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Clinical Updates

Sélim Aractingi, MD, PhD

TCIs: Thinking Outside the Black Box

Selim Aractingi

Friday, December 11, 2009

New classes of active topical medications are a rare occurrence nowadays. In 2000 and 2001, the Food and Drug Administration (FDA), followed shortly after by European countries and then by most of the rest of the world, approved the drugs tacrolimus and pimecrolimus. These medicines are topical calcineurin inhibitors (TCIs) prescribed for the treatment of moderate-to-severe atopic dermatitis (AD). In January 2006, however, a black box warning was introduced by the FDA, indicating that the use of calcineurin inhibitors (CIs) could induce a potential risk of cancer1. Of note, the FDA was also concerned about the fact that these treatments were prescribed sometimes, outside the determined rules, to children under 2 years of age, which in my opinion should never been done. Nevertheless, the European Medicines Agency (EMEA) continued to consider that the balance of benefits vs. risk of TCIs was favorable, but reminded the physicians of the rules of short-term indications2. Moreover, tacrolimus is effective in preventing recurrences of AD and is approved by The Committee for Medicinal Products for Human Use as preventive in the treatment of AD3.

Since the FDA warned physicians about the possible risks, the EMEA has reminded physicians to restrict both the long-term prescriptions and the time period that physicians are allowed to prescribe tacrolimus as a preventive drug. This expert opinion will focus on the safety of TCIs, which remains the cornerstone of the precautions that were underlined by the regulatory authorities. To evaluate this safety, we will briefly address the possible systemic resorption of the molecules, the immune status of recipients treated with TCIs and, finally, the data obtained from long-term cohorts.

Are TCI True Topical Medications, or Is There Significant Systemic Exposure?

When considering the potential oncogenic risks of TCI, a preliminary question concerns the possible transcutaneous passage of the molecules once applied to the skin. Such a process has now been well studied.

Thirty-nine children between the ages of 6 and 12 years old were given 0.1% tacrolimus ointment for the treatment of AD. After 2 weeks of treatment, concentrations in the blood were evaluated at day 1 and at day 14. Ninety-two percent of all blood samples collected contained tacrolimus concentrations <1 ng per mL, whereas 17% of the blood samples were below 0.025 ng per mL, the lower limit of quantification of the collection. There was a trend for systemic exposure to tacrolimus to increase as the size of the treated affected body surface area increased4. A similar study was conducted in adults treated twice daily with 0.1% tacrolimus for a 2-week period. Of all blood samples collected, 94% contained tacrolimus concentrations <1 ng/mL, with 31% of samples being below 0.025 ng/mL5. The highest concentration measured at any time, in any patient, was 1.38 ng/mL, whereas 5 to 20 ng/ml is the concentration used for immunosuppression. Mean blood concentrations at 24 hours after the first and last applications of tacrolimus were 0.13 ± 0.16 and 0.33 ± 0.34 ng/mL, respectively5.  Some diseases cause alterations of skin barrier that could lead to enhanced systemic resorption, as seen with Netherton syndrome treated with pimecrolimus. Therefore, application of TCI is now strictly contraindicated in this disease. Altogether, these data give a precise evaluation of the absence of significant systemic exposure to TCI if used in patients affected with AD.

Immune Status of Patients Treated with TCI

Another important point to address is the effect of TCI drugs on systemic immunity. If these act locally, they should not affect the immune responses of treated patients. The immune status of patients treated with TCIs can be tested through several evaluations. One such way is to evaluate, in vivo, the delayed hypersensitivity reaction using an eight-pronged applicator containing seven preloaded antigens and a vehicle control. A study was performed in patients treated for 6 or 12 months with topical tacrolimus6. The number of positive antigens was 1.3±1.2 at day 1, 1.5±1.3 at 6 months, and 1.8±1.4 at 12 months.  No changes in cellular immunity were detected even in long-term-treated patients.

Another tool was employed to assess effects on immunization. Twenty-three children were treated for 7 weeks with tacrolimus: 3 weeks before receiving the pneumococcal vaccine and 4 weeks after receiving the vaccine. There were specific antibodies detectable in all of these children7. Another study evaluated 132 children who received the meningococcal C vaccine during tacrolimus treatment compared with 44 controls who were challenged without any treatment. Specific antibodies were found in 97.5% in the tacrolimus group vs. 99% of the control group8. Therefore, the cellular and humoral immune responses do not seem to be affected by TCI.

Safety Data on Carcinogenic Risks of CI

The initial warning from the FDA relied on post-market data that included ten cases of neoplasia in pimecrolimus recipients; four children and six adults, with a total of four lymphomas. There were 19 cancers in the tacrolimus-treated patients; three children and 16 adults, with a total of  nine lymphomas. In addition, further studies have shown few single reports of neoplasia, essentially cases that develop in lichen-sclerosus-treated patients, and one melanoma in a vitiligo-treated patient. However, a careful analysis of the FDA reported cases by Ormerod and colleagues found that many of these solid tumors had either powerful oncogenic stimuli, such as smoking, systemic cyclosporine or ultraviolet light (UV), which were able to induce the reported neoplasia9. Furthermore, the same study noted that the features of the reported lymphoma did not correspond to the features observed after immunosuppressive drugs9. It should be noted that lymphomas due to the TCI should have been B cell lymphomas, but these were not seen . Finally, four cohort analyses, including three case-control studies, have been performed10-13.  None of these show any over-risk of malignancy. The largest study has been reported by Fonacier et al. in the USA10. It showed that the incidence of lymphoma was 0.65/100,000 in tacrolimus-treated cases vs. 22/ 100,000 in the general population. The incidence of non-melanoma skin cancer was 0.93/100,000 in tacrolimus-treated cases vs. 533/ 100,000 in the general population10. Therefore, the incidence of lymphomas and cutaneous malignancies is lower in patients receiving TCI's compared with the general population.

Another study analyzed 293,253 patients, from 73 sites in the USA , who have had AD for at least 6 months. Within this study, 294 lymphoma cases were found. These were compared with a population of AD cases without apparent lymphoma12. The adjusted odds ratio for drug exposure was 0.79 for tacrolimus and 0.82 for pimecrolimus12. Of note, the only risk factor for lymphoma in these cases was the severity of AD .

Conclusion

After initial and reasonable precautions, TCI drugs appear to be reasonably safe as long as they are used according to their official indication.

References

  1. Protopic and Elidel presentation for regulatory briefing on January 14, 2005. Available at: www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2_01_02_DPDD%20Consult.pdf 
  2. European Medicines Agency. Last accessed October 2009. Available at: www.emea.europa.eu
  3. European Public Assessment Report (EPAR), Protopic: EPAR Summary for the Public.  Last accessed October 2009. Available at: www.emea.europa.eu/humandocs/PDFs/EPAR/protopic/H-374-en1.pdf
  4. Harper J, Smith C, Rubins A, et al. A multicenter study of the pharmacokinetics of tacrolimus ointment after first and repeated application to children with atopic dermatitis. J Invest Dermatol. 2005;124(4):695-699.
  5. Undre NA, Moloney FJ, Ahmadi S, Stevenson P, Murphy GM. Skin and systemic pharmacokinetics of tacrolimus following topical application of tacrolimus ointment in adults with moderate to severe atopic dermatitis. Br J Dermatol. 2009;160(3):665-669.
  6. Reitamo S, Wollenberg A, Schöpf E, et al. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. The European Tacrolimus Ointment Study Group. Arch Dermatol. 2000;136(8):999-1006.
  7. Stiehm ER, Roberts RL, Kaplan MS, et al. Pneumococcal seroconversion after vaccination for children with atopic dermatitis treated with tacrolimus ointment. J Am Acad Dermatol. 2005;53(2 Suppl 2):S206-13.
  8. Hofman T, Cranswick N, Kuna P, et al; International Tacrolimus Ointment Study Group. Tacrolimus ointment does not affect the immediate response to vaccination, the generation of immune memory, or humoral and cell-mediated immunity in children. Arch Dis Child. 2006;91(11):905-910.
  9. Ormerod AD. Topical tacrolimus and pimecrolimus and the risk of cancer: how much cause for concern? Br J Dermatol. 2005;153(4):701-705.
  10. Fonacier L, Spergel J, Charlesworth EN, et al. American College of Allergy, Asthma and Immunology; American Academy of Allergy, Asthma and Immunology. Report of the Topical Calcineurin Inhibitor Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2005;115(6):1249-1253.
  11. Margolis DJ, Hoffstad O, Bilker W. Lack of association between exposure to topical calcineurin inhibitors and skin cancer in adults. Dermatology. 2007;214(4):289-295.
  12. Arellano FM, Wentworth CE, Arana A, Fernández C, Paul CF. Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis. J Invest Dermatol. 2007;127(4):808-816.
  13. Naylor M, Elmets C, Jaracz E, Rico JM. Non-melanoma skin cancer in patients with atopic dermatitis treated with topical tacrolimus. J Dermatolog Treat. 2005;16(3):149-153.
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