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Concomitant Cyclosporine and Micafungin Pharmacokinetics in Healthy Volunteers

From the University of Washington, Department of Pharmacy, Seattle, Washington (Dr Hebert, Dr Blough); Fujisawa Healthcare Inc, Deerfield, Illinois (Dr Townsend, Dr Buell, Dr Keirns, Dr Bekersky); Covance, Madison, Wisconsin (Dr Austin, Dr Balan).

Address for reprints: Mary F. Hebert, PharmD, University of Washington, Department of Pharmacy, H-375 Health Sciences Center, Box 357630, Seattle, WA 98195-7630.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Cyclosporine is a marketed immunosuppressive agent and a known substrate for CYP3A. Micafungin is an antifungal agent and a mild inhibitor of CYP3A-mediated metabolism in vitro. The objectives of this study were to evaluate the pharmacokinetics of cyclosporine and micafungin before and with concomitant administration. The pharmacokinetics of single-dose oral cyclosporine (5 mg/kg) were estimated on days 1, 9, and 15 (n = 27). Subjects received micafungin (100 mg/d over 1 hour) on days 7, 9, and 11 through 15. Micafungin pharmacokinetics were estimated on days 7, 9, and 15. Mean apparent oral cyclosporine clearances were estimated to be 645±236 mL/h/kg, 546±101 mL/h/kg (P = .01), and 540±104 mL/h/kg (P = .02) for days 1, 9, and 15, respectively. Micafungin appears to be a mild inhibitor of cyclosporine metabolism.

Key Words: Cyclosporine • micafungin • pharmacokinetics • drug interaction

In vitro studies have shown that micafungin is an inhibitor of the metabolism of CYP3A substrates (similar to fluconazole) (data on file, Fujisawa Healthcare Inc, Deerfield, Ill). Micafungin is thought to be metabolized by arylsulfatase to the M-1 metabolite (catechol form), with secondary metabolism by catechol-O-methyltransferase to the M-2 metabolite (methoxy form) in vitro (data on file, Fujisawa Healthcare Inc, Deerfield, Ill). The area under the concentration-time curve for another echinocandin (caspofungin) is increased approximately 35% by cyclosporine.⁶ The objectives of this study were to evaluate the effects of single-dose and steady-state micafungin on the pharmacokinetics of cyclosporine and to evaluate the effects of singledose cyclosporine on micafungin pharmacokinetics.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The concentration-time profiles of single-dose oral cyclosporine in whole blood of healthy volunteers, with and without coadministration of intravenous micafungin, single dose and steady state, were examined. Pharmacokinetic parameters were estimated using noncompartmental techniques. Oral cyclosporine U.S.P. MODIFIED (Neoral, Novartis Pharmaceuticals Corp, East Hanover, NJ) and micafungin (FK463, Fujisawa Healthcare Inc, Deerfield, Ill) were supplied by Fujisawa Healthcare Inc for this study, which was conducted at Covance Clinical Research Unit (Madison, Wis) in accordance with the Declaration of Helsinki and good clinical practices regulations. This protocol was approved by the Covance Clinical Research Unit Institutional Review Board.

Subject Selection
Twenty-eight healthy volunteers (21 men, 7 women) participated in this study after giving informed consent. Twenty-three subjects were white, 3 Hispanic/Latino, and 2 black. The mean age for the subjects was 30 years (range, 19-50 years), mean height was 174.5 cm (range, 159.0-190.5 cm), and mean weight was 71.7 kg (range, 57.0-90.6 kg). One subject (No. 7) did not complete all study days and was excluded from the analysis. Subjects were considered healthy based on medical history, physical examination, and standard blood and urine laboratory tests. All subjects were nonsmokers, on no medications, and within 20% of their ideal body weight.

Dosing Regimen
Each subject received a total of 3 single oral doses of cyclosporine (5 mg/kg adjusted to the nearest 25-mg dose) on study days 1, 9, and 15. In addition, each subject received a single 1-hour intravenous infusion of micafungin (100 mg) on days 7, 9, and then daily from study days 11 through 15. Drugs known to influence cyclosporine pharmacokinetics were prohibited, as were other immunosuppressants, other investigational agents, drugs associated with renal insufficiency, herbal and over-the-counter medications, and drugs that induce or inhibit CYP3A.

Diet Control
On each cyclosporine administration day, subjects fasted for 10 hours prior to dosing until 2 hours following dosing.⁷ Clear liquids were provided during the fasting portion of the study. Subjects received a grapefruit-free diet on all cyclosporine study days to control for the known effect of grapefruit on cyclosporine pharmacokinetics.

Sample Collection
Serial blood samples were collected at times 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours on days 1, 9, and 15 for measurement of cyclosporine concentrations and micafungin concentrations on days 7, 9, and 15. A 48-hour sample was collected on days 7 and 9. All samples were frozen at –60°C to –80°C until analysis. Subjects were confined to the research unit on study days 0 to 1 and 6 to 15. Subjects were released after collection of the 24-hour samples following dosing on days 1 and 15.

Cyclosporine Assay
Whole-blood concentrations of cyclosporine were measured using a validated high-performance liquid chromatography/mass spectrometry (HPLC/MS) assay. The lower limit of quantitation for the assay was 10 ng/mL. In brief, cyclosporine A and the internal standard, cyclosporine U, were extracted from 500 µL of whole blood with methyl-tert-butyl-ether. The extract was dried and reconstituted with acetonitrile/water (65:35, v/v) and analyzed using a reversed-phase C-18 column. For mass spectral detection, the following ions were monitored: mass, 1203 and dwell time, 0.4 seconds for cyclosporine A and mass, 1189 and dwell time, 0.4 seconds for cyclosporine U. Peak area ratios (compound/internal standard) were fitted to a weighted (1/concentration) quadratic regression. The equations for the calibration curves were then used to calculate the concentrations of cyclosporine A in whole blood from their peak area ratios. Calibration curves were then used to calculate the concentrations of cyclosporine A in whole blood from their peak area ratios. Calibration curves were reproducible and demonstrated acceptable linearity in the concentration range from 10.0 to 2000 ng/mL. The correlation coefficients of the calibration curves (n = 20) were 0.9951 for all curves. The overall precision of the method for calibration curves, as measured by the relative standard deviations, ranged from 2.1% to 5.3% (n = 19). For the quality control samples, the overall precision, as measured by the percentage relative standard deviation, was 7.6% for the 30.0-ng/mL samples (n = 40), 6.1% for the 150-ng/mL samples (n = 40), 7.7% for the 1500-ng/mL samples (n = 40), and 5.9% for the 5000-ng/mL (10x dilution) samples (n = 6). The accuracy was determined by comparing the deviation of the means of the measured concentrations of the calibration standards with the theoretical concentration, expressed as percentage deviation of the mean from the theoretical, ranging from –1.4% to 1.1% for cyclosporine A. For the quality control samples (30.0, 150, 1500, 1500 [4x dilution] and 1500 [10x dilution], ng/mL), the deviation of the mean from the theoretical ranged from –20.4% to –2.2% for cyclosporine A in whole blood.

Micafungin Assay
Plasma stabilized with phosphoric acid was analyzed for micafungin concentrations using a validated HPLC assay with fluorescence detection. The lower limit of quantitation for the assay was 0.05 µg/mL. 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, where separation occurred using a ToSoHaas TSK-GEL, ODS 80 TM column (5 µm, 150 x 4.6 mm), column temperature of 50°C, and acetonitrile/20 mM KH₂PO₄ (41:59, v/v) mobile phase. The detector was a Jasco model FP-920 in normal mode, 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 correlation coefficients of the calibration curves (n = 15) were 0.9986 for all curves. Calibration curve data, including the back-calculated calibration standard concentrations and their means, standard deviations, and percentage relative standard deviations, were determined for micafungin in human plasma. The overall precision of the method, as measured by the relative standard deviations, ranged from 1.7% to 5.8% for micafungin for the calibration standards. For the quality control samples, the precision, as measured by the percentage relative standard deviation, was 5.0% for 0.150 µg/mL (n = 29), 8.1% for 2.0 µg/mL (n = 30), and 4.0% for 18.8 µg/mL (n = 29) samples. The accuracy of the method was determined by comparing the deviation of the means of the measured concentrations for the calibration standards with the theoretical concentration expressed as percentage deviation of the mean from the theoretical. The deviation of the mean from the theoretical of the calibration standards ranged from –8.0% to 4.4% for micafungin. The accuracy for the quality control samples (0.150, 2.0, 18.8, and 18.8 [2x dilution] µg/mL) for micafungin ranged from –2.5% to 2.7%.

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 concentration (C_last) by C_last/k_elim, in which k_elim was the terminal elimination rate constant, as determined by log-linear regression. Micafungin AUC was calculated as described above for days 7 and 9. However, for day 9, the measured concentrations were corrected for carryover from day 7 by C = C_meas –Co · e^–k_elim^t, in which _Cmeas was the actual measured concentration, Co was the concentration of micafungin just prior to dosing, k_elim was the terminal elimination rate constant, and t was the time postdose when the concentration was measured. Day 15 AUC values were estimated at steady state; therefore, AUC_0-24 was used in the calculations. Area under the moment curve (AUMC) was calculated by the linear trapezoidal rule.⁸ The AUMC values for days 9 and 15 were based on corrected concentrations as described above.⁹ 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 = CL · MRT) were also estimated.⁸

Cyclosporine Data Analysis
The total area under the observed cyclosporine 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 24-hour time point by C_last/k_elim, in which C_last was the last measurable cyclosporine concentration and k_elim was the terminal elimination rate constant, as determined by log-linear regression. Apparent oral cyclosporine clearance (CL/F = Dose/AUC_po) and apparent oral volume of distribution at steady state (V_ss/F = CL · MRT) were also estimated. All results are reported as mean ± SD.

Statistics
Twenty-eight volunteers were enrolled into this study to ensure that 24 completed the dosing sequence. A sample size of 24 provided 80% power to assess the ratio of log-transformed means of the primary pharmacokinetic parameters of the drug in the presence of the interacting drug to the drug alone. If the confidence intervals are entirely contained within the "no-effect" boundaries of 80% to 125%, then no significant drug-drug interaction is present.¹⁰ Repeated-measures analysis of variance of log-transformed parameters was used to determine significance. P values < .05 were considered significant.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Table I describes the individual and mean estimated pharmacokinetic parameters for cyclosporine alone (day 1) and with single-dose (day 9) and steady-state (day 15) micafungin administration. Apparent oral cyclosporine clearance (CL/F) was statistically significantly lower with single-dose and steady-state micafungin as compared to cyclosporine alone (546 ± 101 mL/h/kg, P = .01; 540 ± 104 mL/h/kg, P = .02; and 645 ± 236 mL/h/kg, respectively). Overall, the mean decrease in apparent oral cyclosporine clearance with concomitant administration of micafungin single dose and steady state was 10.1% ± 18.5% and 10.3% ± 22.1%, respectively. The 90% confidence interval (CI) for apparent oral cyclosporine clearance with single-dose micafungin as compared to cyclosporine alone was 80.4% to 95.2%. The 90% CI for apparent oral cyclosporine clearance with steady-state micafungin as compared to cyclosporine alone was 78.4% to 95.2%. The effect of steady-state intravenous micafungin on cyclosporine apparent oral clearance fell just outside the "no-effect" boundary.

Apparent oral cyclosporine volume of distribution at steady state (V_ss/F) bordered on a statistically significant decrease with single-dose and steady-state micafungin as compared to cyclosporine alone (4.3 ± 0.7 L/kg, P = .04; 4.3 ± 0.7 L/kg, P = .05; and 4.9 ± 1.8 L/kg, respectively). Overall, the mean decrease in apparent oral cyclosporine volume of distribution at steady state with concomitant administration of micafungin single dose and steady state was 7.1% ± 17.9% and 6.8% ± 22.0%, respectively. The 90% CI for apparent oral cyclosporine volume of distribution at steady state with single-dose micafungin as compared to cyclosporine alone was 84.2% to 98.0%. The 90% CI for apparent oral cyclosporine volume of distribution at steady state with steady-state micafungin as compared to cyclosporine alone was 83.0% to 98.4%. These changes in cyclosporine apparent oral volume of distribution at steady state fell within the "no-effect" boundary.

There was a statistically significant increase in cyclosporine half-life with the concomitant administration of steady-state micafungin (9.0 ± 1.7 hours, P = .001) but not with single-dose micafungin (8.6 ± 1.2 hours, P = .08) as compared to cyclosporine alone (8.1 ± 1.2 hours). There was no change in the times to reach maximum concentration with cyclosporine alone as compared to cyclosporine with single-dose or steady-state micafungin (1.5 ± 0.5 hours, 1.5 ± 0.6 hours, and 1.5 ± 0.6 hours, respectively).

Figure 1 graphically depicts the initial apparent oral cyclosporine clearance (day 1) versus the percentage change in apparent oral cyclosporine clearance between day 1 and day 15. The linear correlation coefficient for this relationship is r = 0.8. Only 5 of the healthy volunteers had greater than a 25% change in their apparent oral cyclosporine clearance when comparing cyclosporine alone to cyclosporine with steady-state micafungin. Two healthy volunteers (subjects 15 and 28) with the highest apparent oral cyclosporine clearances during the cyclosporine-alone phase had marked decreases in their apparent oral cyclosporine clearances (56.2% and 59.3% reduction with single-dose micafungin and 56.8% and 62.3% reduction with steady-state micafungin, respectively). The same 2 healthy volunteers with the highest apparent oral cyclosporine clearances during the cyclosporine-alone phase had the most marked decreases in their apparent oral cyclosporine volume of distribution at steady state (37.3% and 53.7% reduction with single-dose micafungin and 25.0% and 54.5% reduction with steady-state micafungin, respectively). Micafungin AUC_0-24s were 113 ± 26 µg·h/mL on day 9 and 147 ± 19 µg·h/mL on day 15. The micafungin AUC_0-24swerenot notably different for the 5 volunteers with the largest interactions as compared to the other subjects participating in this trial.

View larger version (11K): [in this window] [in a new window]   Figure 1. Linear correlation between subjects' initial cyclosporine apparent oral clearance (mL/h/kg, day 1) and the percentage change in cyclosporine apparent oral clearance between cyclosporine alone (day 1) and cyclosporine with steady-state micafungin (day 15).

Intravenous micafungin areas under the concentration-time curves (day 7 AUC_0-inf, day 9 AUC_0-inf with concentrations corrected, and day 15 AUC_0-24) were estimated to be 133.4 ± 19.0 µg·h/mL, 151.0 ± 20.7 µg·h/mL (90% CI: 108%, 118%, P < .0001), and 146.9 ± 18.8 µg·h/mL (90% CI: 108%, 112%, P < .0001) for single-dose micafungin alone, single-dose micafungin with single-dose oral cyclosporine, and steady-state micafungin with single-dose oral cyclosporine, respectively. This is a 14.4% ± 15.1% and a 10.5% ± 6.2% average increase in micafungin AUCs for days 9 and 15, respectively. Micafungin clearance was estimated to be 10.8 ± 1.2 mL/h/kg, 9.4 ± 1.2 mL/h/kg (90% CI: 84%, 91%, P < .0001), and 9.8 ± 1.1 mL/h/kg (90% CI: 89%, 92%, P < .0001) for days 7, 9, and 15, respectively. These changes in AUC and CL for micafungin fell within the no-effect boundary. Micafungin half-life was estimated to be 14.8 ± 1.3 hours, 14.8 ± 2.2 hours (90% CI: 93%, 105%), and 15.3 ± 1.1 hours (90% CI: 101%, 107%) for days 7, 9, and 15, respectively.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
We have entered a new era of evaluation of drug interactions. With the Food and Drug Administration guidance to industry for drug interaction studies suggesting to approach this issue from a bioequivalence perspective, the size of these studies has grown. Although the increased sample size has advantages in some aspects of the evaluation of drug interactions, the endpoint of demonstrating a pharmacokinetic drug interaction based on bioequivalence is best suited for drugs that have fairly large interactions in which all individuals respond similarly. This approach, however, does not directly address the potential for intersubject variability or the issue of pharmacodynamic interactions. Intersubject variability is an important issue in drug interaction evaluation. The larger sample sizes with bioequivalence-type studies provide an opportunity to evaluate a larger range of responses than historically has been done. The likelihood of detecting a small percentage of individuals with an interaction in which the majority of subjects do not undergo a clinically significant interaction is greater as long as these individuals are not ignored or eliminated because they are "outliers."

The results of this study, which demonstrate a statistically significant interaction, with the mean change being clinically insignificant, would likely not have been detected using the previous approach to drug interaction study design. (Historically, most drug interaction studies only evaluated 6 to 12 subjects.) And although one could argue that the value of this knowledge is limited, another important finding of this study also would likely not have been seen had the previous approach to drug interaction studies been taken. Micafungin results in a great deal of intersubject variability in response when given in combination with cyclosporine. The individuals with very high apparent oral cyclosporine clearances to start with underwent the largest decreases in their apparent oral cyclosporine clearances and volumes of distribution at steady state with micafungin.

It is very clear, based on previously published drug interaction studies with cyclosporine^11,12 and similar compounds such as tacrolimus,^13,14 that there is a tremendous amount of intersubject variability both in the case of inhibitors as well as inducers. Looking specifically at cyclosporine and the very strong CYP3A and P-glycoprotein inducer, rifampin, there is a mean increase in cyclosporine hepatic clearance of 39%; however, the increase ranged from 18% to 60% across subjects.¹¹ Similar variability was found in the decrease in bioavailability, with the mean being 59% but ranging from a 32% decrease to an 81% decrease.¹¹ This phenomenon is not unique to the inducers but is also clearly seen with the inhibitors. Ketoconazole, a very strong CYP3A and P-glycoprotein inhibitor, has been shown to markedly affect cyclosporine pharmacokinetics.¹² Ketoconazole administration resulted in a mean decrease in cyclosporine hepatic clearance of 44% but ranged from 35% to 54%. Oral bioavailability increased by a mean of 163% but ranged from an increase in 69% to 295%. With drugs such as rifampin and ketoconazole, which are known to have substantial effects on the pharmacokinetics of cyclosporine, clinicians expect to see an effect when these agents are given in combination. Therefore, clinicians carefully monitor the patient's cyclosporine concentrations when the interacting drugs are initiated or discontinued. Even though the intersubject variability is great with these interactions and clinicians are unable to predict exactly how much they will need to change the dose, they do know that they will need to follow the patient's cyclosporine concentrations closely and adjust dose accordingly.

Micafungin presents a somewhat different situation, in that although it appears to be a rather mild inhibitor for most individuals, in about 19% of the individuals in this study, it appears to be a clinically significant inhibitor. Therefore, in most individuals, micafungin could be initiated, and very little if any changes in cyclosporine concentrations would be seen. But in a small number of the patients, when micafungin is initiated, quite large changes in cyclosporine concentrations would be expected. The most obvious explanation that could explain this phenomenon is that subjects with the highest apparent oral clearance and therefore highest CYP3A and P-glycoprotein activity would have the greatest impact seen with the initiation of an inhibitor. That is, if an interacting compound causes the same percentage inhibition in all subjects, those with the highest clearance to start with would have the greatest decrease. This is consistent with the fairly good correlation between initial apparent oral clearance and percentage inhibition with micafungin.

In this study, it appears as though intravenous micafungin has its greatest effect on first-pass metabolism, with the predominant effect occurring in the intestine. This conclusion is drawn based on the fact that similar changes occurred in both apparent oral cyclosporine clearance and apparent oral volume of distribution, with little change in half-life. Although not surprising, this is another example of the fact that intravenously administered medications clearly have effects on the metabolism in the gut.

Single-dose and steady-state micafungin was found to be affected by single doses of oral cyclosporine to a small degree. Changes in AUC and clearance were found to have P values less than .05, which clinically would be considered insignificant, and all pharmacokinetic parameters fell within the 80% to 125% no-effect boundaries. One limitation of this study is that cyclosporine was given as single doses. Given cyclosporine's toxicity profile, dosing it to steady state in healthy volunteers was not considered a feasible option. However, because this study only evaluated the effects of single-dose oral cyclosporine with micafungin, it is unclear whether steady-state cyclosporine in combination with micafungin will result in the same effect.

In conclusion, micafungin appears to be a mild inhibitor of cyclosporine metabolism in most individuals. However, in approximately one fifth of the individuals studied, micafungin caused a clinically significant increase in cyclosporine concentrations. It appears as though those individuals with the greatest apparent oral cyclosporine clearance initially will undergo the greatest inhibition of metabolism with micafungin. Careful monitoring of cyclosporine concentrations and dosage adjustment as needed are recommended when concomitant micafungin therapy is initiated or discontinued.

	ACKNOWLEDGEMENTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The authors gratefully acknowledge the technical assistance of Mary Dessimoz from Fujisawa Healthcare Inc.

DOI: 10.1177/0091270005278601

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

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