% bioequivalence range for C_max. For AUC_ss, however, the upper 90% confidence interval is equal to 125% and therefore does not fall within the bioequivalence range.

	DISCUSSION

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It is anticipated that the incidence of serious fungal infections will continue to increase due to the use of immunosuppressant agents, the increased number of immunocompromised patients, and increasingly invasive surgical techniques and technologies.

Increases in hepatic transaminase levels are reported when caspofungin is coadministered with cyclosporine, which precludes its concurrent use unless the potential benefit outweighs the risk.^12,18 Caspofungin may also interact with tacrolimus, another immunosuppressant agent, resulting in a 20% decrease in tacrolimus concentrations.^18,19 Drug interactions that affect the plasma or blood concentrations of immunosuppressant agents may lead to toxicity, graft failure, or graft versus host disease.

Most drug-drug interactions involving systemic antifungal agents have negative consequences, resulting in additive adverse events, modifications of antifungal drug kinetics by other drugs, or modification of the kinetics of other drugs by these antifungal agents.²⁰ In vitro studies with HHMPF have shown that anidulafungin concentrations up to 30 mg/L do not inhibit the metabolism of cyclosporine. The concentrations of anidulafungin used in the in vitro study were more than three times higher than the highest plasma concentrations reported in this clinical study.

The purpose of the clinical study was to evaluate the potential for cyclosporine to alter the plasma concentrations of anidulafungin. The results showed that small increases in plasma anidulafungin concentrations occurred with concomitant multiple-dose administration of cyclosporine. However, these increases were small and similar to the observed intersubject variability. Exposures and concentrations observed in this study were similar to those observed in other studies.¹⁶ These findings were therefore not considered clinically relevant and would not necessitate an anidulafungin dosage adjustment.

The relatively small changes in anidulafungin pharmacokinetic parameters are consistent with the drug's mechanism of elimination. The majority of anidulafungin (>90%) is eliminated by slow chemical degradation, with only a small amount (<10%) eliminated intact in feces. Changes in the kinetics of the amount eliminated as intact drug may be responsible for the small increase in drug exposure and decrease in drug clearance with concomitant administration of cyclosporine. The larger changes in pharmacokinetics reported for caspofungin when administered with cyclosporine (single-day administration) may be due to the additional amount of caspofungin that is eliminated by metabolism.²¹

Safety results from this study indicate that anidulafungin, when administered concomitantly with cyclosporine, is generally well tolerated. No subject had an adverse event that was serious or of severe intensity. Based on the results of this study, cyclosporine may be administered concomitantly with anidulafungin. This conclusion is also supported by limited clinical trial data in patients receiving concomitant anidulafungin and cyclosporine.²² These patients had no elevations in ALT or AST and had anidulafungin pharmacokinetic parameters similar to those of patients who received anidulafungin without coadministration of cyclosporine.

A limitation of the clinical study was its single observation (anidulafungin) and noncrossover design.¹⁷ Although a previously reported drug interaction study with cyclosporine and another echinocandin showed a pharmacokinetic interaction, only concentrations of the antifungal were increased.¹² In addition, the results of the in vitro study suggest that administration of anidulafungin with cyclosporine is unlikely to affect cyclosporine metabolism. This study design was considered to be sufficiently robust because multiple and high doses of anidulafungin and multiple doses of cyclosporine were given to maximize the likelihood of observing effects on the safety and pharmacokinetics of anidulafungin. The dosages and concentrations of cyclosporine used in this study were below those typically used for the prevention of early posttransplant graft rejection, and it is unlikely that cyclosporine concentrations completely reached steady-state levels.²³ The use of healthy volunteers in the study mandated the use of a lower cyclosporine dosage. However, multiple doses of cyclosporine were used in this study, and the dosage and respective blood concentrations are representative of patients on later posttransplant maintenance therapy, patients with a low risk of graft rejection, and patients being treated for other autoimmune conditions.

In conclusion, coadministration of anidulafungin and cyclosporine is well tolerated, and these results support the concomitant use of anidulafungin and cyclosporine without the need for dosage adjustments of either drug.

	FOOTNOTES

 
Portions of these data were presented as a poster at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, September 22-25, 2001, and the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy Abstracts, San Diego, September 27-30, 2002.

DOI: 10.1177/0091270004270146

Submitted for publication February 2, 2004; Revised version accepted August 16, 2004.

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