- Email: [email protected]
Pharmacokinetics and safety of tazarotene
PRESENTED AT THE SYMPOSIUM “NEW DIRECTIONS IN THE TREATMENT OF PSORIASIS, ACNE, AND SKIN AGING,” SUPPORTED BY AN UNRESTRICTED EDUCATIONAL GRANT FROM ALLERGAN, INC.
Pharmacokinetics and safety of tazarotene Alan Menter, MD Dallas, Texas The pharmacokinetic profile of tazarotene helps to ensure that systemic exposure to the drug and its metabolites is minimal. First, percutaneous penetration is limited, with less than 6% of the applied drug being absorbed into the bloodstream. Second, tazarotene is rapidly metabolized into tazarotenic acid and other metabolites that are not lipophilic. Third, tazarotene and its metabolites are rapidly eliminated from the blood in the urine and feces. These three pharmacokinetic features help to ensure that post-treatment plasma levels of tazarotene and its metabolites are comparable to those of endogenous retinoids, which suggests that the risk of teratogenic effects is minimal. Limited systemic exposure to the drug also ensures that any adverse effects are local effects rather than systemic effects. Overall, tazarotene has a good safety profile and is not associated with contact sensitization, phototoxicity, photoallergic reactions, mutagenicity, or carcinogenicity. (J Am Acad Dermatol 2000;43:S31-5.)
T
azarotene is the only topical retinoid indicated for plaque psoriasis in the United States and is the most recent topical retinoid to be indicated for acne vulgaris. In psoriasis, tazarotene appears to modulate the three main pathogenic features of psoriasis: abnormal differentiation of keratinocytes, hyperproliferation of keratinocytes, and inflammation.1 Acne vulgaris also involves abnormal keratinization and inflammation. In acne, tazarotene is thought to help normalize the abnormal keratinization in the follicular epithelium that leads to the formation of microcomedones. Furthermore, by improving the microenvironment of the follicle in this way (which helps to prevent follicular blockage), tazarotene is thought to help reduce the proliferation of Propionibacterium acnes. The efficacy of tazarotene in both psoriasis and acne has been widely reported2-8 and, in both indications, adverse events are generally limited to local irritation of the skin. The topical delivery of tazarotene helps to minimize systemic exposure to the drug and thus helps to promote a safety profile that is superior to that of orally administered retinoids. Other aspects of the pharmacokinetic profile of tazarotene, relating to its metabolism and elimination, are also important in maximizing its From the Baylor Psoriasis Research Center, Dallas. Supported by Allergan Skin Care. Reprint requests: Alan Menter, MD, Chairman, Division of Dermatology, Baylor University Medical Center, 3500 Gaston Ave, Dallas TX 75246. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/0/108321 doi:10.1067/mjd.2000.108321
safety profile and ensuring that its safety is comparable with that of other topical retinoids.
PHARMACOKINETICS Absorption The majority of topically applied tazarotene remains on or in the skin. Less than 1% of a dose of [14C]tazarotene is absorbed within 10 hours of application on unoccluded psoriatic skin,9 and less than 6% of a dose of [14C]tazarotene is absorbed within 10 hours of application on occluded normal skin.10 Metabolism Tazarotene is a prodrug that is metabolized in the skin and plasma to its active form, tazarotenic acid, and to sulfoxides, sulfones, and other polar metabolites (Fig 1). The limited percutaneous penetration of tazarotene, together with its rapid metabolism to hydrophilic metabolites, helps to prevent accumulation of the drug in lipophilic tissues of the body. Elimination The elimination half-life for tazarotene and its metabolites is approximately 17 to 18 hours,9,10 and urinary and fecal elimination are virtually complete within 2 to 3 days and 7 days of dosing, respectively.11 This short time of residence in the body, together with the limited percutaneous penetration, results in plasma levels of tazarotene and tazarotenic acid remaining low. As with other retinoids, this is important in minimizing any potential risk for teratogenicity.
SAFETY Because the topical delivery and pharmacokinetic profile of tazarotene help to minimize systemic S31
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Fig 1. Known metabolic pathways of tazarotene. (Reproduced from Tang-Liu DD-S, Matsumoto RM, Usansky JI. Clinical pharmacokinetics and drug metabolism of tazarotene: A novel topical treatment for acne and psoriasis. Clin Pharmacokinet 1999;37:273-87.)
exposure to the drug and its metabolites, tazarotene therapy has little potential for systemic adverse effects, such as skeletal changes and serum lipid elevations, associated with oral retinoids. As with other topical retinoids, adverse events in phase III clinical trials with tazarotene have been limited to local effects, with the most frequently reported adverse events being erythema, pruritus, and burning/stinging in patients with psoriasis,2-4 and a burning sensation, desquamation, dryness, and erythema in patients with acne.7 These were dose-related and generally mild-to-moderate in severity. There have been no consistent, clinically significant drugrelated changes in hematology, blood chemistry, urinalysis, or bone radiographs.9,12 Phase I safety studies have shown that topical tazarotene treatment does not result in contact sensitization, phototoxicity, or photoallergic reactions.5 Results of several mutagenicity tests (Ames, chromosomal aberration, and micronucleus) have also indicated that tazarotene is nonmutagenic and has no chromosomal or clastogenic effects.13 In addition, no carcinogenic effects have been observed in either
a 21-month study with topically applied tazarotene in mice or a 2-year study with orally administered tazarotene in rats.13 Moreover, tazarotene has recently been shown to have anticarcinogenic activity: in a study of 20 patients with basal cell carcinoma, daily applications of tazarotene 0.1% gel for up to 8 months resulted in a complete response in 53% of lesions and a partial response in the remaining 47% of lesions.14 Potential for teratogenicity Extrapolation of the absorption data mentioned earlier, and clinical analyses of post-treatment plasma levels of tazarotene and tazarotenic acid, both suggest that tazarotene has minimal potential for teratogenicity. Extrapolating from the absorption data, if 1% of a dose of tazarotene is absorbed across unoccluded psoriatic skin, and assuming that tazarotene 0.1% gel is applied at a thickness of 2 mg/cm2 to 20% of the estimated body surface area of 1.7 m2 of a 70 kg person, then the total systemic exposure to tazarotene plus tazarotenic acid would be approximately 1000 ng/kg/day.1* In addition, if it is assumed
* 0.01× 2 × (0.2 × 1.7 × 10000) = 1 mg gel/kg/day = 1000 ng active compound/kg/day 70
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Table I. Comparison of endogenous plasma retinoid levels with those after repeated applications of tazarotene gel Retinoid and dosage regimen
Endogenous retinoids No treatment16,17 Tazarotene 0.1% gel q.d. for 7 days to 20% of BSA9 0.05% gel q.d. for 12 weeks to 5%-15% BSA9 0.1% gel q.d. for 12 weeks to 5%-15% BSA9 0.1% gel q.d. for 26 days to face15 0.05% or 0.1% gel q.d. for 12 weeks to face7
Subjects’ skin condition
Mean plasma retinoid concentration (ng/mL)
Mean Cmax ± SD (ng/mL)
Absolute Cmax (ng/mL)
Healthy volunteers
1.32-2.36 (all-trans-RA); < 1.0-1.63 (13-cis-RA); 3.68 (4-oxo-13-cis-RA)
—
—
Healthy volunteers
—
—
Plaque psoriasis
—
Plaque psoriasis
—
Facial acne vulgaris
—
0.72 ± 0.58 (tazarotenic acid) 0.45 ± 0.78 (tazarotenic acid) 0.83 ± 1.22 (tazarotenic acid) 0.14* ± 0.11 (tazarotenic acid) —
Facial acne vulgaris
≤ 0.05 (tazarotene); ≤ 0.05 (tazarotenic acid)
— — — 0.22 (tazarotene); 0.13 (tazarotenic acid)
BSA, body surface area; Cmax, maximum plasma level; q.d., once daily; RA, retinoic acid. *Mean Cmax after last dose.
Table II. Comparison of plasma retinoid levels after administration of tretinoin, adapalene, and isotretinoin Retinoid and dosage regimen
Tretinoin 0.05% cream q.d. for 28 days to face17 0.1% cream q.d. for 26 days to face18 Adapalene 0.1% gel q.d. for 26 days to face18 Isotretinoin 80 mg orally19 80 mg orally19
Subjects’ skin condition
Mean plasma retinoid concentration (ng/mL)
Mean Cmax ± SD (ng/mL)
Absolute Cmax (ng/mL)
Healthy volunteers
2.60 (all-trans-RA)
—
—
Facial acne vulgaris
—
2.6 ± 0.4 (all-trans-RA); 0.5 ± 0.6 (13-cis-RA); 1.6 ± 0.7 (4-oxo-13-cis-RA)
Facial acne vulgaris
0.04 ± 0.03 (adapalene)
Healthy volunteers Acne
256 (13-cis-RA) 262 (13-cis-RA)
459 (13-cis-RA) 535 (13-cis-RA)
Cmax, maximum plasma level; q.d., once daily; RA, retinoic acid.
that the entire amount of drug to which a patient is exposed per day is present in the blood at the same time, and that this 70 kg person has a plasma volume of 3500 mL, then the plasma concentration would be expected to be no higher than 20 ng/mL. However, in practice, elimination of drug from the blood will likely reduce this concentration (the elimination half-life for tazarotene and its metabolites being approximately 17-18 hours) and it would be highly unusual for the gel to be applied to as large a proportion of the body surface area as the 20% coverage that was assumed in this calculation. Furthermore, in facial acne, the area of skin to which gel is applied is
substantially lower than it is in psoriasis (the face represents approximately 2% of body surface area), and this would also result in a lower plasma retinoid concentration. Analyses of plasma levels of tazarotenic acid in healthy volunteers who applied tazarotene 0.1% gel to 20% of their body surface area once daily for 7 days demonstrate that mean maximum plasma levels are actually no more than 0.72 ng/mL (Table I).9 Similarly, in patients with psoriasis treated with tazarotene 0.1% gel for 12 weeks, the mean maximum plasma level of tazarotenic acid has been reported to be 0.83 ng/mL (and 0.45 ng/mL with
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tazarotene 0.05% gel).9 Therapeutic drug monitoring throughout clinical efficacy studies of 601 patients with psoriasis treated with one of the tazarotene gels revealed that only 4 patients had quantifiable concentrations of tazarotene (all were ≤ 0.12 ng/mL).9 Approximately 50% of the plasma samples taken from the 601 patients showed levels of tazarotenic acid to be below the limit of quantitation (< 0.05 ng/mL), whereas approximately 90% of the samples showed levels to be less than 1 ng/mL. The highest level observed in any patient was 6.1 ng/mL. Thus, these data all indicate that the actual plasma levels of tazarotenic acid attained during treatment are considerably lower than the potential levels calculated previously using the “maximum application scenario” where the gel is applied to 20% of the body surface area. The smaller surface area of treated skin in patients with acne will in all likelihood lead to lower plasma levels of tazarotenic acid than in patients with psoriasis. In one study of patients with acne treated with daily applications of tazarotene 0.1% gel to the entire face, the mean maximal plasma level of tazarotenic acid after the last application on day 26 was 0.14 ng/mL.15 Similarly, the highest reported plasma levels of tazarotene and tazarotenic acid during therapeutic drug monitoring in a 12-week study were 0.22 ng/mL and 0.13 ng/mL, respectively.7 Tazarotene was detectable (> 0.05 ng/mL) in the plasma in only 5% (4/86) of these patients with acne, and tazarotenic acid was detectable in 16% (12/76) of the patients. These data show that the levels of tazarotene and tazarotenic acid are comparable to the endogenous levels of retinoids; in healthy volunteers, the mean plasma levels of endogenous retinoids have been reported to be at least 5 ng/mL for all-trans-retinoic acid, 13-cis-retinoic acid, and 4-oxo-13-cis-retinoic acid combined (Table I).16,17 Similarly, the tazarotene post-treatment data are comparable to the posttreatment plasma retinoid levels after therapy with tretinoin or adapalene (Table II).17-19 Although it is difficult to know with certainty what plasma level of any retinoid might be associated with a clinically relevant risk of teratogenicity, oral isotretinoin treatment results in retinoid plasma levels that are approximately 100-fold higher than those after topical retinoid treatment. This highlights the much higher risk of teratogenicity with oral retinoids than with topical retinoids. Even though applications of tazarotene, tretinoin, and adapalene result in similarly low plasma retinoid levels, the FDA has categorized tretinoin and adapalene as Category C drugs and tazarotene as a Category X drug. The Category C definition indicates
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that such a drug “should be used only if the potential benefit justifies the risk” or “should be given to a pregnant woman only if clearly needed.” Such a categorization means that no human studies exist and that animal studies may exist that show an adverse effect. The Category X definition indicates that such a drug “may or can cause fetal harm when administered to a pregnant woman… and is contraindicated in women who are or may become pregnant.” Such a categorization means that fetal abnormalities have been demonstrated in either animals or humans. Nevertheless, tazarotene-related fetal abnormalities are not known to have occurred in humans. At least 6 women are known to have become pregnant during clinical studies with tazarotene (despite instructions to the contrary) and all reported the birth of healthy babies.2,20 However, because the timing and extent of exposure in relation to the gestation time are not certain, the significance of these findings is not known. As with other retinoids, oral doses of tazarotene given to experimental animals have resulted in developmental delays in rats. Also, teratogenic effects and post-implantation fetal loss have been observed in rats and rabbits at doses producing 0.7 and 13 times, respectively, the systemic exposure (AUC0-24hrs) in patients with psoriasis, when extrapolated for topical treatment of 20% of body surface area. The reasons for the different category classifications among retinoids are partially historical and partially because, unlike tretinoin or adapalene, tazarotene was simultaneously approved for use in both acne and psoriasis. Because of this dual approval, and because tazarotene is likely to be used on a larger surface area in patients with psoriasis than are any of the topical retinoids in patients with acne, tazarotene received just one category for pregnancy labeling—one that was based on psoriasis pharmacokinetic data (ie, with coverage of up to 20% body surface area) rather than acne pharmacokinetic data (which were not available at the time and which would involve a smaller area of application). The FDA itself recognizes that its categories for labeling teratogenicity potential are not optimal and it is reviewing the current classification system. Meanwhile, many dermatologists (including the author) do not refrain from prescribing tazarotene for the topical treatment of psoriasis in female patients of childbearing potential as long as the patients are fully informed of the potential risks and are fully compliant in using reliable contraceptive measures. Patients should be advised to discontinue therapy immediately if pregnancy still occurs despite these precautions. However, because of the rapid elimination of tazarotene and its metabolites from
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the blood, evidence so far does not indicate any necessity for women wishing to become pregnant to undergo a washout period after discontinuing tazarotene therapy.9
DISCUSSION Topical treatment with tazarotene gel results in extremely limited systemic exposure to tazarotene and its metabolites. This is because: the vast majority of the applied dose is not absorbed into the bloodstream; tazarotene is rapidly metabolized into its active form, tazarotenic acid, and other hydrophilic metabolites that do not accumulate in lipophilic tissues; and tazarotene and its metabolites are rapidly eliminated from the plasma via the urine and feces. Because of this pharmacokinetic profile, the plasma levels of tazarotene and tazarotenic acid are approximately 100-fold lower than plasma retinoid levels after oral isotretinoin treatment. Tazarotene thus has a far superior safety profile than that of oral isotretinoin. Importantly, the plasma levels of tazarotene and tazarotenic acid are not only comparable to plasma retinoid levels after tretinoin and adapalene treatment, but are also comparable to those of endogenous retinoids. This suggests that the teratogenic potential of tazarotene treatment is minimal. Nevertheless, because the risk cannot be eliminated completely, it is important that women of childbearing potential use reliable contraceptive measures throughout the treatment period. REFERENCES 1. Duvic M, Asano AT, Hager C, Mays S. The pathogenesis of psoriasis and the mechanism of action of tazarotene. J Am Acad Dermatol 1998;39(suppl):S129-33. 2. Weinstein GD, Krueger GG, Lowe NJ, Duvic M, Friedman DJ, Jegasothy BV, et al. Tazarotene gel, a new retinoid, for topical therapy of psoriasis: vehicle-controlled study of safety, efficacy, and duration of therapeutic effect. J Am Acad Dermatol 1997; 37:85-92. 3. Lebwohl M, Ast E, Callen JP, Cullen SI, Hong SR, Kulp-Shorten CL, et al. Once-daily tazarotene gel versus twice-daily fluocinonide cream in the treatment of plaque psoriasis. J Am Acad Dermatol 1998;38:705-11.
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4. Lebwohl MG, Breneman DL, Goffe BS, Grossman JR, Ling MR, Milbauer J, et al. Tazarotene 0.1% gel plus corticosteroid cream in the treatment of plaque psoriasis. J Am Acad Dermatol 1998; 39:590-6. 5. Duvic M.Tazarotene: a review of its pharmacological profile and potential for clinical use in psoriasis. Exp Opin Invest Drugs 1997;6:1537-51. 6. Guenther LC. Tazarotene, a receptor-selective topical retinoid, in the treatment of psoriasis.Today Ther Trends 1999;17:133-45. 7. Shalita AR, Chalker DK, Griffith RF, Herbert AA, Hickman JG, Maloney JM, et al. Tazarotene gel is safe and effective in the treatment of acne vulgaris. Cutis 1999;63:349-54. 8. Bershad S, Poulin YP, Berson DS, Sabean J, Brodell RT, Shalita AR, et al. Topical retinoids in the treatment of acne vulgaris. Cutis 1999;64(2S):1-23. 9. Tang-Liu DD-S, Matsumoto RM, Usansky JI. Clinical pharmacokinetics and drug metabolism of tazarotene. Clin Pharmacokinet 1999;37:273-87. 10. Franz TJ, Lehman PA, Franz S, Lew-Kaya DA, Matsumoto R, TangLiu D. Percutaneous absorption of AGN 190168 0.1 gel, a new synthetic retinoid, through human skin in vivo [abstract]. J Invest Dermatol 1992;98:650. 11. Marks R. Pharmacokinetics and safety review of tazarotene. J Am Acad Dermatol 1998;39(suppl):S134-8. 12. NDA 20-600. Approved June 13, 1997. 13. Chandraratna RAS. Tazarotene: the first receptor-selective topical retinoid for the treatment of plaque psoriasis. J Am Acad Dermatol 1997;37(suppl):S12-S17. 14. Peris K, Fargnoli MC, Chimenti S. Preliminary observations on the use of topical tazarotene to treat basal-cell carcinoma. N Engl J Med 1999;341:1767-8. 15. Yu Z, Matsumoto RM, Sefton J, Lew-Kaya D, Kopper S, Walker PS, et al. Pharmacokinetics of tazarotene in female patients with facial acne following facial application of 0.1% tazarotene gel for 28 days. Poster presented at the 58th Annual Meeting of the American Academy of Dermatology, March 10-15, 2000, San Francisco, CA. 16. Eckhoff C, Nau H. Identification and quantitation of all-transand 13-cis-retinoic acid and 13-cis-4-oxoretinoic acid in human plasma. J Lipid Res 1990;31:1445-54. 17. Latriano L,Tzimas G,Wong F,Wills RJ.The percutaneous absorption of topically applied tretinoin and its effect on endogenous concentrations of tretinoin and its metabolites after single doses or long-term use. J Am Acad Dermatol 1997;36(suppl): S37-S46. 18. Data on file, Allergan Inc. Study 022. 19. Physicians’ Desk Reference, 2000. Medical Economics Company, Montvale, NJ; pp. 502-3. 20. Tazorac® patient package insert. Irvine, Calif 92612 USA, Allergan, Inc., 1997.
Pharmacokinetics and safety of tazarotene Alan Menter, MD Dallas, Texas The pharmacokinetic profile of tazarotene helps to ensure that systemic exposure to the drug and its metabolites is minimal. First, percutaneous penetration is limited, with less than 6% of the applied drug being absorbed into the bloodstream. Second, tazarotene is rapidly metabolized into tazarotenic acid and other metabolites that are not lipophilic. Third, tazarotene and its metabolites are rapidly eliminated from the blood in the urine and feces. These three pharmacokinetic features help to ensure that post-treatment plasma levels of tazarotene and its metabolites are comparable to those of endogenous retinoids, which suggests that the risk of teratogenic effects is minimal. Limited systemic exposure to the drug also ensures that any adverse effects are local effects rather than systemic effects. Overall, tazarotene has a good safety profile and is not associated with contact sensitization, phototoxicity, photoallergic reactions, mutagenicity, or carcinogenicity. (J Am Acad Dermatol 2000;43:S31-5.)
T
azarotene is the only topical retinoid indicated for plaque psoriasis in the United States and is the most recent topical retinoid to be indicated for acne vulgaris. In psoriasis, tazarotene appears to modulate the three main pathogenic features of psoriasis: abnormal differentiation of keratinocytes, hyperproliferation of keratinocytes, and inflammation.1 Acne vulgaris also involves abnormal keratinization and inflammation. In acne, tazarotene is thought to help normalize the abnormal keratinization in the follicular epithelium that leads to the formation of microcomedones. Furthermore, by improving the microenvironment of the follicle in this way (which helps to prevent follicular blockage), tazarotene is thought to help reduce the proliferation of Propionibacterium acnes. The efficacy of tazarotene in both psoriasis and acne has been widely reported2-8 and, in both indications, adverse events are generally limited to local irritation of the skin. The topical delivery of tazarotene helps to minimize systemic exposure to the drug and thus helps to promote a safety profile that is superior to that of orally administered retinoids. Other aspects of the pharmacokinetic profile of tazarotene, relating to its metabolism and elimination, are also important in maximizing its From the Baylor Psoriasis Research Center, Dallas. Supported by Allergan Skin Care. Reprint requests: Alan Menter, MD, Chairman, Division of Dermatology, Baylor University Medical Center, 3500 Gaston Ave, Dallas TX 75246. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/0/108321 doi:10.1067/mjd.2000.108321
safety profile and ensuring that its safety is comparable with that of other topical retinoids.
PHARMACOKINETICS Absorption The majority of topically applied tazarotene remains on or in the skin. Less than 1% of a dose of [14C]tazarotene is absorbed within 10 hours of application on unoccluded psoriatic skin,9 and less than 6% of a dose of [14C]tazarotene is absorbed within 10 hours of application on occluded normal skin.10 Metabolism Tazarotene is a prodrug that is metabolized in the skin and plasma to its active form, tazarotenic acid, and to sulfoxides, sulfones, and other polar metabolites (Fig 1). The limited percutaneous penetration of tazarotene, together with its rapid metabolism to hydrophilic metabolites, helps to prevent accumulation of the drug in lipophilic tissues of the body. Elimination The elimination half-life for tazarotene and its metabolites is approximately 17 to 18 hours,9,10 and urinary and fecal elimination are virtually complete within 2 to 3 days and 7 days of dosing, respectively.11 This short time of residence in the body, together with the limited percutaneous penetration, results in plasma levels of tazarotene and tazarotenic acid remaining low. As with other retinoids, this is important in minimizing any potential risk for teratogenicity.
SAFETY Because the topical delivery and pharmacokinetic profile of tazarotene help to minimize systemic S31
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Fig 1. Known metabolic pathways of tazarotene. (Reproduced from Tang-Liu DD-S, Matsumoto RM, Usansky JI. Clinical pharmacokinetics and drug metabolism of tazarotene: A novel topical treatment for acne and psoriasis. Clin Pharmacokinet 1999;37:273-87.)
exposure to the drug and its metabolites, tazarotene therapy has little potential for systemic adverse effects, such as skeletal changes and serum lipid elevations, associated with oral retinoids. As with other topical retinoids, adverse events in phase III clinical trials with tazarotene have been limited to local effects, with the most frequently reported adverse events being erythema, pruritus, and burning/stinging in patients with psoriasis,2-4 and a burning sensation, desquamation, dryness, and erythema in patients with acne.7 These were dose-related and generally mild-to-moderate in severity. There have been no consistent, clinically significant drugrelated changes in hematology, blood chemistry, urinalysis, or bone radiographs.9,12 Phase I safety studies have shown that topical tazarotene treatment does not result in contact sensitization, phototoxicity, or photoallergic reactions.5 Results of several mutagenicity tests (Ames, chromosomal aberration, and micronucleus) have also indicated that tazarotene is nonmutagenic and has no chromosomal or clastogenic effects.13 In addition, no carcinogenic effects have been observed in either
a 21-month study with topically applied tazarotene in mice or a 2-year study with orally administered tazarotene in rats.13 Moreover, tazarotene has recently been shown to have anticarcinogenic activity: in a study of 20 patients with basal cell carcinoma, daily applications of tazarotene 0.1% gel for up to 8 months resulted in a complete response in 53% of lesions and a partial response in the remaining 47% of lesions.14 Potential for teratogenicity Extrapolation of the absorption data mentioned earlier, and clinical analyses of post-treatment plasma levels of tazarotene and tazarotenic acid, both suggest that tazarotene has minimal potential for teratogenicity. Extrapolating from the absorption data, if 1% of a dose of tazarotene is absorbed across unoccluded psoriatic skin, and assuming that tazarotene 0.1% gel is applied at a thickness of 2 mg/cm2 to 20% of the estimated body surface area of 1.7 m2 of a 70 kg person, then the total systemic exposure to tazarotene plus tazarotenic acid would be approximately 1000 ng/kg/day.1* In addition, if it is assumed
* 0.01× 2 × (0.2 × 1.7 × 10000) = 1 mg gel/kg/day = 1000 ng active compound/kg/day 70
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Table I. Comparison of endogenous plasma retinoid levels with those after repeated applications of tazarotene gel Retinoid and dosage regimen
Endogenous retinoids No treatment16,17 Tazarotene 0.1% gel q.d. for 7 days to 20% of BSA9 0.05% gel q.d. for 12 weeks to 5%-15% BSA9 0.1% gel q.d. for 12 weeks to 5%-15% BSA9 0.1% gel q.d. for 26 days to face15 0.05% or 0.1% gel q.d. for 12 weeks to face7
Subjects’ skin condition
Mean plasma retinoid concentration (ng/mL)
Mean Cmax ± SD (ng/mL)
Absolute Cmax (ng/mL)
Healthy volunteers
1.32-2.36 (all-trans-RA); < 1.0-1.63 (13-cis-RA); 3.68 (4-oxo-13-cis-RA)
—
—
Healthy volunteers
—
—
Plaque psoriasis
—
Plaque psoriasis
—
Facial acne vulgaris
—
0.72 ± 0.58 (tazarotenic acid) 0.45 ± 0.78 (tazarotenic acid) 0.83 ± 1.22 (tazarotenic acid) 0.14* ± 0.11 (tazarotenic acid) —
Facial acne vulgaris
≤ 0.05 (tazarotene); ≤ 0.05 (tazarotenic acid)
— — — 0.22 (tazarotene); 0.13 (tazarotenic acid)
BSA, body surface area; Cmax, maximum plasma level; q.d., once daily; RA, retinoic acid. *Mean Cmax after last dose.
Table II. Comparison of plasma retinoid levels after administration of tretinoin, adapalene, and isotretinoin Retinoid and dosage regimen
Tretinoin 0.05% cream q.d. for 28 days to face17 0.1% cream q.d. for 26 days to face18 Adapalene 0.1% gel q.d. for 26 days to face18 Isotretinoin 80 mg orally19 80 mg orally19
Subjects’ skin condition
Mean plasma retinoid concentration (ng/mL)
Mean Cmax ± SD (ng/mL)
Absolute Cmax (ng/mL)
Healthy volunteers
2.60 (all-trans-RA)
—
—
Facial acne vulgaris
—
2.6 ± 0.4 (all-trans-RA); 0.5 ± 0.6 (13-cis-RA); 1.6 ± 0.7 (4-oxo-13-cis-RA)
Facial acne vulgaris
0.04 ± 0.03 (adapalene)
Healthy volunteers Acne
256 (13-cis-RA) 262 (13-cis-RA)
459 (13-cis-RA) 535 (13-cis-RA)
Cmax, maximum plasma level; q.d., once daily; RA, retinoic acid.
that the entire amount of drug to which a patient is exposed per day is present in the blood at the same time, and that this 70 kg person has a plasma volume of 3500 mL, then the plasma concentration would be expected to be no higher than 20 ng/mL. However, in practice, elimination of drug from the blood will likely reduce this concentration (the elimination half-life for tazarotene and its metabolites being approximately 17-18 hours) and it would be highly unusual for the gel to be applied to as large a proportion of the body surface area as the 20% coverage that was assumed in this calculation. Furthermore, in facial acne, the area of skin to which gel is applied is
substantially lower than it is in psoriasis (the face represents approximately 2% of body surface area), and this would also result in a lower plasma retinoid concentration. Analyses of plasma levels of tazarotenic acid in healthy volunteers who applied tazarotene 0.1% gel to 20% of their body surface area once daily for 7 days demonstrate that mean maximum plasma levels are actually no more than 0.72 ng/mL (Table I).9 Similarly, in patients with psoriasis treated with tazarotene 0.1% gel for 12 weeks, the mean maximum plasma level of tazarotenic acid has been reported to be 0.83 ng/mL (and 0.45 ng/mL with
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tazarotene 0.05% gel).9 Therapeutic drug monitoring throughout clinical efficacy studies of 601 patients with psoriasis treated with one of the tazarotene gels revealed that only 4 patients had quantifiable concentrations of tazarotene (all were ≤ 0.12 ng/mL).9 Approximately 50% of the plasma samples taken from the 601 patients showed levels of tazarotenic acid to be below the limit of quantitation (< 0.05 ng/mL), whereas approximately 90% of the samples showed levels to be less than 1 ng/mL. The highest level observed in any patient was 6.1 ng/mL. Thus, these data all indicate that the actual plasma levels of tazarotenic acid attained during treatment are considerably lower than the potential levels calculated previously using the “maximum application scenario” where the gel is applied to 20% of the body surface area. The smaller surface area of treated skin in patients with acne will in all likelihood lead to lower plasma levels of tazarotenic acid than in patients with psoriasis. In one study of patients with acne treated with daily applications of tazarotene 0.1% gel to the entire face, the mean maximal plasma level of tazarotenic acid after the last application on day 26 was 0.14 ng/mL.15 Similarly, the highest reported plasma levels of tazarotene and tazarotenic acid during therapeutic drug monitoring in a 12-week study were 0.22 ng/mL and 0.13 ng/mL, respectively.7 Tazarotene was detectable (> 0.05 ng/mL) in the plasma in only 5% (4/86) of these patients with acne, and tazarotenic acid was detectable in 16% (12/76) of the patients. These data show that the levels of tazarotene and tazarotenic acid are comparable to the endogenous levels of retinoids; in healthy volunteers, the mean plasma levels of endogenous retinoids have been reported to be at least 5 ng/mL for all-trans-retinoic acid, 13-cis-retinoic acid, and 4-oxo-13-cis-retinoic acid combined (Table I).16,17 Similarly, the tazarotene post-treatment data are comparable to the posttreatment plasma retinoid levels after therapy with tretinoin or adapalene (Table II).17-19 Although it is difficult to know with certainty what plasma level of any retinoid might be associated with a clinically relevant risk of teratogenicity, oral isotretinoin treatment results in retinoid plasma levels that are approximately 100-fold higher than those after topical retinoid treatment. This highlights the much higher risk of teratogenicity with oral retinoids than with topical retinoids. Even though applications of tazarotene, tretinoin, and adapalene result in similarly low plasma retinoid levels, the FDA has categorized tretinoin and adapalene as Category C drugs and tazarotene as a Category X drug. The Category C definition indicates
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that such a drug “should be used only if the potential benefit justifies the risk” or “should be given to a pregnant woman only if clearly needed.” Such a categorization means that no human studies exist and that animal studies may exist that show an adverse effect. The Category X definition indicates that such a drug “may or can cause fetal harm when administered to a pregnant woman… and is contraindicated in women who are or may become pregnant.” Such a categorization means that fetal abnormalities have been demonstrated in either animals or humans. Nevertheless, tazarotene-related fetal abnormalities are not known to have occurred in humans. At least 6 women are known to have become pregnant during clinical studies with tazarotene (despite instructions to the contrary) and all reported the birth of healthy babies.2,20 However, because the timing and extent of exposure in relation to the gestation time are not certain, the significance of these findings is not known. As with other retinoids, oral doses of tazarotene given to experimental animals have resulted in developmental delays in rats. Also, teratogenic effects and post-implantation fetal loss have been observed in rats and rabbits at doses producing 0.7 and 13 times, respectively, the systemic exposure (AUC0-24hrs) in patients with psoriasis, when extrapolated for topical treatment of 20% of body surface area. The reasons for the different category classifications among retinoids are partially historical and partially because, unlike tretinoin or adapalene, tazarotene was simultaneously approved for use in both acne and psoriasis. Because of this dual approval, and because tazarotene is likely to be used on a larger surface area in patients with psoriasis than are any of the topical retinoids in patients with acne, tazarotene received just one category for pregnancy labeling—one that was based on psoriasis pharmacokinetic data (ie, with coverage of up to 20% body surface area) rather than acne pharmacokinetic data (which were not available at the time and which would involve a smaller area of application). The FDA itself recognizes that its categories for labeling teratogenicity potential are not optimal and it is reviewing the current classification system. Meanwhile, many dermatologists (including the author) do not refrain from prescribing tazarotene for the topical treatment of psoriasis in female patients of childbearing potential as long as the patients are fully informed of the potential risks and are fully compliant in using reliable contraceptive measures. Patients should be advised to discontinue therapy immediately if pregnancy still occurs despite these precautions. However, because of the rapid elimination of tazarotene and its metabolites from
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the blood, evidence so far does not indicate any necessity for women wishing to become pregnant to undergo a washout period after discontinuing tazarotene therapy.9
DISCUSSION Topical treatment with tazarotene gel results in extremely limited systemic exposure to tazarotene and its metabolites. This is because: the vast majority of the applied dose is not absorbed into the bloodstream; tazarotene is rapidly metabolized into its active form, tazarotenic acid, and other hydrophilic metabolites that do not accumulate in lipophilic tissues; and tazarotene and its metabolites are rapidly eliminated from the plasma via the urine and feces. Because of this pharmacokinetic profile, the plasma levels of tazarotene and tazarotenic acid are approximately 100-fold lower than plasma retinoid levels after oral isotretinoin treatment. Tazarotene thus has a far superior safety profile than that of oral isotretinoin. Importantly, the plasma levels of tazarotene and tazarotenic acid are not only comparable to plasma retinoid levels after tretinoin and adapalene treatment, but are also comparable to those of endogenous retinoids. This suggests that the teratogenic potential of tazarotene treatment is minimal. Nevertheless, because the risk cannot be eliminated completely, it is important that women of childbearing potential use reliable contraceptive measures throughout the treatment period. REFERENCES 1. Duvic M, Asano AT, Hager C, Mays S. The pathogenesis of psoriasis and the mechanism of action of tazarotene. J Am Acad Dermatol 1998;39(suppl):S129-33. 2. Weinstein GD, Krueger GG, Lowe NJ, Duvic M, Friedman DJ, Jegasothy BV, et al. Tazarotene gel, a new retinoid, for topical therapy of psoriasis: vehicle-controlled study of safety, efficacy, and duration of therapeutic effect. J Am Acad Dermatol 1997; 37:85-92. 3. Lebwohl M, Ast E, Callen JP, Cullen SI, Hong SR, Kulp-Shorten CL, et al. Once-daily tazarotene gel versus twice-daily fluocinonide cream in the treatment of plaque psoriasis. J Am Acad Dermatol 1998;38:705-11.
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4. Lebwohl MG, Breneman DL, Goffe BS, Grossman JR, Ling MR, Milbauer J, et al. Tazarotene 0.1% gel plus corticosteroid cream in the treatment of plaque psoriasis. J Am Acad Dermatol 1998; 39:590-6. 5. Duvic M.Tazarotene: a review of its pharmacological profile and potential for clinical use in psoriasis. Exp Opin Invest Drugs 1997;6:1537-51. 6. Guenther LC. Tazarotene, a receptor-selective topical retinoid, in the treatment of psoriasis.Today Ther Trends 1999;17:133-45. 7. Shalita AR, Chalker DK, Griffith RF, Herbert AA, Hickman JG, Maloney JM, et al. Tazarotene gel is safe and effective in the treatment of acne vulgaris. Cutis 1999;63:349-54. 8. Bershad S, Poulin YP, Berson DS, Sabean J, Brodell RT, Shalita AR, et al. Topical retinoids in the treatment of acne vulgaris. Cutis 1999;64(2S):1-23. 9. Tang-Liu DD-S, Matsumoto RM, Usansky JI. Clinical pharmacokinetics and drug metabolism of tazarotene. Clin Pharmacokinet 1999;37:273-87. 10. Franz TJ, Lehman PA, Franz S, Lew-Kaya DA, Matsumoto R, TangLiu D. Percutaneous absorption of AGN 190168 0.1 gel, a new synthetic retinoid, through human skin in vivo [abstract]. J Invest Dermatol 1992;98:650. 11. Marks R. Pharmacokinetics and safety review of tazarotene. J Am Acad Dermatol 1998;39(suppl):S134-8. 12. NDA 20-600. Approved June 13, 1997. 13. Chandraratna RAS. Tazarotene: the first receptor-selective topical retinoid for the treatment of plaque psoriasis. J Am Acad Dermatol 1997;37(suppl):S12-S17. 14. Peris K, Fargnoli MC, Chimenti S. Preliminary observations on the use of topical tazarotene to treat basal-cell carcinoma. N Engl J Med 1999;341:1767-8. 15. Yu Z, Matsumoto RM, Sefton J, Lew-Kaya D, Kopper S, Walker PS, et al. Pharmacokinetics of tazarotene in female patients with facial acne following facial application of 0.1% tazarotene gel for 28 days. Poster presented at the 58th Annual Meeting of the American Academy of Dermatology, March 10-15, 2000, San Francisco, CA. 16. Eckhoff C, Nau H. Identification and quantitation of all-transand 13-cis-retinoic acid and 13-cis-4-oxoretinoic acid in human plasma. J Lipid Res 1990;31:1445-54. 17. Latriano L,Tzimas G,Wong F,Wills RJ.The percutaneous absorption of topically applied tretinoin and its effect on endogenous concentrations of tretinoin and its metabolites after single doses or long-term use. J Am Acad Dermatol 1997;36(suppl): S37-S46. 18. Data on file, Allergan Inc. Study 022. 19. Physicians’ Desk Reference, 2000. Medical Economics Company, Montvale, NJ; pp. 502-3. 20. Tazorac® patient package insert. Irvine, Calif 92612 USA, Allergan, Inc., 1997.