5-Methoxypsoralen (Bergapten) for photochemotherapy

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1 Volume 18 Number 2, Part 1 February 1988 Anxiety and anger in acne patients Worden TJ. The experience and expression of anger. In: Chesney MA, Rosenman R/I, Goldston SE, eds. Anger and hostility in cardiovascular and behavioral disorders. New York: Hemisphere/McGraw-Hill, Fenigstein A, Scheier MF, Buss AH. Public and private self-consciousness: assessment and theory. J Consult Clin Psychol 1974;43: Coopersmith F. Antecedents of self-esteem. San Francisco: WH Freeman, Lorenz TH, Gizaham DT, Wolf S. The relation of life stress and" emotions to human sebum secretion and the mechanism of ache vulgaris. J Lab Clin Med 1953;41: I _ II III I 5-Methoxypsoralen (Bergapten) for photochemotherapy Bioavailability, phototoxicity, and clinical efficacy in psoriasis of a new drug preparation Adrian Tanew, M.D., Bernhard Ortel, M.D., Klemens Rappersberger, M.D., and Herbert H6nigsmann, M.D. Vienna, Austria In a previous study we evaluated a microcrystalline preparation of 5-methoxypsoralen (5-MOP; Bergapten) for its photochemotherapeutic properties. Preliminary data indicated that the clinical efficacy of 5-MOP is comparable to that of 8-methoxypsoralen. 5-MOP appeared as a promising alternative photosensitizer for the management of psoriasis because of the almost complete lack of phototoxic and drug intolerance reactions that are frequently encountered in patients undergoing 8-MOP photochemotherapy. With a new liquid preparation of 5-MOP we have now extended our earlier investigation on a larger clinical scale and have correlated the clinical response with the bioavailability of the drug. Serum level determinations showed an absorption rate of only approximately 25% that of 8-MOP. When administered in the same dosage as 8-MOP, 5-MOP turned out to be significantly less effective; however, by doubling the oral dosage, comparable results in terms of clearing of psoriasis were obtained. Also with this high-dose 5-MOP regimen, no drug intolerance was noted and other side effects, such as severe erythema, pruritus, and nausea, occurred only rarely. We propose 5-MOP as a valuable alternative for photochemotherapy (PUVA) of PUVA-responsive diseases. (J AM ACAD DERMATOL 1988; 18:333-8.) In an earlier report we compared the efficacy of 5-methoxypsoralen (5-MOP) and From the Division of Photobiology, Department of Dermatology I, University of Vienna. Accepted for publication Aug. 17, Reprint requests to: Dr. Herbert Hrnigsmann, Division of Photobiology, Department of Dermatology I, University of Vienna, A1- serstrasse 4, A-1090 Vienna, Austria. 8-methoxypsoralen (8-MOP) in oral photochemotherapy (PUVA) for psoriasis.~ In this study a microcrystalline form of 5-MOP administered in two different dosages was shown to be equally effective as 8-MOP with regard to the number of exposures and total ultraviolet A (UVA) dose required for clearing psoriasis. The lower phototoxic potential and the complete lack of drug intolerance reactions, such as nausea and/or vomiting, were 333

2 334 Tanew et al Journal of the American Academy of Dermatology Table I. Treatment regimens Regimen Total number of patients Type of psoriasis l Acute guttate [ Chronic or seborrheic 1 plaque 5-MOP (33%) 39 (67%) 8-MOP (31%) 33 (69%) 5-MOP (33%) 42 (67%) considered as a definite advantage over 8-MOP. Since the availability of 5-MOP was limited at that time, the drug was not further evaluated despite its favorable properties. We have now had access to a new liquid preparation of 5-MOP in quantities sufficient to investigate the following issues: (1) the kinetics, the range, and the reproducibility of the serum levels; (2) the phototoxic (erythemogenic) properties of the new preparation; (3) the therapeutic efficacy in psoriasis; and (4) the spectrum and incidence of short-term side effects. MATERIAL AND METHODS Patients and treatment regimens A total of 169 patients was included in the study; they were randomly assigned to one of the three PUVA regimens listed in Table I. The distribution of skin types was almost identical in all treatment groups. In each group approximately one third of the patients had the acute guttate or seborrheic type of psoriasis and two thirds had chronic plaque-type psoriasis (Table I). In general, patients with the plaque type were treated with a retinoid-puva combination (RePUVA) regimen. Etretinate (Tegison, USA, Hoffmann-La Roche Inc., Nutley, N J; Tigason, Europe, F. Hoffmann-La Roche & Co., Basel, Switzerland) was administered in a dosage of 1 mg/kg body weight per day. Treatment with etretinate was started 5 days before the initiation of PUVA and lasted throughout the entire clearing phase. Drugs Both psoralens were used as a liquid preparation in soft gelatin capsules obtained by Gerot Pharmazeutika GmbH, Vienna, Austria. 8-MOP (Oxsoralen) was administered orally in a dose of 0.6 mg/kg 1 hour before irradiation and 5-MOP (investigational drug) was given in two different dosages, 0.6 mg and 1.2 mg/kg, 2 hours prior to irradiation. The patients were instructed to combine the drug intake with a high-fat meal to promote psoralen absorption. Serum level determinations 5-MOP serum levels were determined by highpressure liquid chromatography, as described earlier.-" Seventeen 24-hr serum profiles of 10 patients were evaluated. Blood was taken at intervals of 30 minutes and l, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after 5-MOP intake. The serum levels under therapeutic conditions, that is, 2 hours after drug ingestion, were studied in 263 samples of 28 patients under the low-dose 5-MOP regimen and 38 samples of 17 patients under the high-dose 5-MOP regimen. Ultraviolet sources A Waldmann PUVA 6000 and a WaIdmann PUVA 8001 (H. Waldmann; Werk fiir Lichttechnik, Schwennigen, Federal Republic of Germany), equipped with Sylvania FR 90 T 12 PUVA fluorescence bulbs, were used for the irradiations. Phototoxicity tests were performed with a Waldmann PUVA 500 irradiation unit. Phototoxicity testing and treatment protocol Minimal phototoxicity dose (MPD) testing and treatment were performed according to routine methods as described previously) Depending on skin type and psoralen dosage, the range of test irradiations was joules/era ~ (skin types I and II) or joules/era 2 (skin types Ili and IV) for 8-MOP and joules/cm 2 (all skin types, high drug dose) or 3-18 joules/cm 2 (all skin types, low drug dose) for 5-MOP. The MPD served as the initial UVA treatment dose. In patients with a negative MPD test, the initial exposure dose was determined arbitrarily according to skin typing. 4 During treatment the irradiation was adjusted according to the response of the psoriatic lesions. Treatment consisted of four PUVA exposures per week 1 hour (8-MOP) or 2 hours (5-MOP) after psoralen ingestion until complete clearing of psoriasis. RESULTS Serum levels Evaluation of the hour serum profiles in 10 patients confirmed the previous clinical experience that treatment is most effective if the UVA irradiation is performed 2 hours after drug administration, because a definite peak of the mean se-

3 Volume 18 Number 2, Part 1 February Methoxypsoralen for photochemotherapy ~a _ a, ' I ' I I ' I ' I I i ' I i ' I I ' I fo ~ 4 ~ Io 18, hours Fig MOP serum level profile (5-MOP dose: 0.6 mg/kg). Mean values over a time period of 24 hr. Peak formation occurs between 90 and 120 minutes. Table II. Serum levels of 8-MOP and 5-MOP at the time of irradiation* Table III. Minimal phototoxicity dose (MPD) (167 patients) No. of Mean serum Regimen samples level (ng/ml) NO. of patients tested Regimen reaction (joules/em 1) 5-MOP MOP MOP 87t _ 184t 8-MOP MOP MOP * 1 hr after S-MOP and 2 hr after 5-MOP administration. "tdata from H6nigsmann et al? Patients with MDP Mean MPD* *Mean values were calculated only from patients with positive reactions. rum concentration was found between 90 and 120 minutes after 5-MOP ingestion (Fig. 1). Thereafter the serum level curves exhibited a steep decline, and 5-MOP was almost completely eliminated from the serum after 12 hours. The mean serum level 2 hours after intake of 0.6 mg/kg 5-MOP was 80.5 ng/ml (Table II). This indicates an absorption rate of approximately 25% compared to that of liquid 8-MOP as reported by our group in a previous study'- in which we also found that the liquid preparation of 8-MOP peaks as early as 1 hour after ingestion. An increase of the 5-MOP dosage to 1.2 mg/kg led to a mean serum concentration of ng/ml 2 hours after ingestion (Table II). Similar to what has been reported for 8-MOP, 2,5'~ the 2-hour 5-MOP serum levels also showed considerable inter- and intraindividual variation. MPD testing The results of phototoxicity testing are shown in Table III. As expected from the serum level determinations, skin photosensitivity as assessed by the MPD reaction was clearly dependent on the 5-MOP dosage. A mean MPD of 6,4 joules/cm 2 was determined in the low-dose 5-MOP cohort as opposed to 3.5 joules/cm 2 in the high-dose group. The latter value came close to the mean MPD seen 1 hour after ingestion of 0.6 mg/kg 8-MOP, which was 2.7 joules/cm 2. Twenty-eight percent of the

4 336 Tanew et al Journal of the American Academy of Dermatology Table IV. Treatment results Regimen Total Total UVA number of dose patients (joules/cm 2) No. of exposures* Duration of treatment (days)* 5-MOP 58 (3)t 132 _--2-87~: 8-MOP MOP _ _+7 36 _ *All values significantly different from each other at the (!.05 level,?figure in brackets indicates number of treatment failures. :~Signifieantly different from the two other values at the 0.05 level (Tukey's Studentized Range Test). Table V, Side effects Frequency of side effects (%) 8-MOP* 5-MOP* (48 patients) (58 patients) 5-MOP* (63 patients) Severe erythema reaction 19% 0 3% Pruritus 17 % 0 3 % Nausea/vomiting 10% 0 0 Rash 0 0 8% *Of the 8-MOP group three patients had both erythema and nausea and one patient had erythema and pruritus. patients showed no MPD reaction within the range of test irradiations and were thus excluded from the calculation of the mean MPD. Treatment results The clinical efficacy of the two 5-MOP regimens and the 8-MOP regimen was assessed as a function of the total UVA dose, number of exposures, and time needed for inducing complete remission of psoriasis. These data are summarized in Table IV for each group. Since the percentage of patients who received a combination therapy with etretinate was roughly equal in all three groups, their data were not considered separately. The difference between the low-dose 5-MOP group and the two other groups was statistically significant for all three parameters of therapeutic efficacy. Also, with the high-dose 5-MOP regimen significantly more exposures and a longer treatment period were required for clearing patients compared to the 8-MOP regimen. However, with regard to the cumulative UVA dose, no signi- ficant difference was found between the highdose 5-MOP and 8-MOP-treated patient cohorts (Fig. 2). Treatment failures (3 patients with severe plaque psoriasis) were seen only in the low-dose 5-MOP group. Serum level determinations in two of these subjects yielded mean 5-MOP concentrations of 63.6 and 18.6 ng/ml, respectively. The switch to an 8-MOP-retinoid combination resulted in >195% clearing of all three patients. Short-term side effects Throughout the whole treatment period patients were continuously monitored for subjective and objective signs of short-term side effects. Severe erythema reaction, pruritus, and nausea were observed in 18 of the 48 patients treated with 8-MOP (Table V). No such side effects were associated with the low-dose 5-MOP regimen. Treatment with high-dose 5-MOP produced severe erythema and blistering in 2 of 63 patients; another two reported pruritus. No patient experienced nausea,

5 Volume 18 Number 2, Part 1 February Methoxypsoralen for photochemotherapy g0 b0 40 2(9 :q.,;,', ^ ^~., "~'fx? ;aa.a,%.%'>'3 ~A.aA r ^^^, GROUPS Fig. 2. Mean total UVA dose requirements (joules/era 2) for clearing psoriasis in the three treatment groups (1 = 5-MOP 0.6 mg/kg; 2 = 8-MOP 0.6 mg/kg; 3 = 5-MOP 1.2 mg/kg). although some overweight individuals received 5-MOP in single doses of 120 mg and more. A peculiar asymptomatic maculopapular rash appeared predominantly in the intertriginous areas of five high-dose 5-MOP patients within the first 2 weeks of treatment (Fig. 3), which, after persisting for a few days, spontaneously subsided without recurrence despite continuation of therapy. Biopsy specimens taken for histopathologic and immunofluorescent examination gave no clue as to the etiology of this phenomenon. The epidermis showed occasional sunburn cells and areas of spongiosis. Around the superficial dermal blood vessels a scanty lymphocytic infiltrate was present. Neither the characteristic features of phototoxic or photoallergic dermatitis nor the pattern of polymorphous light eruption were found. Direct immunofluorescence showed negative findings. Routine laboratory examinations, including screening for antinuclear antibodies, at the time of the skin eruption, did not reveal any pathologic finding. Another aspect of 5-MOP treatment was its marked potency of pigment induction. Tanning usually started earlier and became intense more rapidly than in patients treated with 8-MOP photochemotherapy. However, after completion of the clearing phase, the degree of pigmentation was comparable in all groups. Fig. 3. Maculopapular rash developing after six exposures to 5-MOP-PUVA (high dose) in a 27-year-old psoriatic patient. Note involvement of body folds. DISCUSSION 8-MOP photochemotherapy is widely accepted as one of the standard treatment modalities for severe forms of psoriasis. Not infrequently, however, its use is limited by drug intolerance manifesting as nausea and/or vomiting, or rendered more difficult because of its relatively narrow therapeutic range, which requires a very cautious UVA dosimetry especially in light-sensitive individuals. In a previous study a microcrystalline preparation of the naturally occurring 5-MOP appeared to be a promising alternative to 8-MOP because of its equal therapeutic effectiveness and the almost complete lack of acute side effects. I The reevaluation of 5-MOP in a new drug preparation on a larger clinical scale in combination with investigations on the kinetics of the 5-MOP serum concentration essentially confirmed our earlier findings. In addition, it allowed for a better characterization of the pharmacodynamic and phototherapeutic properties of this drug. The serum level determinations strongly indicated that the absence of phototoxic reactions reported previously is not due to lower phototoxic properties but presumably is related to the lower serum levels of 5-MOP compared to 8-MOP. Consequently, an increase of the 5-MOP dosage resalted in higher serum levels and also in an increased incidence of erythematous reactions, with a conesponding decrease of the mean minimal phototoxicity dose. Thus, the high-dose regimen resulted in MPD values that approximated

6 338 Tanew et al Journal of the American Academy of Dermatology the range of photosensitivity seen with 8-MOP treatment. In contrast to our earlier observation, 5-MOP, when given in the same dosage as 8-MOP, clearly was not as effective as 8-MOP in inducing remission of psoriasis. However, by doubling the dose of 5-MOP, the therapeutic results came close to those obtained with 8-MOP. In particular, there was no significant difference in the most important parameter, namely, the cumulative UVA dose required for clearing. Likewise, no treatment failures were found in the high-dose 5-MOP group. A comment should be made with regard to the RePUVA-treated patients. It is known from several studies that the combination of PUVA with retinoids shortens the treatment period and lowers the cumulative UVA dose required for clearing psoriasis. TM In the present study the patients were assigned either to PUVA or to RePUVA according to the severity of their disease: chronic plaque-type psoriasis patients most commonly received additional etretinate treatment and the seborrheic and eruptive type were preferentially treated with PUVA alone. Since there was a similar distribution of PUVA- and RePUVA-treated patients in all three groups and we were interested only in the effects of 5-MOP, their data were pooled for statistical comparison of the three regimens. 5-MOP was well tolerated by all patients and there was a very low incidence of pronounced phototoxic reactions. Most patients rapidly developed a cosmetically appealing tan. As a result there was a high patient acceptance in the 5-MOP-treated groups. In conclusion, 5-MOP may be considered a drug for routine photochemotherapy for psoriasis and, in particular, for the treatment of light-sensitive subjects and patients with 8-MOP intolerance. Moreover, due to its marked melanogenic potential, it may be of benefit in the management of photodermatoses and vitiligo. REFERENCES 1. H6nigsmann H, Jasehke E, Gschnait F, Brenner W, Fritseh P, Wolff K. 5-Methoxypsoralen (Bergapten) in photochemotherapy of psoriasis. Br J Dermatol 1979; 101: H6nigsmann H, Jaschke E, Nitsche V, Brenner W, Rausehmeier W, Wolff K. Serum levels of 8-methoxypsoralen in two different drug preparations: correlation with photosensitivity and UV-A dose requirements for photochemotherapy. J Invest Dermatol 1982;79: Henseler T, H6nigsmann H, Wolff K, Christophers E. Oral 8-methoxypsoralen photochemotherapy of psoriasis. The European PUVA study: a cooperative study among 18 European.centres. Lancet 1981;1: Current status of oral PUVA therapy for psoriasis. J AM AC.AD DSRMATOL 1979; 1 : Ljunggren B, Cartel" M, Albert J, Reid T. Plasma levels of 8-methoxypsoralen determined by high-pressure liquid chromatography in psoriatic patients ingesting drug from two manufacturers. J Invest Dermatol 1980;.74: Stolk L, Kammeyer A, Cormane RH, van Zwieten PA. Serum levels of 8-methoxypsoralen: difference between two oral methods of administration. Br J Dermatol 1980;103: Schiifer-Korting M, Korting HC. Intraindividual variations of 8-methoxypsoralen plasma levels. Arch Derrnatol Res 1982;272: Jans6n CT, Wil6n G, Ylitalo P, Malmiharju T. inter- and intraindividual variations in serum methoxsalen levels during repeated 0ral exposure. Curr Ther Res 1983; 33: Herfst MJ, De Wolff FA. Intraindividual and interindividual variability in 8-methoxypsoralen kinetics and effect in psoriatic patients. Clin Pharmaeol Ther 1983; 34:117-24, 10. De Wolff FA, Tholrias TV. Clinical pharmacokinetics of methoxsalen and other psoralens. Clin Pharmacokinet 1986; 11: I 1. Fritsch PO, H6nigsmann H; Jaschke E, Wolff K. Augmentation of oral methoxsalen photochemotherapy with an oral retinoie acid derivative. J Invest Dermatol 1978;70: Fritsch P, H6nigsmann H, Jascb.ke E, Wolff K. Photochemotherapie bei Psoriasis: Steigerung der Wirksamkeit dutch ein orales aromatisches Retinoid. Klinische Erfahrung bei 134 Patienten. Dtsch Med Woehensehr 1978; 103: Heidbreder G, Christophers E. Therapy of psoriasis with retinoid plus PUVA: clinical and histologic data. Arch Derrnatol Res 1979;264: Grupper C, Berretti B. Treatment of psoriasis by oral PUVA therapy combined with aromatic retinoid (Ro ; TigasonR). Dermatologica 1981;162: Lauharanta J, Juvakoski T, Lassus A. A clinical evaluation of the effects of an aromatic retinoid (Tigason), combination of retinoid and PUVA, and PUVA alone in severe psoriasis. Br l Derrnatol 1981;104: Grupper C, Berretti B. 5-MOP in PUVA and RE-PUVA. 250 patients with a follow-up of three years. In Farber EM, Cox AJ, Nail L, Jacobs PH, eds. Psoriasis. New York: Grune & Stratton, 1982:503-8.