Dermatologica 166: 136-140 (1983)@ 1983 S. Karger AG, Basel

OOII-9075/83/1663-b136$2.75/0

Possible Dosage Regimens for Topical Steroids, Assessed byVasoconstrictor Assays Using Multiple. Applications

R. Woodford,J.M. Haigh, B. W BarrySchool of Pharmacy, Portsmouth Polytechnic, Portsmouth, Hants., UK

Key Words. Topical steroids . Bioavailabilit~ and activity. Corticosteroids .Vasoconstrictor. Amcinonide . Dosage regimens

Abstract. The bioavailabilities and activities of three amcinonide preparations and Betno-vate cream were assessed using three multiple-dosage regimen .vasoconstrictor assays in10 volunteers. Applications were made once daily, twice daily and every alternate day withan initial three times daily loading dose applied on the first day only. Blanching responsesfirst increased and then decreased due to tachyphylaxis. It is proposed that clinicall1lhe mostadvantageous dosage regimen is a once daily application with no loading dose.

Patients may become resistant to topicalsteroids after constant use [7]. Such tachy-phylaxis has also been demonstrated in thevasoconstrictor assay for corticosteroids,with considerable recovery occurring if a

~rest period' intervenes in the dosage regi-men [2,4,5]. The authors' previous studiesusing a non-occluded multiple-dosage regi-men involveda three times daily application[2]: less frequent administration might pro-duce less marked tachyphylaxis. Lack ofclinical studies comparing the use of potenttopical steroids in twice daily, daily and al-ternate-day regimens [3] prompted investi-gation of such regimens in the repeated-ap-plication skin-blanching test.

Materials and Methods

Corticosteroid Formulations

Topical preparations (Cyanamid of Great Britain

Ltd.) containing amcinonide (16a., 17a.-cyclopentylide-nedioxy-9a.-fluoro-II~, 21-dihydroxy-1 ,4-pregnadiene-3,20-dione 21-acetate) were amcinonide cream, 0.1%,amcinonide cream, 0.025%, and amcinonide ointment,0.1 %. The 0.1 % formulations are marketed in Europe asPenticort. Betnovate cream (betamethasone velerate0.1 %) was employed as a standard preparation for com-parative purposes.

Volunteers

10 volunteers were selected ITom an experiencedpanel as those demonstrating consistency of response toa standard preparation (Betnovate cream) in the vaso-constrictor test [I]. None had received topical corticoste-roid application for at least 3 months prior to the study.

Topical Steroid Regimens Assessment by Vasoconstrictor Assays 137

Methods

Dosage Regimens. Each regimen included threeapplications on day 1, the loadingdose (at 0,4 and 7 h),the preparations thereafterbeing applied (days 2-5) ineach of three modes: (a) twice daily at 9.30 hand16.30 h; (b)once daily, at 9.30 h, and (c) on alternat~days, at 9.30 h on days 3 and 5. Days 6 and 7 were restperiods. From day 8, the procedurewas repeated at thesame sites, omitting two of the applications of theloading dose.

Application Procedure and Result Assessment.5 :!: 1mg of each formulationwere rubbed (1 min) intoa 7 x 7 mm area on each forearmof 10volunteers,usinga glassrod, and with referenceto a randomization chart.Holes in a plastic sheet located the application sites:indelibleinkmarkersfacilitatedsubsequentapplication.Blanching was estimated using a ()...4scale with half-point ratings forintermediate readings: 0 =normal skin;1=slight vasoconstriction of indistinct outline;2 =more intense vasoconstriction with at least twocornersoutlined; 3=generalevenvasoconstrictionwitha clear outline of the square;4 =more marked vasocon-striction with very distinct blanching.

Double-blind estimations of skin blanching weremade at each application time immediately before re-applying the formulationsand at additional times indi-cated on the figure.Siteswereunguardedand volunteerslivednorm~ soas to mimicdomiciliaryuse of topicalsteroids.

Results and Discussion

The results were summed for all volun-teers at each time, expressedas a percentageof the total possible score [1] and wereplotted as functions of time. Results for allfour steroid preparations were similar there-fore only those for amcinonide cream 0.1%are shown ~s an example (fig. 1).

The blanching responses are in table I.The results for the individual scores in eachpreparation/regimen were submitted to acomputer-assisted analysis of variancefollowed by applicatioQ of the Studentizedrange test on the preferred 'square root trans-formation' data [1, 10]. Statistically signifi-

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Fig. 1. Blanching profiles for amcinonide cream0.1% in daily (a) alternate-day (b) and twice daily (c)regimens. An arrow representssteroid application anda line indicates an additional readingtime.

t HC =amcinonide cream, 0.1%; LC = amcinonide cream, 0.025%; 0 = amcinonide ointment, 0.1%; BV =

Betnovate cream; A = daily application; B = twice daily; C = alternate day.2 Obtainedby planimetry ofthe blanching profiles.3 The sum ofthe scoresfor all volunteers over all reading times.4 The sum of the % total possible scores for all volunteers over all readingtimes.5 The Tmil 0 mean value is the square root transformation of the sum of scores (Tm) divided by the number ofvolunteers (10).The minimum significant range value k =1.53 (p = 0.05), i.e. if two Tm/lO vaprls differby morethan 1.53 there is a significant difference between the two preparations/regimens [6].

cant differencesexisted between the values(F = 1.91,p < 0.05), the minimum signifi-cant range value k being 1.53 (p=0.05,12 means, 99 d. f.).

The three times daily application onday 1 produced a large blanching responseand subsequent application caused tachy-phylaxis, irrespective of potency or dosageregimen. Sites recovered over days 6 and 7and the blanching profiles obtained duringthe second week showed a lower degree oftolerance than for days 1-5 (fig. 1). The in-cidence of tachyphylaxis in the second weekwas less than that demonstrated by Barryand Woodford [2] using the more drasticregimen of three times daily application.The areas under the blanching curves for

both weeksweresimilar, mean values for thefirst week being 49.1% (range 45.7-54.4%,depending on formulation/regimen) and forthe second week, 50.9%(range45.6-54.3%)of the total values (table I).

The rank order of blanching effectivenessfor the application regimens was (a) amcin-onide cream 0.025% and Betnovate cream:twice daily> daily> alternate day; (b)am-cinonide cream 0.1% and ointment 0.1%daily> twice daily> alternate da:Statistical analysis suggested that the 0.1~cream was significantly more potent(p =0.05) (a) in the once daily regimen thanwhen applied on alternate days,and (b)thanamcinonide cream 0.025% and Betnovatecream applied in the once daily mode.

138 Woodford/Haigh/Barry

Table I. Blanchingresponse to each preparation used in each regimen

Preparation Area under Total Summed% Tm/lOand the curve score3 total possible meanregiment (%x b)2 score4 valueS

HC/A 7,580 981 1,226 9.77HC/B 6,170 798 998 8.84HC/C 5,260 684 854 8.20LC/A 4,980 637 796 7.90LC/B 5,230 669 836 8.07LC/C 3,920 494 619 6.97O/A 6,210 799 998 8.84O/B 5,750 740 925 8.46O/C 5,040 629 786 7.86BV/A 4,130 516 644 7.10BV/B 4,870 625 781 7.78BV/C 3,840 472 589 6.76

Topical Steroid Regimens Assessment by Vasoconstrictor Assays 139

Amcinonide ointment was significantlymore potent than Betnovate cream in theonce daily regimen.

Clinical Significance: Preftrred DosageRegimenResults suggest that once daily applica-

tion should be preferred clinically to twicedaily use.for the followingreasons.

(1) It was the only regimen permittingstatistical differentiation at the 5% levelbetween formulations,e.g. .the apparentsuperiority of the 0.1% cream over the0.025% preparation and Betnovate cream.This confirms potency classificationsprevi-ously obtained in the single6 hour occludedvasoconstrictor assay of (a) the 0.1% amcin-onide preparations'being 'very potent' by theUnited Kingdom Mims classification [8],and (b)the 0.025%and Betnovatecreams as'potent' [10, 11].

(2) Less total steroid would be applied,

thus miniJPising unwanted side-effects oftopical cifrticosteroid therapy.

(3) Once daily application should facili-tate patient compliance and the use ofsmaller quantities is more economic.

(4) If therapy commenced with amcino-nide cream 0.1% in a once daily regimen(this preparation/regimen produces thelargest blanching parameters), once thecondition was stabilised it could be main-tained by changing to the 0.025% formula-tion. Because three times daily applicationijn day 1 produced considerable tachyphy-~s not evident on day 8 it may be advan-t,ageousin the clinical situation to omit theIt>ading dose.

The observation [9] that once daily appli-cation of 0.1% halcinonide cream was

almost as effective as three times daily appli-cation in atopic dermatitis suggests that less

frequent use of very potent formulations incertain skin disorders may be preferable.

Bioavailability of 0.1% PreparationsAmcinonide ointment 0.1% was rather

less effective than the corresponding creamin all dosage regimens (table I). This agreeswith the formulation of these two prepara-tions: both contain the steroid completely insolution, but whereas it is nearing saturationin the cream, the ointment system is less sat-urated [Cyanamid of Great Britain, personalcommun.].

Acknowledgement

JMH acknowledgesthe award of a bursarytrom theSouth Mrican Council for Scientific and IndustrialResearch.

References

1 Barry, B.W; Woodford, R.: Comparative bioavail-ability of proprietary topical corticosteroid prepa-rations; vasoconstrictor assays on thirty creams andgels. Br. J. Derm. 91: 323-338 (1974).

2 Barry, B.W.; Woodford, R.: Vasoconstrictor activi-ties and bioavailabilities of seven proprietary corti-costeroid creams assessed using a non-occluded;

multiple dosage regimen; clinical implications. Br. J.,Derm. 97: 555-560 (1977).

3 Cornell, R.C.; Stoughton, R.B.: Use of glucocorti-costeroids in psoriasis. Pharmacol. Ther. 11:497-508 (1980).

4 Du Vivier, A; Stoughton, R.B.: Tachyphylaxis tothe action of topically applied corticosteroids.Archs. Derm. 111: 581-583 (1975). ,.,

5 Du Vivier, A; Stoughton, R.B.: Acute tolerance toeffects of topical glucocorticosteroids. Br. J. Derm.94: suppl. 12, pp. 25-32 (1976).

6 Goldstein, A: Biostatistics: an introductory text(Macmillan, New York 1964).

7 Miller, J.A; Munro, D.D.: Topical corticosteroids:clinical pharmacology and therapeutic use. Drugs19: 119-134 (1980).

140 Woodford/Haigh/Barry

8 Mims(MonthlyIndex of Medical Specialities)Feb.,pp. 258-259 (1982).

9 Sudilovsky, A.; Muir, J.G.; Bocobo, F.e.: Acomparison of single and multiple applications ofhalcinonide cream. Int. J. Derm. 20: 609-613(1981~ .

10 Woodford, R.; Barry, B.W.: Activity and bioavail-

ability of amcinonide and triamcinolone acetonidein experimental and proprietary topical prepara-tions. Curr. ther. Res. 21: 877-886 (1977).

II Woodford, R.; Haigh, J.M.: Bioavailability andactivity of 0.1% amcinonide preparations: compar-

ison with proprietary topical corticosteroid formula-tions of differing potencies. Curr. ther. Res. 26:301-310 (1979).

Received: September I, 1980Accepted: July I, 1982

Dr. R. Woodford,School of Pharmacy,Portsmouth Polytechnic,King Henry I Street,Portsmouth, Hants. POI 2DZ (UK)