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Pharmacokinetics of Micafungin in Healthy Volunteers, Volunteers With Moderate Liver Disease, and Volunteers With Renal Dysfunction

From the Department of Pharmacy (Dr Hebert) and the Department of Pharmaceutics (Dr H. E. Smith), University of Washington, Seattle; Orlando Clinical Research Center, Orlando, Florida (Dr Marbury); DaVita Clinical Research & Hennepin County Medical Center, Minneapolis, Minnesota (Dr Swan); New Orleans Center for Clinical Research, New Orleans, Louisiana (Dr W. B. Smith); and Fujisawa Healthcare, Inc, Deerfield, Illinois (Dr Townsend, Dr Buell, Dr Keirns, Dr Bekersky). Dr Townsend is currently at Kos Pharmaceuticals, Inc, Weston, Florida. Dr Bekersky is currently at Quark Biotech, Inc, Pleasanton, California.

Address for reprints: Mary F. Hebert, PharmD, Professor, University of Washington, Department of Pharmacy, H-375 Health Sciences Center, Box 357630, Seattle, WA 98195-7630; e-mail: mhebert{at}u.washington.edu.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Micafungin is an antifungal agent metabolized by arylsulfatase with secondary metabolism by catechol-O-methyltransferase. The objectives of this study were to estimate the pharmacokinetic parameters and plasma protein binding of micafungin in volunteers with moderate hepatic dysfunction (n = 8), volunteers with creatinine clearance <30 mL/min (n = 9), and matched controls (n = 8 and n = 9, respectively). Single-dose micafungin pharmacokinetics were estimated using noncompartmental techniques. There was a statistically lower area under the observed micafungin concentration-time curve (AUC) from time 0 to infinity for subjects with moderate hepatic dysfunction as compared to control subjects (97.5 ± 19 µg·h/mL vs 125.9 ± 26.4 µg·h/mL, P = .03), although there was no difference in micafungin weight-adjusted clearance (10.9 ± 1.7 mL/h/kg vs 9.8 ± 1.8 mL/h/kg, P = .2). The difference in area under the concentration-time curve may be explained by the differences in body weight between subjects and controls. Renal dysfunction did not alter micafungin pharmacokinetics.

Key Words: Micafungin • liver disease • renal disease • pharmacokinetics

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
This is a phase I, parallel-group, open-label pharmacokinetic study of single-dose intravenous micafungin in healthy volunteers, volunteers with moderate hepatic disease (Child-Pugh scores 7-9),¹ and volunteers with renal dysfunction (glomerular filtration rate [GFR] <30 mL/min). Micafungin (FK463, Fujisawa Healthcare, Inc) was supplied by Fujisawa Healthcare, Inc for this study. The study was conducted at the New Orleans Center for Clinical Research, the Orlando Clinical Research Center, and Davita Clinical Research in accordance with the Declaration of Helsinki and good clinical practices regulations. This protocol was approved by the New Orleans Center for Clinical Research; the Independent Institutional Review Board of Plantation, Florida; and Davita Clinical Research Institutional Review Boards.

Hepatic Study Subject Selection
Eight volunteers with moderate hepatic impairment and 8 age- and gender-matched healthy controls (2 women and 6 men in each group) participated in this study after giving informed consent. Eleven subjects were Caucasian, 4 were African American, and 1 was Hispanic/Latino. Subject demographics for the subjects with moderate hepatic impairment included (mean ± SD) the following: age, 52 ± 10 years; weight, 98 ± 19 kg; height, 175 ± 9 cm; serum albumin, 3.6 ± 0.6 g/dL; serum alanine aminotransferase, 114 ± 172 U/L; aspartate aminotransferase, 108 ± 92 U/L; total serum bilirubin, 1.6 ± 1.6 mg/dL; serum alkaline phosphatase, 168 ± 65 U/L; and international normalized ratio (INR), 1.2 ± 0.1. Etiologies of subjects' liver disease, Child-Pugh scores, and hepatic complications are listed in Table I. Concomitant medications for subjects with hepatic disease included the following: subject 1 (spironolactone, ibuprofen, ursodeoxycholic acid, hydroxyzine, and insulin), subject 2 (none), subject 3 (none), subject 4 (diclofenac), subject 5 (multiple vitamin), subject 6 (glipizide, furosemide, spironolactone, and folic acid), subject 7 (diazepam, hydrocodone, hydrochlorothiazide, atenolol, and multiple vitamin), and subject 8 (furosemide and amiloride). Subject demographics for the control subjects include (mean ± SD) the following: age, 53 ± 9 years; weight, 84 ± 9 kg; height, 169 ± 8 cm; and normal liver function tests. Of the subjects with moderate liver disease, subjects 1, 3, 4, and 8 were all receiving diuretics for management of edema and/or ascites. Subjects were excluded if they were pregnant or nursing, had a creatinine clearance (CrCl) <80 mL/min estimated by Cockcroft and Gault,² had evidence of active deep or disseminated fungal infection or were receiving systemic antifungal agents, were known to be infected with HIV, had a history of allergy to echinocandin antifungal agents, had medical conditions that might have created an unacceptable risk to the volunteer, had donated blood within 60 days of the study, or had a platelet count <50,000/mm³.

Renal Study Subject Selection
Nine volunteers with CrCl <30 mL/min and 9 age-, weight-, and gender-matched volunteers with CrCl >80 mL/min (5 women and 4 men in each group) participated in this study after giving informed consent. Twelve of the subjects were Caucasian, 5 were African American, and 1 was Hispanic/Latino. Subject demographics for the subjects with CrCl <30 mL/min included (mean ± SD) the following: age, 60 ± 15 years; weight, 84 ± 24 kg; height, 170 ± 10 cm; serum creatinine, 3.9 ± 1.4 mg/dL; blood urea nitrogen, 55 ± 24 mg/dL; creatinine clearance, 22.3 ± 5.4 mL/min; and serum albumin, 3.9 ± 0.3 g/dL. Concomitant medications for subjects with renal dysfunction included the following: subject 1 (fosinopril, felodipine, allopurinol, colchicine, lovastatin, atenolol, aspirin, and furosemide), subject 2 (lisinopril, felodipine, and ranitidine), subject 3 (amlodipine, hydrochlorothiazide, losartan, furosemide, and terazosin), subject 4 (minoxidil, furosemide, nitroglycerin, atorvastatin, metoprolol, iron, clonazepam, and erythropoietin), subject 5 (medications were not recorded), subject 6 (insulin, furosemide, felodipine, nifedipine, and metolozone), subject 7 (sertraline, nitroglycerin, atenolol, lorazepam, atorvastatin, aspirin, senna, calcitonin, ascorbic acid, and erythropoietin), subject 8 (candesartan, furosemide, amlodipine, glyburide, simvastatin, isosorbide, aspirin, erythropoietin, vitamin E, sodium polystyrene sulfonate, and iron), and subject 9 (loxapine, carbamazepine, lorazepam, citalopram, amantadine, atorvastatin, sodium citrate, citric acid, polyethylene glycol, and calcium carbonate). Healthy control subjects' demographics included (mean ± SD) the following: age, 60 ± 14 years; weight, 85 ± 15 kg; height, 167 ± 9 cm; serum creatinine, 0.9 ± 0.1 mg/dL; blood urea nitrogen, 12 ± 4 mg/dL; creatinine clearance, 96.5 ± 17.3 mL/min; and albumin, 4.0 ± 0.4 g/dL. Potential female study subjects were not included if they were pregnant or nursing. Potential subjects were also excluded if they had evidence of liver disease, had taken other investigational drugs within the past 30 days, had evidence of an active deep or disseminated fungal infection prior to enrollment or had received systemic antifungal agents 72 hours prior to the infusion of micafungin, were allergic to echinocandin antifungals, had concomitant medical conditions that elevated their risk of participation, or had donated blood within 60 days of the micafungin administration.

Dosing Regimen
Each subject received a single dose of micafungin (100 mg) intravenously over 1 hour. Micafungin was diluted with normal saline, and opaque bags were used for covering the infusion bag.

Sample Collection and Analysis
Serial blood samples were collected at times 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, and 72 hours after initiation of the infusion for measurement of micafungin concentrations in subjects with hepatic impairment and controls. Blood sampling was completed at 48 hours for subjects with renal dysfunction and controls.

Plasma was analyzed for micafungin concentrations using a high-performance liquid chromatography (HPLC) with a fluorescence detection system. The method was validated by MDS Harris Laboratories, Inc (Lincoln, Neb). In brief, 50 µL of acidified human plasma samples containing micafungin and the internal standard (FR195743, Fujisawa Pharmaceutical Co, Ltd, Osaka, Japan) underwent protein precipitation. An aliquot of supernatant and a specified volume of phosphate buffer were then injected onto the HPLC system, where separation occurred using a ToSoHaas TSK-GEL ODS 80 TM column (5 µm, 150 x 4.6 mm), a column temperature of 50°C, and an acetonitrile/20-mM KH₂PO₄ (41:59, v/v) mobile phase. The detector was Jasco model FP-920 in normal mode, with a wavelength excitation of 273 nm and emission of 464 nm. Sample batches included a calibration curve, a matrix blank, a control zero (matrix blank containing internal standard), a reagent blank, and duplicate quality control samples at 3 concentrations within the calibration range. Calibration curves for micafungin in human plasma were reproducible and demonstrated acceptable linearity in the concentration range from 0.05 to 25.0 µg/mL. The interday coefficients of variation for the micafungin quality control samples including 0.15, 2.00, and 18.75 µg/mL were 5.4%, 1.8%, and 4.1%, respectively. Intraday coefficients of variation for micafungin quality control samples including 0.15, 2.00, and 18.75 µg/mL were 0.9%, 0.4%, and 1.2%, respectively. The lower limit of quantitation for the assay was 0.05 µg/mL. All samples were frozen at –70°C until analysis.

Urine samples for determining creatinine clearance, urinary pH, and electrolytes were collected at the initiation of the micafungin administration and during the time intervals of 0 to 2, 2 to 4, 4 to 8, and 8 to 24 hours postdose in the renal subjects and controls.

Micafungin Data Analysis
The total area under the observed micafungin concentration-time curve (AUC) was calculated using the linear trapezoidal rule for ascending concentrations and the log trapezoidal rule for descending concentrations. The AUC values were extrapolated to infinity from the last measurable micafungin concentration (C_last) by C_last/k_elim, in which k_elim was the terminal elimination rate constant, as determined by log-linear regression. The half-life was estimated by ln 2/k_elim. Area under the moment curve (AUMC) was calculated by the linear trapezoidal rule.³ Intravenous micafungin mean residence time (MRT = [AUMC/AUC] – [Infusion duration/2]), intravenous micafungin clearance (CL = Dose/AUC), and steady-state volume of distribution (V_ss = CLxMRT) were also estimated.³ Clearance and volume of distribution at steady state are reported as weight-adjusted values based on total body weight. All results are reported as mean ± SD.

Protein Binding
The extent of protein binding of micafungin was measured at the end of the infusion (1 hour) and 8 hours after the initiation of infusion. Plasma protein binding was determined by ultracentrifugation using Centrifree cartridges (Millipore, Billerica, Mass) at 37°C. To minimize the effects of nonspecific binding, Centrifree membranes were washed first with isotonic phosphate buffer (pH 7.4) and then 3 times with plasma-containing micafungin. The percent unbound was calculated by (ultrafiltrate concentration/plasma concentration) x 100.

Statistics
Unpaired Student t test was used to evaluate differences in pharmacokinetic parameters between the 2 groups. P values <.05 were considered to be significant.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Hepatic Subjects and Controls
Table II describes the individual and mean estimated pharmacokinetic parameters for micafungin in the subjects with moderate hepatic dysfunction and in the matched healthy controls. There was a statistically lower area under the observed micafungin concentration-time curve from time 0 to infinity for the subjects with moderate hepatic dysfunction as compared to the healthy control subjects (97.5 ± 19 µg·h/mL vs 125.9 ± 26.4 µg·h/mL, P = .03). There was no statistical difference in weight-adjusted clearance (10.9 ± 1.7 mL/h/kg vs 9.8 ± 1.8 mL/h/kg; P = .2), weight-adjusted volume of distribution at steady state (212 ± 37 mL/kg vs 199 ± 29 mL/kg; P = .4), or half-life (14.3 ± 1.5 h vs 14.6 ± 3.0 h; P = .8) when comparing those subjects with moderate hepatic dysfunction to the healthy controls. Measured maximum micafungin concentrations had a tendency toward lower concentrations seen with moderate hepatic disease as compared to healthy controls, although this did not reach statistical significance (7.0 ± 1.9 µg/mL vs 8.8 ± 1.8 µg/mL; P = .07). There was no change in micafungin percent unbound in plasma at the 1-hour (0.20% ± 0.03% vs 0.20% ± 0.02%, P =1) or 8-hour (0.18% ± 0.03% vs 0.19% ± 0.02%, P = .6) time points between patients with moderate liver dysfunction and healthy controls.

Renal Subjects and Controls
Table III describes the individual and mean estimated pharmacokinetic parameters for micafungin in subjects with creatinine clearances <30 mL/min and the matched healthy controls. There were no differences found between subjects with CrCl <30 mL/min and matched healthy controls for micafungin AUC (116.2 ± 32.4 µ·h/mL vs 120.9 ± 16.7 µ·h/mL; P = .7), CL (11.1 ± 1.9 mL/h/kg vs 10.0 ± 1.6 mL/h/kg; P =.2), V_ss (215 ± 30 mL/kg vs 202 ± 36 mL/kg; P = .4), half-life (14.8 ± 1.7 h vs 15.1 ± 1.8 h; P = .7), and maximum micafungin concentration (8.7 ± 2.9 µg/mL vs 8.2 ± 1.4 µg/mL; P = .6). There was no significant difference in the plasma unbound fraction of micafungin in patients with renal dysfunction compared to healthy subjects at either 1 hour or 8 hours postdose. At 1 hour postdose, the percentage of the measured micafungin unbound to plasma proteins was 0.24% ± 0.04% in subjects with renal dysfunction and 0.23% ± 0.07% (P = .7) in healthy controls. At 8 hours postdose, the percentage of micafungin unbound in the plasma was 0.24% ± 0.05% and 0.21% ± 0.04% (P = .3) in subjects with renal dysfunction and healthy controls, respectively.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
A few factors potentially play a role in altering micafungin pharmacokinetics in subjects with hepatic dysfunction. First, micafungin is a drug that is primarily metabolized and has a low hepatic extraction ratio. Very little of the micafungin dose (<1%) is excreted unchanged in the urine. The enzymes involved in the metabolism of micafungin are arylsulfatase and catechol-O-methyltransferase. Second, micafungin is a drug with very high protein binding (>99%) in the plasma. Micafungin primarily binds to albumin, although 1-acid glycoprotein also contributes (data on file, Fujisawa Healthcare, Inc). Finally, 90% of micafungin and its metabolites are eliminated through the bile.

From a metabolism standpoint, limited information is available on arylsulfatase activity in liver disease. That being said, the information that is available in animal models is consistent with increased activity in liver disease and the corresponding decrease in micafungin concentrations. Arylsulfatase activity in the rat cirrhosis model (bile duct ligation) and carbon tetrachloride-induced fatty liver was dramatically increased.^4,5 In the bile duct ligation model, arylsulfatase activity was increased with cholestasis prior to development of cirrhosis.⁴ However, leukocyte arylsulfatase activity was 58% less active in patients with alcohol-related cirrhosis with a history of encephalopathy and 38% less active in patients with alcohol-related cirrhosis without encephalopathy as compared to healthy controls.⁶ Because sulfatases are present in all tissues, it is unclear what effect cirrhosis will have on total arylsulfatase activity in humans.

Catechol-O-methyltransferase (COMT) is an enzyme expressed in soluble and membrane-bound forms.⁷ It uses S-adenosylmethionine (SAM) as a methyl donor and magnesium ion as a cofactor.⁸ It catalyzes the methylation of catechols, including neurotransmitters (eg, dopamine, epinephrine, and norepinephrine) and some medications (eg, methyldopa and L-dopa).^9-11 The cytosolic form of human COMT is highly expressed in liver and kidney, whereas the membrane-bound form is predominantly expressed in the brain.¹² Catechol-O-methyltransferase activity in erythrocytes has been shown to correlate well with COMT activity in the liver, renal cortex, lung, and lymphocytes.^13-15 Catechol-O-methyltransferase activity in erythrocytes of alcoholics does not appear to be different from that of controls.¹⁶ However, it is not clear whether overall COMT activity would be altered in moderate hepatic dysfunction. There is a common genetic polymorphism of COMT (codon 108/158 for soluble COMT and membrane-bound COMT, respectively) that results in a 3- to 4-fold variation in COMT enzyme activity.^15,17,18 COMT genetics were not assessed in this study.

Alterations in protein binding could be an explanation for the changes in estimated pharmacokinetic parameters seen in this study with patients with moderate hepatic dysfunction as compared to healthy controls. Measurement of protein binding for medications that have less than 1% unbound is technically challenging. For micafungin, a drug with low hepatic extraction and high plasma protein binding, changes in binding will have dramatic changes in fraction unbound, and total concentrations will decrease, but the unbound steady-state concentration will be expected to remain unchanged. In this study, albumin concentrations were in the normal range for some of the subjects but quite low in others. Using an ultracentrifugation technique, no differences were seen in protein binding at 1 hour and 8 hours following dosing in the subjects with moderate hepatic dysfunction as compared to the healthy controls. If there were a significant increase in unbound fraction, it would be expected that therewouldbeacorresponding increaseinvolumeof distribution, which was seen in the estimated volume of distribution at steady state when looking at absolute values. However, no differences were seen between weight-adjusted values. In addition, no correlation was seen between serum albumin or bilirubin concentrations and micafungin volume of distribution at steady state.

Because 90% of micafungin is eliminated as parent compound or metabolites through the bile, it is possible that patients with cholestatic liver disease may have alterations in their pharmacokinetic profiles. However, subjects with moderate hepatic disease and elevated bilirubin (subjects 2, 4, and 8) did not have marked differences in their estimated pharmacokinetic parameters when compared to the other subjects.

Moderate hepatic dysfunction in this study led to an average 22% decrease in micafungin AUC as compared to matched controls. This is most likely explained by the differences in body weight between subjects (98 ± 19 kg) and controls (84 ± 9 kg), given that no differences were seen in weight-adjusted clearance, volume of distribution, or half-life. Contrary to the general approach taken for metabolized drugs, which is to decrease the dose of the medication in patients with liver disease (at least for patients with moderate hepatic dysfunction), based on the results of this study, dose reduction of micafungin should not be done.

Shifting the focus to renal issues, COMT¹⁹ and arylsulfatase²⁰ are also expressed in human kidneys. It is possible that renal disease could alter the expression and activity of arylsulfatases and COMT in the kidney. However, there are no data in the literature to confirm that COMT expression changes with kidney disease, and the limited studies available regarding arylsulfatase indicate that its activity does not change in renal cell carcinoma compared to normal tissues.²¹ No information is available regarding whether the elimination and metabolism of other substrates for these enzymes are affected by renal disease. The results of this study do not indicate that such changes in arylsulfatase and COMT expression and activity in renal disease occurred. For patients who are uremic, dialysis may affect COMT activity. Catechol-O-methyltransferase activity is significantly elevated in erythrocytes of uremic patients on maintenance hemodialysis, although this is likely due to the accumulation of endogenous methyl acceptors in the plasma rather than an effect of renal disease on the expression of the enzyme in the erythrocytes.^22,23

The data that are available indicate that renal elimination is not the primary route of micafungin elimination (data on file, Fujisawa Healthcare, Inc). That other routes of elimination are more important than renal elimination is supported by the current findings that renal dysfunction does not affect the pharmacokinetics of micafungin. There were no significant differences in AUC, CL, V_ss, t_1/2, or C_max when comparing the estimated pharmacokinetic parameters in subjects with renal dysfunction to healthy controls. There were also no differences between these 2 subject groups in micafungin plasma protein binding. This study evaluated subjects with creatinine clearances between 15.0 and 29.2 mL/min and those with normal serum albumin. The effects of end-stage renal disease and low serum albumin have not been studied. Although the dialyzability of micafungin has not been studied, given the extremely high protein binding of micafungin (99.8%), it is not expected to be eliminated to any significant extent by dialysis. The finding that renal dysfunction does not alter the pharmacokinetic parameters of micafungin indicates that dosage adjustments for micafungin need not be made for patients with creatinine clearances between 15.0 and 29.2 mL/min. These findings are consistent with the data available regarding the lack of importance of the kidneys in micafungin elimination.

Micafungin weight-adjusted pharmacokinetic parameters (clearance, volume of distribution, and protein binding) do not appear to be different in patients with creatinine clearance between 15 and 29 mL/min or with Child-Pugh scores between 7 and 9 as compared to matched healthy controls. Further studies would be needed to evaluate the effects of more severe renal or hepatic disease on micafungin pharmacokinetics.

DOI: 10.1177/0091270005279580

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