Mechanism of Action

The exact mechanism of action of methoxsalen is not known. The best-known biochemical reaction of methoxsalen is with DNA. Methoxsalen, upon photoactivation, conjugates and forms covalent bonds with DNA which leads to the formation of both monofunctional (addition to a single strand of DNA) and bifunctional adducts (crosslinking of psoralen to both strands of DNA). Reactions with proteins have also been described.

For the palliative treatment of cutaneous T-cell lymphoma, the UVAR Photopheresis System removes a portion of the patient's blood and separates the red blood cells from the white cell layer (buffy coat) by centrifugation. The red cells are returned to the patient and the UVADEX Sterile Solution is then injected into the UVAR system and mixed with the buffy coat. The UVAR system then irradiates this drug-cell mixture with ultraviolet light (UVA light, 320-400 nm) and returns the treated cells to the patient. See the UVAR Photopheresis System Operator's Manual for details of this process. Although extracorporeal phototherapy exposes less than 10% of the total body burden of malignant cells to methoxsalen plus light, some patients achieve a complete response. Animal studies suggest that the photopheresis may activate an immune-mediated response against the malignant T-cells.

Use of the UVAR system after oral administration of methoxsalen was previously approved for the treatment of cutaneous T-cell lymphoma. Interpatient variability in peak plasma concentration after an oral dose of methoxsalen ranges from 6 to 15 fold. UVADEX is injected directly into the separated buffy coat in the UVAR system in an attempt to diminish this interpatient variability and to improve the exposure of the cells to the drug.

Methoxsalen is reversibly bound to serum albumin and is also preferentially taken up by epidermal cells. Methoxsalen is rapidly metabolized in humans, with approximately 95% of the drug excreted as metabolites in the urine within 24 hours.

Systemic administration of methoxsalen followed by UVA exposure leads to cell injury. The most obvious manifestation of this injury after skin exposure is delayed erythema, which may not begin for several hours and peaks at 48-72 hours. The inflammation is followed over several days to weeks, by repair which is manifested by increased melanization of the epidermis and thickening of the stratum corneum.

The total dose of methoxsalen used with the UVAR system in conjunction with UVADEX is substantially lower (approximately 200 times) than that used with oral administration.

Clinical Studies

Three single-arm studies were performed to evaluate the effectiveness of photopheresis in the treatment of the skin manifestations of cutaneous T-cell lymphoma (CTCL). In the first study (CTCL 1), 39 patients were treated with the oral formulation of methoxsalen in conjunction with the UVAR Photopheresis System. The second study (CTCL 2) was a 5-year post approval follow-up of 57 C.C. patients that was conducted to evaluate long-term safety. This study also used the oral dosage formulation of methoxsalen. In the third study (CTCL 3), 51 patients were treated with the UVADEX formulation of methoxsalen in conjunction with the UVAR Photopheresis System. In study CTCL 3, 86% of the patients were Caucasian, the median age was 62 years, and the average number of prior therapies was 4.3.

Bookmark this page: