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A pharmacokinetic evaluation of 0.5% and 5% fluorouracil topical cream in patients with actinic keratosis
CLINICAL THERAPEUTXYWOL.
23, NO. 6,200l
A Pharmacokinetic Evaluation of 0.5 % and 5 % Fluorouracil Topical Cream in Patients with Actinic Keratosis Sharon Levy, MD, Katharine Furst, BS, and Wendy Chern, PhD De&k
Laboratories, Inc, Berwyn, Pennsylvania
ABSTRACT
Background: Systemic absorption of topical fluorouracil, although usually low, may vary as a result of the specific skin disease, product formulation, and other factors. Objective: The present study was conducted to determine the pharmacokinetic profile and tolerability of a new topical 0.5% fluorouracil cream formulation compared with that of a currently available topical formulation of 5% fluorouracil cream. Methods: This was an open-label, parallel-group study in which patients with actinic keratosis (AK) were randomized to treatment with either topical 0.5% fluorouracil once daily or topical 5% fluorouracil twice daily for up to 28 days. Results: lIvemy-one patients (all white; mean age, 64 years) participated in the study, 11 receiving topical 0.5% fluorouracil and 10 receiving topical 5% fluorouracil. Ten patients receiving 0.5% fluorouracil and 7 patients receiving 5% fluorouracil completed the 28-day study. Plasma concentrations of fluorouracil were detectable in 3 of 10 patients treated with 0.5% fluorouracil and 9 of 10 patients treated with 5% fluorouracil; fluorouracil was detected in the urine of 5 and 9 patients, respectively. Despite the one-tenth difference in drug concentration between formulations, the cumulative amount excreted in the urine of the 0.5% fluorouracil group was approximately one fortieth that of the 5% fluorouracil group. This difference may be a result of variations in vehicle formulations. At least 1 adverse event was reported by 4 of 11 patients in the 0.5% fluorouracil group and all 10 patients in the 5% fluorouracil group. The most common adverse event, facial irritation, was evident with both formulations but reached a plateau during treatment with 0.5% fluorouracil. All patients treated with 0.5% fluorouracil tolerated the full course of therapy, whereas 3 patients in the 5% fluorouracil group discontinued treatment early. No serious treatment-related adverse events were reported. Accepted for pub/ha tion April 77, 200 I. Printed in the USA. Reproduction
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in whole or part is not permitted.
0149-2918/01/$19.00
S. LEVY ET AL. Conclusions: These data suggest that 0.5% fluorouracil has minimal systemic absorption and is well tolerated in patients with AK. Key words: fluorouracil, topical administration, pharmacokinetics, keratosis, skin absorption, permeability. (ClipzThel: 200 1; 23:908-920)
INTRODUCTION Actinic keratosis (AK) is a precancerous cutaneous lesion that commonly occurs in fair-skinned elderly people with a history of excessive sun exposure. l-3 The lifetime risk of progression from AK to squamous cell carcinoma has been estimated to range from 6% to 10% in patients with multiple lesions.4,5 Thus, patients are urged to seek treatment for AK to avoid potential progression and more extensive treatment of a subsequent malignancy.6 Cryosurgery, curettage, photodynamic therapy, and topical fluorouracil are common treatments for isolated AK lesions, with cryosurgery and curettage being the most commonly used.7 Some clinicians consider topical fluorouracil to be the standard treatment for widespread actinic damage.* Fluorouracil demonstrates widely differing toxicity patterns depending on the dose, schedule, and route of administration used. When fluorouracil is administered topically to intact skin, ~10% of the dose appears to undergo systemic absorption.9**0A study in patients with AK who received 1-g doses of radiolabeled 5% fluorouracil twice daily found that -6% of the fluorouracil dose was absorbed systemically.9 However, a study comparing the absorption of topical fluorouracil in healthy and diseased skin found that absorption may be up to 75 times greater in diseased than in healthy skin.”
Currently, topical fluorouracil is available in concentrations ranging from 1% to 5% in both solution and cream formulations.3 Limitations on the use of these formulations include notable discomfort due to significant ulceration, inflammation, and crusting, and patients’ reluctance to be retreated, if necessary, based on their initial experiences. 3*7In addition, application of products containing higher concentrations of fluorouracil may result in greater systemic exposure than with products containing lower concentrations. Toxicities resulting from systemic exposure can be more severe in patients with deficiencies of dihydropyrimidine dehydrogenase (DPD), a key enzyme that degrades 80% to 90% of fluorouracil. A recent case report described the occurrence of a lifethreatening toxicity after topical fluorouracil treatment of a patient subsequently found to have profound DPD deficiency.12 A recently developed cream formulation contains 0.5% fluorouracil in an acrylic copolymer Microsponge@ (Enhanced Derm Technologies, Inc, Redwood City, California) delivery system. This lowconcentration formulation was designed to deliver a therapeutic dose of active ingredient to the skin while minimizing local and systemic toxicities. Dose-ranging studies have shown that this 0.5% formulation provides efficacy equal to that of currently available formulations at a lower dose.13 The objective of this study was to determine plasma and urine concentrations of fluorouracil with the 0.5% formulation and to evaluate its tolerability compared with that of a currently marketed 5% fluorouracil topical cream.* To maximize ex*Trademark: Efudex” (ICN Pharmaceuticals, Costa Mesa, California).
Inc,
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CLINICAL THERAPEUTICS”
posure and reflect use in the general population in a clinical setting, the products were administered to patients with AK who received daily treatment for up to 28 days, as tolerated. METHODS Patient Population
Eligible patients were adults with ~3 AK lesions on the face or anterior bald scalp that were either palpable or visible to the unaided eye. Women of childbearing potential were eligible, provided they agreed to use adequate contraception during the study. Patients who had been treated with fluorouracil or systemic chemotherapy 6 months before initiation of the study or had been treated with tretinoin, topical corticosteroids, or other topical agents for AK 1 month before the study were excluded. Concomitant medications were allowed with prior approval from the investigator. The study protocol was approved by the local institutional review board, and all patients provided written informed consent before study enrollment. Study Design
This was a randomized, open-label, parallel-group study. Patients were randomized to receive topical 0.5% fluorouracil cream 1 g daily or 5% fluorouracil cream 1 g twice daily (total daily dose, 2 g) at daily clinic visits for up to 28 days, as tolerated. This multidose regimen was designed to yield steadystate conditions and maximize systemic exposure to fluorouracil. After administration of the final dose, patients were confined to the study center for 24 910
hours for completion of plasma and urine sampling. Blood and Urine Sampling and Analysis
Blood samples (10 mL) were collected in sodium heparin-containing Vacutainer@ tubes before the final dose and at 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours after the final dose. Plasma samples were separated by centrifugation at -2500 rpm for 15 minutes at 4°C. Samples were kept at room temperature under fluorescent lighting before shipping. Within 60 minutes of collection, plasma samples were stored in labeled polypropylene containers in a freezer set at 52O’C until shipped. They were then packed in dry ice and sent to the CEDRA Corporation (Austin, Texas) for processing. Fluorouracil plasma concentrations were determined using a standard method (CEDRA procedure TM-330) validated for the range from 0.25 to 125 ng/mL using 0.8 mL of heparinized human plasma. Fluorouracil and an internal standard, chlorouracil, were extracted from plasma into an organic solvent. The reconstituted extract was injected onto a SCIEX API III-Plus (Applied Biosystems, Foster, California) liquid chromatography/ tandem mass spectrometer (LC-MS-MS) after centrifugation and evaporation. Peak areas of the rnlz 129-42 product ion of fluorouracil were measured against peak areas of the m/z 145+42 product ion of the internal standard. All samples were analyzed in a total of 6 analytical runs. Duplicate quality control samples at each of 3 concentrations (100, 25, and 1 ng/mL) were analyzed with each analytical run. The coefficients of variance for the quality control samples ranged from 9.5% to’ 11.4%.
S. LEVY ET AL.
Urine samples (all urine voided) were collected in polypropylene jugs and stored in the refrigerator before the final dose and at the following intervals after the final dose: 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, and 12 to 24 hours. For each patient, a lo-mL aliquot was stored frozen in a polypropylene container in a freezer set at 520°C until shipped. After all collections were complete, the samples were packed in dry ice and sent to the CEDRA Corporation. Samples were analyzed for fluorouracil using a standard method (CEDRA procedure TM-348) validated for the range from 6 to 1000 ng/mL using 0.8 mL of human urine. Fluorouracil and an internal standard, 5chlorouraci1, were extracted with acetonitrile. After centrifugation, the clear upper layer was transferred and injected onto a SCIEX API III-Plus LC-MS-MS. Peak areas of the m/z 129-42 product ion of fluorouracil were measured against peak areas of the m/z 145-42 product ion of the internal standard in electrospray ionization mode. Quantification was performed using a 1/x2 weighted linear leastsquares regression line generated from spiked urine calibration samples prepared fresh before each run. At least 2 quality control samples at each of 3 concentrations (800, 250, and 8 ng/mL) were analyzed with each analytical run. The coefficients of variance for the quality control samples ranged from 5.6% to 14.3%. The absolute deviations ranged from 0.37% to 5.7%. Phunnacokinetic
Evaluations
Maximum observed drug concentration (C_), time to maximum drug concentration (T,,,), and area under the drug concentration-time curve (AUC) were calculated based on plasma sampling. Urine
samples were used to calculate the amount of drug excreted during a single collection interval (Ae); the cumulative amount excreted over the entire study (Cum Ae); and the excretion rate (Ex Rate), calculated as Ae divided by the interval duration. Safety Evaluations
Vital signs, physical examination, laboratory tests, and recording of adverse events were used to monitor tolerability. Patients were evaluated on days 4, 7, 11, 14, 18, 21, 25, and 28 for facial irritation and other adverse events. A dermatologist blinded to treatment assignment rated adverse reactions as mild (easily tolerated, no interference with daily activities), moderate (interference with daily activities but patient able to function), or severe (incapacitating, requiring medical intervention). Patients were permitted to withdraw before completion of the 28-day study if they experienced severe facial irritation. If treatment was discontinued for this reason, final plasma and urine samples were obtained after the final dose. Adverse events were followed to resolution, regardless of whether or not patients completed the study. Stutitical
Analysis
Demographic characteristics were summarized by treatment group and for continuous variables (age, height, body weight) using descriptive statistics (mean, SD, minimum, maximum, and sample size). Frequency counts were tabulated for categorical demographic variables (eg, sex, race, frame size) by treatment group and overall. Descriptive statistics were calculated for each pharmacokinetic evaluation of plasma and urine. Adverse 911
CLINICAL THERAPEUTICS’
events were summarized according to the number and percentage of patients experiencing each event. This study contained few patients and was not powered to calculate a priori differences. To the best of the authors’ knowledge, this is not uncommon in pharmacokinetic studies with small numbers of patients. RESULTS Patient Characteristics and Disposition Of the 21 patients enrolled in the trial, 15 were male and 6 female. All study participants were white, and their mean age was 64 years (Table I). The average number of AK lesions at baseline (8 or 9 in each group) and extent of actinic damage were similar between the 2 groups. Eleven patients were randomized to 0.5% fluorouracil and 10 to 5% fluorouracil. Ten of 11 patients randomized to 0.5% fluorouracil and 7 of 10 patients randomized to 5% fluorouracil completed the 28-day study. One patient in the 0.5% flu-
orouracil group was withdrawn after 24 days because of noncompliance, and 3 patients in the 5% fluorouracil group discontinued because of intolerable facial irritation after 35 doses (18 days of treatment). Pharmacokinetic Parameters Three patients receiving 0.5% fluorouracil cream and 9 receiving 5% fluorouracil cream had measurable plasma concentrations of fluorouracil. In the remaining patients, fluorouracil plasma concentrations were below the limit of quantification (co.25 ng/mL). Treatment with 5% fluorouracil resulted in higher initial mean plasma drug concentrations compared with 0.5% fluorouracil (Figure 1). The highest individual concentrations in the 3 patients in the 0.5% fluorouracil group ranged from 0.258 to 1.87 ng/mL. The highest individual concentrations in the 9 patients in the 5% fluorouracil group ranged from 2.03 to 27.2 ng/mL. Of the 3 patients with detectable fluorouracil plasma concentrations in the 0.5%
Table I. Demographic and baseline characteristics.
Sex Male Female White race Frame size Small Medium Large Age, y (mean f SD) Body weight, lb (mean f SD) Height, in (mean + SD)
912
0.5% Fluorouracil Cream (n = 11)
5% Fluorouracil Cream (n = 10)
8 3 11
7 3 10
1 6 4 63 + 9 186.1 + 20.1 69.0 + 4.3
2 5 3 64* 10 165.4 f 30.8 66.2 f 3.7
S. LEVY ET AL.
+ +
Predose
1 2
4
6
6
10
12
0.5% Fluorouracil (n = 3) 5% Fluorouracil (n = 9)
16
24
Hours After Dosing
Figure 1. Mean plasma drug concentrations in patients receiving 0.5% fluorouracil and 5% fluorouracil cream. group, only 1 had sufficient data points to allow calculation of pharmacokinetic parameters. The C,,,, TmX, and AUC for this patient were 0.768 ng/mL, 0.996 hours, and 2.803 ng.h/mL, respectively. Six of the 9 patients in the 5% fluorouracil group with measurable plasma concentrations had sufficient data points for calculation of pharmacokinetic parameters. In these patients, the C,, ranged from 5.050 to 27.200 ng/mL, the T_ from 0.999 to 1.075 hours, and the AUC from 14.507 to 37.518 ngb/mL (Table II). Five of 10 patients in the 0.5% fluorouracil group and 9 of 10 patients in the 5% fluorouracil group had measurable urine concentrations (~6 ng/mL). Of these, 1 in the 0.5% fluorouracil group and 2 in the 5% fluorouracil group had measurable concentrations of fluorouracil in the urine immediately before application of the final dose. In patients treated with 0.5% fluorouracil, the mean Cum Ae over 24
hours was 2.737 pg (range, O-15.022 pg), with a mean maximum Ex Rate of 0.392 kg/h. Patients treated with 5% fluorouracil had a mean Cum Ae of 119.833 p,g over 24 hours (range, nondetectable329.866 Fg) and a mean maximum Ex Rate of 40.443 pg/h. Table III summarizes the mean Ae, Cum Ae, and Ex Rate data at various time points in the study. The Ex Rate was highest for both formulations during the interval between 0 and 2 hours after the final dose, coinciding with the T_. The percentage of the applied dose excreted in the urine was used to estimate the systemic absorption of fluorouracil from each product. Fluorouracil urinary excretion was 0.055% (2.737 p,g [mean Cum Ae]/l g x 0.5% = 2.737 pg/5000 p,g) of the final dose of 0.5% fluorouracil and 0.24% (119.8 Fg [mean Cum Ae]/l g x 5% = 119.8 pg/50,000 pg) of the final dose of 5% fluorouracil. Using a conser913
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Table II. Pharmacokinetic parameters of topically applied 0.5% fluorouracil cream and 5% fluorouracil cream. Cmax’ng/mt-
T max’ h
0.768
0.996
2.803
10.400 5.260 8.340 5.050 27.200 12.700
1.075 1.031 0.999 1.017 1.027 1.000
14.507 21.578 20.528 21.788 37.518 18.420
11.492
1.025
22.390
AUC, ngh/mL
0.5% Fluorouracil cream Patient 7 5% Fluorouracil Patient 1 Patient 4 Patient 9 Patient 11 Patient 22 Patient 23
cream
Mean
Cmax= maximum observed drug concentration; T,, concentration-time curve.
= time to C,,
(calculated); AUC = area under the drug
Tolerability
vative ratio of systemically available fluorouracil excreted in urine ( 1:10),14 the urinary excretion data suggest that the respective systemic absorption of 0.5% and 5% fluorouracil cream were 0.55% and 2.4%.
As stated, 3 patients in the fluorouracil 5% group discontinued treatment because of intolerable facial irritation. At least 1 adverse event was reported by 4 of 11 pa-
Table III. Mean
after topical
urinary
rouracil
cream
excretion (0.5%)
parameters and
k a Interval, h
0.5%
administration
of 0.5%
Cum Ae, u,g 5%
fluo-
5% fluorouracil cream (5%) (N = 20).
0.5%
Ex Rate, l~g/h 5%
0.5%
5%
0*
0.158
0.435
0.158
0.435
-
-
O-2
0.379
80.539
0.537
80.844
0.190
40.270 7.766
24
0.223
15.532
0.760
94.823
0.111
4-6
0.205
7.764
0.965
102.586
0.102
3.882
6-8
0.168
4.011
1.133
106.597
0.084
2.006
8-12
0.127
3.648
1.234
110.246
0.032
0.912
12-24
1.669
9.587
2.737
119.833
0.139
0.799
Ae = amount excreted; Cum Ae = cumulative amount excreted; Ex Rate = excretion rate. *Hour of the final dose.
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S. LEVY ET AL.
tients in the 0.5% fluorouracil group and all 10 patients in the 5% fluorouracil group. The most common adverse events in the 0.5% fluorouracil group, occurring in 2 patients each, were application-site reaction, exfoliative dermatitis, and headache (Table IV). The most common adverse events in the 5% fluorouracil group were maculopapular rash, application-site reaction, and erythema. All adverse events were considered mild or moderate in severity. No serious adverse events were reported during the study. Other than application-site reactions, none of the adverse events were considered drug related. The time of onset of application-site reactions ranged from day 3 to day 25 in the 0.5% fluorouracil group and from day 5 to day 23 in the 5% fluorouracil group. The duration of these reactions ranged from 23 hours to 30 days in the 0.5% fluorouracil group and 15 minutes to 95 days in the 5% fluorouracil group. Fifty-five percent of patients in the 0.5% fluorouracil group had mild facial irritation at day 11, and 64% had moder-
ate irritation at day 14. At day 21,45% of patients had mild facial irritation, and 55% had moderate facial irritation. At the day-28 evaluation (end of treatment), 50% of patients in this group had mild irritation, and 50% had moderate irritation. In contrast, 80% of patients in the 5% fluorouracil group had moderate irritation at day 7. On day 11 and days 18 through 28, 100% of patients in the 5% fluorouracil group experienced moderate irritation, and there was no decline in the severity of irritation during the later interval (Figure 2).
DISCUSSION The results of this study suggest that fluorouracil has minimal systemic absorption after repeated topical administration. Plasma concentrations of both fluorouracil formulations were measurable in only 12 patients, 3 randomized to 0.5% fluorouracil and 9 randomized to 5% fluorouracil. Pharmacokinetic profiles were evaluable in only 1 of 3 patients in the 0.5% fluorouracil group and 6 of 9 patients in the 5% fluorouracil group. Given
Table IV Number (%) of adverse events reported in r2 patients after topical administration of 0.5% fluorouracil cream and 5% fluorouracil cream. 0.5% Pluorouracil Cream
Adverse Event Application-site reaction Dry skin Erytbema Exfoliative dermatitis Headache Maculopapular rash PIWihlS
Sweating
(n= 11) 2 (18) 0 (0) I (9) 2 (18) 2 (18) 1 (9) 1 (9) 0 (0)
5% Pluorouracil Cream (n = 10) 5 (50) 4 (40) 5 (50) 3 (30) 2 (20) 6 (60) 4 W) 2 (20)
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+ +
100 90 co E $
0.5% Fiuorouracil (n = 3) 5% Fluorouracil (n = 9)
1
80 70 -
d 3
80-
E8
40 50 -
8 $ a
30-
-
20 -
0
4
7
11
14
18
21
25
28
Day
Figure 2. Percentage
of patients with moderate facial irritation.
final doses of 5 and 50 mg after administration of 0.5% fluorouracil and 5% fluorouracil, respectively, a IO-fold difference in plasma concentrations would be anticipated. The AUC calculated for the 1 patient in the 0.5% fluorouracil group with evaluable plasma drug concentrations was -10% of that calculated for the 6 patients in the fluorouracil 5% group with evaluable plasma concentrations. However, a 1: 10 ratio may overestimate the true exposure to fluorouracil in the 0.5% fluorouracil group, because 9 patients in this group had undeterminable plasma pharmacokinetic profiles. In comparison with these findings on absorption after topical administration, a recent study reported that plasma concentrations ranged from 30 to 260 ng/mL after administration of infusions of fluorouracil 300 mg/m2 daily.15 An earlier study reported a mean peak plasma fluorouracil concentration of 0.8 mg/L in pa-
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tients treated with a constant infusion of fluorouracil 600 mg/m2.16 In another study, after a 2Ominute infusion of fluorouracil 500 mg/m2, the mean AUC and peak plasma concentration were 436 mg/L per minute and 21 mg/L, respectively.17 However, there is wide interpatient variability in fluorouracil metabolism, and plasma concentrations of fluorouracil have been reported to vary greatly.18 Urinary pharmacokinetic data were evaluable in 5 patients receiving 0.5% fluorouracil and 9 patients receiving 5% fluorouracil. As with plasma concentrations, a lo-fold difference in excretion would be anticipated based on differences in the fluorouracil dose in each group. However, the mean absolute Cum Ae in patients receiving 5% fluorouracil cream (119.833 kg) was >40 times that in patients receiving 0.5% fluorouracil cream (2.737 pg). These results should be interpreted with caution because of the small number of
S. LEVY ET AL.
patients in whom urine concentrations were evaluable. In a recent in vitro study, Levy et al compared the flux and percutaneous absorption of the 0.5% fluorouracil formulation evaluated in the present study with those of 5% fluorouracil.19 In that study, the flux of the 5% formulation was -20 to 40 times higher than that of the 0.5% formulation, indicating that the flux over time in the in vitro study was comparable to the systemic exposure observed in the present pharmacokinetic study. The differences in the observed Cum Ae between the 2 formulations may be due to the variation in urine collection times, which occurred 12 hours after the last dose of twice-daily 5% fluorouracil and 24 hours after the last dose of oncedaily 0.5% fluorouracil. More residual fluorouracil may have been present in the urine of patients randomized to the 5% fluorouracil formulation. In addition, because the urine assay was volume dependent, a large volume could result in dilution below the limit of sensitivity of the assay. Alternatively, the difference in fluorouracil excretion between the 2 groups may represent true differences in the systemic absorption or bioavailability of the 2 preparations, possibly as a result of the different vehicles (eg, the Microsponge copolymers) used in the respective formulations. Vehicles are known to significantly affect the dermal absorption of active ingredients. Although this study did not address the availability of active drug to the different layers of the epidermis and dermis with the 2 formulations, Levy et al demonstrated that at 24 hours, -86% to 92% of 0.5% fluorouracil remained in the skin, compared with 55% of 5% fluorouracil, suggesting significantly less systemic absorption of the 0.5% fluorouracil formulation.19
In the present study, the calculated absorption rates for fluorouracil were lower in the 0.5% fluorouracil group compared with the 5% fluorouracil group (0.55% and 2.4%, respectively). These results differ somewhat from the findings of previous studies, in which -6% of the administered dose of radiolabeled 5 % fluorouracil was absorbed systemically, corresponding to a systemic absorption of 5 to 6 mg/lOO mg.9 In a study in which patients with warts were treated with a solution of 0.5% fluorouracil and 10% salicylic acid, the median extent of systemic absorption was 0.085% after a single application and 0.035% after multiple applications.20 In a study by Erlanger et al, the difference in absorption between healthy and diseased skin was evaluated by measuring the amount of drug excreted in the urine to indicate the quantity of drug absorbed from the skin after topical application of radiolabeled 5% fluorouracil.” Only a small percentage (0.3%-l. 1%) of a single dose (11.1-175.5 mg) was detected in the urine after application to healthy skin. However, when patients with diseased skin received similar or lower doses of 5% fluorouracil (11.1-63.2 mg). the percentage of the total dose excreted in the urine was higher (15.8%-61.2%). These data suggest that diseased skin absorbs 15 to 75 times more drug than healthy skin when applied at equal doses per unit of area.” The reasons for the discrepancy between earlier results and those of the present study may include differences in the disease states treated or the sensitivity of the urinary assays used, or the fact that +l of the previous studies did not distinguish between fluorouracil and its metabolic byproducts.9 The present study measured the parent compound only and thus may
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CLINICAL THERAPEUTICS”
have underestimated absorption. However, use of a 1: 10 ratio of urinary excretion to the amount in systemic circulation is likely to have overestimated exposure with the 0.5% formulation. Possible limitations of this study include its open-label design, which may have biased the tolerability data and caused patients to associate more frequent administration of drug with increased facial irritation. Also, the low number of plasma and urine samples with measurable fluorouracil concentrations (1 and 5, respectively) may have led to overestimation of the systemic absorption of 0.5% fluorouracil. The 0.5% fluorouracil formulation appeared to be better tolerated than the 5% fluorouracil formulation. Of 14 patients reporting r 1 adverse event during the trial, 10 were treated with the 5% fluorouracil formulation. A higher percentage of patients in the 5% fluorouracil group experienced moderate facial irritation at each evaluation compared with patients in the 0.5% fluorouracil group, and fewer adverse events were reported by patients in the 0.5% fluorouracil group. All patients randomized to treatment with 0.5% fluorouracil completed the study, whereas 3 patients in the 5% fluorouracil group discontinued treatment after 18 days because of facial irritation. In addition, patients in the 0.5% fluorouracil group experienced a plateau or lessening of moderate facial irritation after 14 days of therapy, despite continued treatment. This effect was not observed in patients treated with 5% fluorouracil. A recent case report described an incident of life-threatening toxicity after administration of topical fluorouracil in a patient with severe DPD deficiency.‘* Thus, a fluorouracil formulation with less
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systemic absorption may decrease the potential for serious adverse effects in such patients.
CONCLUSIONS Topical application of 2 fluorouracil formulations in patients with AK resulted in minimal systemic absorption, as evidenced by low measurable plasma and urine concentrations. The C,,, (0.768 ng/mL) and AUC (2.803 ngh/mL) were substantially lower for the 0.5% fluorouracil formulation than for the 5% fluorouracil formulation (11.492 ng/mL and 22.390 ng*h/mL, respectively). Because the mean Cum Ae of 0.5% fluorouracil (2.737 pg) was one fortieth that of 5% fluorouracil (119.833 pg), the systemic absorption of the former was estimated to be substantially lower than that of the latter. Furthermore, 0.5% fluorouracil cream appeared to be better tolerated than 5% fluorouracil cream. Facial irritation was mild to moderate with 0.5% fluorouracil cream throughout the treatment period; the incidence of moderate facial irritation reached a plateau or abated by day 14 despite continued treatment. In contrast, all patients receiving 5% fluorouracil cream experienced moderate irritation by day 11, and 3 patients in this group discontinued therapy after 18 days because of intolerable facial irritation. Although both formulations were associated with minimal systemic exposure, the delivery of the 0.5% formulation into the skin was associated with a lower potential for systemic exposure, suggesting a corresponding lower potential for systemic toxicities. It is unknown whether the favorable results with the 0.5% formulation were associated with the lower concentration itself or with a component of the vehicle formulation.
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11. Erlanger M, Martz G, Ott F, et al. Cuta-
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5-Fluorouracil steady state pharmacokinetics and outcome in patients receiving protracted venous infusion for advanced colorectal 600-603.
cancer. Br J Cancer. 2001;84:
16. Metzger G, Massari C, Etienne M-C, et al. Spontaneous or imposed circadian changes in plasma concentrations of 5fluorouracil coadministered with folinic acid and oxaliplatin: Relationship with mucosal toxicity in patients with cancer. Clin Pharmacol Thel: 1994;56:190-201. 17. Larsson PA, Carlsson G, Gustavsson B, et al. Different intravenous administration techniques for 5-fluorouracil. Pharmacokinetics and pharmacodynamic effects. Acta Oncol. 1996;35:207-212. 18. Young AM, Daryanani S, Kerr DJ. Can pharmacokinetic monitoring improve clinical use of fluorouracil? Clin Pharmacokinet. 1999;36:391-398.
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19. Levy S, Furst K, Chem W. A comparison of the skin permeation of three topical 0.5% fluorouracil formulations with that of a 5% formulation. Clin 7’hel: 2001;23: 901-907.
20. Senff H, Reinel D, Mattbies C, Witts D. Topical Sfluorouracil solution in the treatment of warts-clinical experience and percutaneous absorption. Br .I Derrnatol. 1988;118:409Jl14.
Address correspondence to: Sharon Levy, MD, Dermik Laboratories, Inc, 1050 Westlakes Drive, Benvyn,
920
PA 19312. E-mail: [email protected]
23, NO. 6,200l
A Pharmacokinetic Evaluation of 0.5 % and 5 % Fluorouracil Topical Cream in Patients with Actinic Keratosis Sharon Levy, MD, Katharine Furst, BS, and Wendy Chern, PhD De&k
Laboratories, Inc, Berwyn, Pennsylvania
ABSTRACT
Background: Systemic absorption of topical fluorouracil, although usually low, may vary as a result of the specific skin disease, product formulation, and other factors. Objective: The present study was conducted to determine the pharmacokinetic profile and tolerability of a new topical 0.5% fluorouracil cream formulation compared with that of a currently available topical formulation of 5% fluorouracil cream. Methods: This was an open-label, parallel-group study in which patients with actinic keratosis (AK) were randomized to treatment with either topical 0.5% fluorouracil once daily or topical 5% fluorouracil twice daily for up to 28 days. Results: lIvemy-one patients (all white; mean age, 64 years) participated in the study, 11 receiving topical 0.5% fluorouracil and 10 receiving topical 5% fluorouracil. Ten patients receiving 0.5% fluorouracil and 7 patients receiving 5% fluorouracil completed the 28-day study. Plasma concentrations of fluorouracil were detectable in 3 of 10 patients treated with 0.5% fluorouracil and 9 of 10 patients treated with 5% fluorouracil; fluorouracil was detected in the urine of 5 and 9 patients, respectively. Despite the one-tenth difference in drug concentration between formulations, the cumulative amount excreted in the urine of the 0.5% fluorouracil group was approximately one fortieth that of the 5% fluorouracil group. This difference may be a result of variations in vehicle formulations. At least 1 adverse event was reported by 4 of 11 patients in the 0.5% fluorouracil group and all 10 patients in the 5% fluorouracil group. The most common adverse event, facial irritation, was evident with both formulations but reached a plateau during treatment with 0.5% fluorouracil. All patients treated with 0.5% fluorouracil tolerated the full course of therapy, whereas 3 patients in the 5% fluorouracil group discontinued treatment early. No serious treatment-related adverse events were reported. Accepted for pub/ha tion April 77, 200 I. Printed in the USA. Reproduction
908
in whole or part is not permitted.
0149-2918/01/$19.00
S. LEVY ET AL. Conclusions: These data suggest that 0.5% fluorouracil has minimal systemic absorption and is well tolerated in patients with AK. Key words: fluorouracil, topical administration, pharmacokinetics, keratosis, skin absorption, permeability. (ClipzThel: 200 1; 23:908-920)
INTRODUCTION Actinic keratosis (AK) is a precancerous cutaneous lesion that commonly occurs in fair-skinned elderly people with a history of excessive sun exposure. l-3 The lifetime risk of progression from AK to squamous cell carcinoma has been estimated to range from 6% to 10% in patients with multiple lesions.4,5 Thus, patients are urged to seek treatment for AK to avoid potential progression and more extensive treatment of a subsequent malignancy.6 Cryosurgery, curettage, photodynamic therapy, and topical fluorouracil are common treatments for isolated AK lesions, with cryosurgery and curettage being the most commonly used.7 Some clinicians consider topical fluorouracil to be the standard treatment for widespread actinic damage.* Fluorouracil demonstrates widely differing toxicity patterns depending on the dose, schedule, and route of administration used. When fluorouracil is administered topically to intact skin, ~10% of the dose appears to undergo systemic absorption.9**0A study in patients with AK who received 1-g doses of radiolabeled 5% fluorouracil twice daily found that -6% of the fluorouracil dose was absorbed systemically.9 However, a study comparing the absorption of topical fluorouracil in healthy and diseased skin found that absorption may be up to 75 times greater in diseased than in healthy skin.”
Currently, topical fluorouracil is available in concentrations ranging from 1% to 5% in both solution and cream formulations.3 Limitations on the use of these formulations include notable discomfort due to significant ulceration, inflammation, and crusting, and patients’ reluctance to be retreated, if necessary, based on their initial experiences. 3*7In addition, application of products containing higher concentrations of fluorouracil may result in greater systemic exposure than with products containing lower concentrations. Toxicities resulting from systemic exposure can be more severe in patients with deficiencies of dihydropyrimidine dehydrogenase (DPD), a key enzyme that degrades 80% to 90% of fluorouracil. A recent case report described the occurrence of a lifethreatening toxicity after topical fluorouracil treatment of a patient subsequently found to have profound DPD deficiency.12 A recently developed cream formulation contains 0.5% fluorouracil in an acrylic copolymer Microsponge@ (Enhanced Derm Technologies, Inc, Redwood City, California) delivery system. This lowconcentration formulation was designed to deliver a therapeutic dose of active ingredient to the skin while minimizing local and systemic toxicities. Dose-ranging studies have shown that this 0.5% formulation provides efficacy equal to that of currently available formulations at a lower dose.13 The objective of this study was to determine plasma and urine concentrations of fluorouracil with the 0.5% formulation and to evaluate its tolerability compared with that of a currently marketed 5% fluorouracil topical cream.* To maximize ex*Trademark: Efudex” (ICN Pharmaceuticals, Costa Mesa, California).
Inc,
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CLINICAL THERAPEUTICS”
posure and reflect use in the general population in a clinical setting, the products were administered to patients with AK who received daily treatment for up to 28 days, as tolerated. METHODS Patient Population
Eligible patients were adults with ~3 AK lesions on the face or anterior bald scalp that were either palpable or visible to the unaided eye. Women of childbearing potential were eligible, provided they agreed to use adequate contraception during the study. Patients who had been treated with fluorouracil or systemic chemotherapy 6 months before initiation of the study or had been treated with tretinoin, topical corticosteroids, or other topical agents for AK 1 month before the study were excluded. Concomitant medications were allowed with prior approval from the investigator. The study protocol was approved by the local institutional review board, and all patients provided written informed consent before study enrollment. Study Design
This was a randomized, open-label, parallel-group study. Patients were randomized to receive topical 0.5% fluorouracil cream 1 g daily or 5% fluorouracil cream 1 g twice daily (total daily dose, 2 g) at daily clinic visits for up to 28 days, as tolerated. This multidose regimen was designed to yield steadystate conditions and maximize systemic exposure to fluorouracil. After administration of the final dose, patients were confined to the study center for 24 910
hours for completion of plasma and urine sampling. Blood and Urine Sampling and Analysis
Blood samples (10 mL) were collected in sodium heparin-containing Vacutainer@ tubes before the final dose and at 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours after the final dose. Plasma samples were separated by centrifugation at -2500 rpm for 15 minutes at 4°C. Samples were kept at room temperature under fluorescent lighting before shipping. Within 60 minutes of collection, plasma samples were stored in labeled polypropylene containers in a freezer set at 52O’C until shipped. They were then packed in dry ice and sent to the CEDRA Corporation (Austin, Texas) for processing. Fluorouracil plasma concentrations were determined using a standard method (CEDRA procedure TM-330) validated for the range from 0.25 to 125 ng/mL using 0.8 mL of heparinized human plasma. Fluorouracil and an internal standard, chlorouracil, were extracted from plasma into an organic solvent. The reconstituted extract was injected onto a SCIEX API III-Plus (Applied Biosystems, Foster, California) liquid chromatography/ tandem mass spectrometer (LC-MS-MS) after centrifugation and evaporation. Peak areas of the rnlz 129-42 product ion of fluorouracil were measured against peak areas of the m/z 145+42 product ion of the internal standard. All samples were analyzed in a total of 6 analytical runs. Duplicate quality control samples at each of 3 concentrations (100, 25, and 1 ng/mL) were analyzed with each analytical run. The coefficients of variance for the quality control samples ranged from 9.5% to’ 11.4%.
S. LEVY ET AL.
Urine samples (all urine voided) were collected in polypropylene jugs and stored in the refrigerator before the final dose and at the following intervals after the final dose: 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, and 12 to 24 hours. For each patient, a lo-mL aliquot was stored frozen in a polypropylene container in a freezer set at 520°C until shipped. After all collections were complete, the samples were packed in dry ice and sent to the CEDRA Corporation. Samples were analyzed for fluorouracil using a standard method (CEDRA procedure TM-348) validated for the range from 6 to 1000 ng/mL using 0.8 mL of human urine. Fluorouracil and an internal standard, 5chlorouraci1, were extracted with acetonitrile. After centrifugation, the clear upper layer was transferred and injected onto a SCIEX API III-Plus LC-MS-MS. Peak areas of the m/z 129-42 product ion of fluorouracil were measured against peak areas of the m/z 145-42 product ion of the internal standard in electrospray ionization mode. Quantification was performed using a 1/x2 weighted linear leastsquares regression line generated from spiked urine calibration samples prepared fresh before each run. At least 2 quality control samples at each of 3 concentrations (800, 250, and 8 ng/mL) were analyzed with each analytical run. The coefficients of variance for the quality control samples ranged from 5.6% to 14.3%. The absolute deviations ranged from 0.37% to 5.7%. Phunnacokinetic
Evaluations
Maximum observed drug concentration (C_), time to maximum drug concentration (T,,,), and area under the drug concentration-time curve (AUC) were calculated based on plasma sampling. Urine
samples were used to calculate the amount of drug excreted during a single collection interval (Ae); the cumulative amount excreted over the entire study (Cum Ae); and the excretion rate (Ex Rate), calculated as Ae divided by the interval duration. Safety Evaluations
Vital signs, physical examination, laboratory tests, and recording of adverse events were used to monitor tolerability. Patients were evaluated on days 4, 7, 11, 14, 18, 21, 25, and 28 for facial irritation and other adverse events. A dermatologist blinded to treatment assignment rated adverse reactions as mild (easily tolerated, no interference with daily activities), moderate (interference with daily activities but patient able to function), or severe (incapacitating, requiring medical intervention). Patients were permitted to withdraw before completion of the 28-day study if they experienced severe facial irritation. If treatment was discontinued for this reason, final plasma and urine samples were obtained after the final dose. Adverse events were followed to resolution, regardless of whether or not patients completed the study. Stutitical
Analysis
Demographic characteristics were summarized by treatment group and for continuous variables (age, height, body weight) using descriptive statistics (mean, SD, minimum, maximum, and sample size). Frequency counts were tabulated for categorical demographic variables (eg, sex, race, frame size) by treatment group and overall. Descriptive statistics were calculated for each pharmacokinetic evaluation of plasma and urine. Adverse 911
CLINICAL THERAPEUTICS’
events were summarized according to the number and percentage of patients experiencing each event. This study contained few patients and was not powered to calculate a priori differences. To the best of the authors’ knowledge, this is not uncommon in pharmacokinetic studies with small numbers of patients. RESULTS Patient Characteristics and Disposition Of the 21 patients enrolled in the trial, 15 were male and 6 female. All study participants were white, and their mean age was 64 years (Table I). The average number of AK lesions at baseline (8 or 9 in each group) and extent of actinic damage were similar between the 2 groups. Eleven patients were randomized to 0.5% fluorouracil and 10 to 5% fluorouracil. Ten of 11 patients randomized to 0.5% fluorouracil and 7 of 10 patients randomized to 5% fluorouracil completed the 28-day study. One patient in the 0.5% flu-
orouracil group was withdrawn after 24 days because of noncompliance, and 3 patients in the 5% fluorouracil group discontinued because of intolerable facial irritation after 35 doses (18 days of treatment). Pharmacokinetic Parameters Three patients receiving 0.5% fluorouracil cream and 9 receiving 5% fluorouracil cream had measurable plasma concentrations of fluorouracil. In the remaining patients, fluorouracil plasma concentrations were below the limit of quantification (co.25 ng/mL). Treatment with 5% fluorouracil resulted in higher initial mean plasma drug concentrations compared with 0.5% fluorouracil (Figure 1). The highest individual concentrations in the 3 patients in the 0.5% fluorouracil group ranged from 0.258 to 1.87 ng/mL. The highest individual concentrations in the 9 patients in the 5% fluorouracil group ranged from 2.03 to 27.2 ng/mL. Of the 3 patients with detectable fluorouracil plasma concentrations in the 0.5%
Table I. Demographic and baseline characteristics.
Sex Male Female White race Frame size Small Medium Large Age, y (mean f SD) Body weight, lb (mean f SD) Height, in (mean + SD)
912
0.5% Fluorouracil Cream (n = 11)
5% Fluorouracil Cream (n = 10)
8 3 11
7 3 10
1 6 4 63 + 9 186.1 + 20.1 69.0 + 4.3
2 5 3 64* 10 165.4 f 30.8 66.2 f 3.7
S. LEVY ET AL.
+ +
Predose
1 2
4
6
6
10
12
0.5% Fluorouracil (n = 3) 5% Fluorouracil (n = 9)
16
24
Hours After Dosing
Figure 1. Mean plasma drug concentrations in patients receiving 0.5% fluorouracil and 5% fluorouracil cream. group, only 1 had sufficient data points to allow calculation of pharmacokinetic parameters. The C,,,, TmX, and AUC for this patient were 0.768 ng/mL, 0.996 hours, and 2.803 ng.h/mL, respectively. Six of the 9 patients in the 5% fluorouracil group with measurable plasma concentrations had sufficient data points for calculation of pharmacokinetic parameters. In these patients, the C,, ranged from 5.050 to 27.200 ng/mL, the T_ from 0.999 to 1.075 hours, and the AUC from 14.507 to 37.518 ngb/mL (Table II). Five of 10 patients in the 0.5% fluorouracil group and 9 of 10 patients in the 5% fluorouracil group had measurable urine concentrations (~6 ng/mL). Of these, 1 in the 0.5% fluorouracil group and 2 in the 5% fluorouracil group had measurable concentrations of fluorouracil in the urine immediately before application of the final dose. In patients treated with 0.5% fluorouracil, the mean Cum Ae over 24
hours was 2.737 pg (range, O-15.022 pg), with a mean maximum Ex Rate of 0.392 kg/h. Patients treated with 5% fluorouracil had a mean Cum Ae of 119.833 p,g over 24 hours (range, nondetectable329.866 Fg) and a mean maximum Ex Rate of 40.443 pg/h. Table III summarizes the mean Ae, Cum Ae, and Ex Rate data at various time points in the study. The Ex Rate was highest for both formulations during the interval between 0 and 2 hours after the final dose, coinciding with the T_. The percentage of the applied dose excreted in the urine was used to estimate the systemic absorption of fluorouracil from each product. Fluorouracil urinary excretion was 0.055% (2.737 p,g [mean Cum Ae]/l g x 0.5% = 2.737 pg/5000 p,g) of the final dose of 0.5% fluorouracil and 0.24% (119.8 Fg [mean Cum Ae]/l g x 5% = 119.8 pg/50,000 pg) of the final dose of 5% fluorouracil. Using a conser913
CLINICAL THERAPEUTICS”
Table II. Pharmacokinetic parameters of topically applied 0.5% fluorouracil cream and 5% fluorouracil cream. Cmax’ng/mt-
T max’ h
0.768
0.996
2.803
10.400 5.260 8.340 5.050 27.200 12.700
1.075 1.031 0.999 1.017 1.027 1.000
14.507 21.578 20.528 21.788 37.518 18.420
11.492
1.025
22.390
AUC, ngh/mL
0.5% Fluorouracil cream Patient 7 5% Fluorouracil Patient 1 Patient 4 Patient 9 Patient 11 Patient 22 Patient 23
cream
Mean
Cmax= maximum observed drug concentration; T,, concentration-time curve.
= time to C,,
(calculated); AUC = area under the drug
Tolerability
vative ratio of systemically available fluorouracil excreted in urine ( 1:10),14 the urinary excretion data suggest that the respective systemic absorption of 0.5% and 5% fluorouracil cream were 0.55% and 2.4%.
As stated, 3 patients in the fluorouracil 5% group discontinued treatment because of intolerable facial irritation. At least 1 adverse event was reported by 4 of 11 pa-
Table III. Mean
after topical
urinary
rouracil
cream
excretion (0.5%)
parameters and
k a Interval, h
0.5%
administration
of 0.5%
Cum Ae, u,g 5%
fluo-
5% fluorouracil cream (5%) (N = 20).
0.5%
Ex Rate, l~g/h 5%
0.5%
5%
0*
0.158
0.435
0.158
0.435
-
-
O-2
0.379
80.539
0.537
80.844
0.190
40.270 7.766
24
0.223
15.532
0.760
94.823
0.111
4-6
0.205
7.764
0.965
102.586
0.102
3.882
6-8
0.168
4.011
1.133
106.597
0.084
2.006
8-12
0.127
3.648
1.234
110.246
0.032
0.912
12-24
1.669
9.587
2.737
119.833
0.139
0.799
Ae = amount excreted; Cum Ae = cumulative amount excreted; Ex Rate = excretion rate. *Hour of the final dose.
914
S. LEVY ET AL.
tients in the 0.5% fluorouracil group and all 10 patients in the 5% fluorouracil group. The most common adverse events in the 0.5% fluorouracil group, occurring in 2 patients each, were application-site reaction, exfoliative dermatitis, and headache (Table IV). The most common adverse events in the 5% fluorouracil group were maculopapular rash, application-site reaction, and erythema. All adverse events were considered mild or moderate in severity. No serious adverse events were reported during the study. Other than application-site reactions, none of the adverse events were considered drug related. The time of onset of application-site reactions ranged from day 3 to day 25 in the 0.5% fluorouracil group and from day 5 to day 23 in the 5% fluorouracil group. The duration of these reactions ranged from 23 hours to 30 days in the 0.5% fluorouracil group and 15 minutes to 95 days in the 5% fluorouracil group. Fifty-five percent of patients in the 0.5% fluorouracil group had mild facial irritation at day 11, and 64% had moder-
ate irritation at day 14. At day 21,45% of patients had mild facial irritation, and 55% had moderate facial irritation. At the day-28 evaluation (end of treatment), 50% of patients in this group had mild irritation, and 50% had moderate irritation. In contrast, 80% of patients in the 5% fluorouracil group had moderate irritation at day 7. On day 11 and days 18 through 28, 100% of patients in the 5% fluorouracil group experienced moderate irritation, and there was no decline in the severity of irritation during the later interval (Figure 2).
DISCUSSION The results of this study suggest that fluorouracil has minimal systemic absorption after repeated topical administration. Plasma concentrations of both fluorouracil formulations were measurable in only 12 patients, 3 randomized to 0.5% fluorouracil and 9 randomized to 5% fluorouracil. Pharmacokinetic profiles were evaluable in only 1 of 3 patients in the 0.5% fluorouracil group and 6 of 9 patients in the 5% fluorouracil group. Given
Table IV Number (%) of adverse events reported in r2 patients after topical administration of 0.5% fluorouracil cream and 5% fluorouracil cream. 0.5% Pluorouracil Cream
Adverse Event Application-site reaction Dry skin Erytbema Exfoliative dermatitis Headache Maculopapular rash PIWihlS
Sweating
(n= 11) 2 (18) 0 (0) I (9) 2 (18) 2 (18) 1 (9) 1 (9) 0 (0)
5% Pluorouracil Cream (n = 10) 5 (50) 4 (40) 5 (50) 3 (30) 2 (20) 6 (60) 4 W) 2 (20)
915
CLINICAL THl3APEUTICS”
+ +
100 90 co E $
0.5% Fiuorouracil (n = 3) 5% Fluorouracil (n = 9)
1
80 70 -
d 3
80-
E8
40 50 -
8 $ a
30-
-
20 -
0
4
7
11
14
18
21
25
28
Day
Figure 2. Percentage
of patients with moderate facial irritation.
final doses of 5 and 50 mg after administration of 0.5% fluorouracil and 5% fluorouracil, respectively, a IO-fold difference in plasma concentrations would be anticipated. The AUC calculated for the 1 patient in the 0.5% fluorouracil group with evaluable plasma drug concentrations was -10% of that calculated for the 6 patients in the fluorouracil 5% group with evaluable plasma concentrations. However, a 1: 10 ratio may overestimate the true exposure to fluorouracil in the 0.5% fluorouracil group, because 9 patients in this group had undeterminable plasma pharmacokinetic profiles. In comparison with these findings on absorption after topical administration, a recent study reported that plasma concentrations ranged from 30 to 260 ng/mL after administration of infusions of fluorouracil 300 mg/m2 daily.15 An earlier study reported a mean peak plasma fluorouracil concentration of 0.8 mg/L in pa-
916
tients treated with a constant infusion of fluorouracil 600 mg/m2.16 In another study, after a 2Ominute infusion of fluorouracil 500 mg/m2, the mean AUC and peak plasma concentration were 436 mg/L per minute and 21 mg/L, respectively.17 However, there is wide interpatient variability in fluorouracil metabolism, and plasma concentrations of fluorouracil have been reported to vary greatly.18 Urinary pharmacokinetic data were evaluable in 5 patients receiving 0.5% fluorouracil and 9 patients receiving 5% fluorouracil. As with plasma concentrations, a lo-fold difference in excretion would be anticipated based on differences in the fluorouracil dose in each group. However, the mean absolute Cum Ae in patients receiving 5% fluorouracil cream (119.833 kg) was >40 times that in patients receiving 0.5% fluorouracil cream (2.737 pg). These results should be interpreted with caution because of the small number of
S. LEVY ET AL.
patients in whom urine concentrations were evaluable. In a recent in vitro study, Levy et al compared the flux and percutaneous absorption of the 0.5% fluorouracil formulation evaluated in the present study with those of 5% fluorouracil.19 In that study, the flux of the 5% formulation was -20 to 40 times higher than that of the 0.5% formulation, indicating that the flux over time in the in vitro study was comparable to the systemic exposure observed in the present pharmacokinetic study. The differences in the observed Cum Ae between the 2 formulations may be due to the variation in urine collection times, which occurred 12 hours after the last dose of twice-daily 5% fluorouracil and 24 hours after the last dose of oncedaily 0.5% fluorouracil. More residual fluorouracil may have been present in the urine of patients randomized to the 5% fluorouracil formulation. In addition, because the urine assay was volume dependent, a large volume could result in dilution below the limit of sensitivity of the assay. Alternatively, the difference in fluorouracil excretion between the 2 groups may represent true differences in the systemic absorption or bioavailability of the 2 preparations, possibly as a result of the different vehicles (eg, the Microsponge copolymers) used in the respective formulations. Vehicles are known to significantly affect the dermal absorption of active ingredients. Although this study did not address the availability of active drug to the different layers of the epidermis and dermis with the 2 formulations, Levy et al demonstrated that at 24 hours, -86% to 92% of 0.5% fluorouracil remained in the skin, compared with 55% of 5% fluorouracil, suggesting significantly less systemic absorption of the 0.5% fluorouracil formulation.19
In the present study, the calculated absorption rates for fluorouracil were lower in the 0.5% fluorouracil group compared with the 5% fluorouracil group (0.55% and 2.4%, respectively). These results differ somewhat from the findings of previous studies, in which -6% of the administered dose of radiolabeled 5 % fluorouracil was absorbed systemically, corresponding to a systemic absorption of 5 to 6 mg/lOO mg.9 In a study in which patients with warts were treated with a solution of 0.5% fluorouracil and 10% salicylic acid, the median extent of systemic absorption was 0.085% after a single application and 0.035% after multiple applications.20 In a study by Erlanger et al, the difference in absorption between healthy and diseased skin was evaluated by measuring the amount of drug excreted in the urine to indicate the quantity of drug absorbed from the skin after topical application of radiolabeled 5% fluorouracil.” Only a small percentage (0.3%-l. 1%) of a single dose (11.1-175.5 mg) was detected in the urine after application to healthy skin. However, when patients with diseased skin received similar or lower doses of 5% fluorouracil (11.1-63.2 mg). the percentage of the total dose excreted in the urine was higher (15.8%-61.2%). These data suggest that diseased skin absorbs 15 to 75 times more drug than healthy skin when applied at equal doses per unit of area.” The reasons for the discrepancy between earlier results and those of the present study may include differences in the disease states treated or the sensitivity of the urinary assays used, or the fact that +l of the previous studies did not distinguish between fluorouracil and its metabolic byproducts.9 The present study measured the parent compound only and thus may
917
CLINICAL THERAPEUTICS”
have underestimated absorption. However, use of a 1: 10 ratio of urinary excretion to the amount in systemic circulation is likely to have overestimated exposure with the 0.5% formulation. Possible limitations of this study include its open-label design, which may have biased the tolerability data and caused patients to associate more frequent administration of drug with increased facial irritation. Also, the low number of plasma and urine samples with measurable fluorouracil concentrations (1 and 5, respectively) may have led to overestimation of the systemic absorption of 0.5% fluorouracil. The 0.5% fluorouracil formulation appeared to be better tolerated than the 5% fluorouracil formulation. Of 14 patients reporting r 1 adverse event during the trial, 10 were treated with the 5% fluorouracil formulation. A higher percentage of patients in the 5% fluorouracil group experienced moderate facial irritation at each evaluation compared with patients in the 0.5% fluorouracil group, and fewer adverse events were reported by patients in the 0.5% fluorouracil group. All patients randomized to treatment with 0.5% fluorouracil completed the study, whereas 3 patients in the 5% fluorouracil group discontinued treatment after 18 days because of facial irritation. In addition, patients in the 0.5% fluorouracil group experienced a plateau or lessening of moderate facial irritation after 14 days of therapy, despite continued treatment. This effect was not observed in patients treated with 5% fluorouracil. A recent case report described an incident of life-threatening toxicity after administration of topical fluorouracil in a patient with severe DPD deficiency.‘* Thus, a fluorouracil formulation with less
918
systemic absorption may decrease the potential for serious adverse effects in such patients.
CONCLUSIONS Topical application of 2 fluorouracil formulations in patients with AK resulted in minimal systemic absorption, as evidenced by low measurable plasma and urine concentrations. The C,,, (0.768 ng/mL) and AUC (2.803 ngh/mL) were substantially lower for the 0.5% fluorouracil formulation than for the 5% fluorouracil formulation (11.492 ng/mL and 22.390 ng*h/mL, respectively). Because the mean Cum Ae of 0.5% fluorouracil (2.737 pg) was one fortieth that of 5% fluorouracil (119.833 pg), the systemic absorption of the former was estimated to be substantially lower than that of the latter. Furthermore, 0.5% fluorouracil cream appeared to be better tolerated than 5% fluorouracil cream. Facial irritation was mild to moderate with 0.5% fluorouracil cream throughout the treatment period; the incidence of moderate facial irritation reached a plateau or abated by day 14 despite continued treatment. In contrast, all patients receiving 5% fluorouracil cream experienced moderate irritation by day 11, and 3 patients in this group discontinued therapy after 18 days because of intolerable facial irritation. Although both formulations were associated with minimal systemic exposure, the delivery of the 0.5% formulation into the skin was associated with a lower potential for systemic exposure, suggesting a corresponding lower potential for systemic toxicities. It is unknown whether the favorable results with the 0.5% formulation were associated with the lower concentration itself or with a component of the vehicle formulation.
S. LEVY ET AL.
11. Erlanger M, Martz G, Ott F, et al. Cuta-
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SM. The treatment of actinic keratoses. J Am Acad Dermutol. 2000;42: S25-S28.
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N. New and emerging ments for photoaging. Dermatol 2000;18:99-112.
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9. Dillaha CJ, Jansen GT, Honeycutt
WM, Holt GA. Further studies with topical 5 fluorouracil. Arch Dermatol. 1965;92: 410-417.
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Address correspondence to: Sharon Levy, MD, Dermik Laboratories, Inc, 1050 Westlakes Drive, Benvyn,
920
PA 19312. E-mail: [email protected]