Quantitative Prediction of Oral Bioavailability of a Lipophilic Antineoplastic Drug Bexarotene Administered in Lipidic Formulation Using a Combined In Vitro Lipolysis/Microsomal Metabolism Approach

For performance assessment of the lipid-based drug delivery systems (LBDDSs), in vitro lipolysis is commonly applied because traditional dissolution tests do not reflect the complicated in vivo micellar formation and solubilization processes. Much of previous research on in vitro lipolysis has mostly focused on rank-ordering formulations for their predicted performances. In this study, we have incorporated in vitro lipolysis with microsomal stability to quantitatively predict the oral bioavailability of a lipophilic antineoplastic drug bexarotene (BEX) administered in LBDDS. Two types of LBDDS were applied: lipid solution and lipid suspension. The predicted oral bioavailability values of BEX from linking in vitro lipolysis with microsomal stability for lipid solution and lipid suspension were 34.2 ± 1.6% and 36.2 ± 2.6%, respectively, whereas the in vivo oral bioavailability of BEX was tested as 31.5 ± 13.4% and 31.4 ± 5.2%, respectively. The predicted oral bioavailability corresponded well with the oral bioavailability for both formulations, demonstrating that the combination of in vitro lipolysis and microsomal stability can quantitatively predict oral bioavailability of BEX. In vivo intestinal lymphatic uptake was also assessed for the formulations and resulted in <1% of the dose, which confirmed that liver microsomal stability was necessary for correct prediction of the bioavailability.     

Hypertriglyceridaemia with bexarotene in cutaneous T cell lymphoma: the role of omega-3 fatty acids

Bexarotene is approved for the treatment of cutaneous T cell lymphomas in patients refractory to at least one prior systemic therapy. Associated hypertriglyceridaemia requires monitoring, but can readily be managed with concomitant medication, such as fenofibrate. Here we report three cases of hypertriglyceridaemia secondary to bexarotene assumption, which was adequately managed with omega-3 fatty acids. If fenofibate-related side effects occur, or a statin is required to control low-density lipoprotein-cholesterol, omega-3 fatty acids should be considered as a good alternative therapy to lower lipid levels during bexarotene treatment.     

Retinoids: therapeutic applications and mechanisms of action in cutaneous T-cell lymphoma

Retinoids, natural and synthetic derivatives of vitamin A, are biological regulators of differentiation, proliferation, apoptosis, and immune response. Retinoic-acid-receptor-selective retinoids (all-trans retinoic acid, 13-cis-retinoic acid, and the synthetic analogs isotretinoin, etretinate and acitretin) have been used for years as monotherapy and/or in combination for treatment of cutaneous T-cell lymphoma (CTCL). Orally administered bexarotene, the first synthetic highly selective retinoid-X-receptor retinoid to be approved by the FDA for CTCL, was shown to be active against the cutaneous manifestations of all stages of CTCL. The topical gel formulation was also effective for early cutaneous manifestations of CTCL or as an adjunct to systemic or phototherapy. Bexarotene treatment induces apoptosis of CTCL cells with down-regulation of its receptors and of survivin, an inhibitor of apoptosis. Identification of new receptor subtype-selective retinoids, combination of various receptor-selective retinoids or other agents, and a new drug delivery system may improve the clinical efficacy of retinoids in the future.     

Novel treatment of chronic severe hand dermatitis with bexarotene gel

BACKGROUND: Hand dermatitis is an eczematous inflammation of the hands that is related to occupation or to routine activities. It often becomes chronic, and in some patients may become severe and disabling. Topical corticosteroids are effective treatment, particularly for milder forms, but they often lose effectiveness with time and can produce skin atrophy. OBJECTIVES: To evaluate bexarotene gel topical therapy for safety, tolerability and efficacy in patients with chronic hand dermatitis. METHODS: A phase I-II open-label randomized clinical study of bexarotene gel, alone and in combination with a low- and a mid-potency steroid, was conducted in 55 patients with chronic severe hand dermatitis at two academic clinics. RESULTS: Patients using bexarotene gel monotherapy reached a 79% response rate for > or = 50% clinical improvement and a 39% response rate for > or = 90% clearance of hands. Adverse events possibly related to treatment in all patients were stinging or burning (15%), flare of dermatitis (16%) and irritation (29%). Thirteen patients (24%) withdrew early, including two for related adverse events and five for inadequate response. CONCLUSIONS: Bexarotene gel appears to be safe, tolerated by most patients, with useful therapeutic activity in chronic severe hand dermatitis.     

贝沙罗汀软胶囊在复发难治性皮肤T细胞淋巴瘤患者中的药代动力学研究

目的:评价贝沙罗汀在复发难治性皮肤T细胞淋巴瘤患者中的药物代谢动力学。方法:建立荧光液相色谱法,以乙腈、乙酸铵、乙酸等为流动相成分,在激发波长260 nm、发射波长430 nm的色谱条件下进行方法学考察及血药浓度测定。所得到的血药浓度以DAS 2.0药代动力学参数计算程序进行参数计算。皮肤T细胞淋巴瘤患者接受贝沙罗汀口服300 mg.m-2,qd,连用4周,进行单剂量和多剂量药代动力学分析。结果:建立的荧光液相色谱法在10～1 000 ng.mL-1之间线性关系良好(r=0.999 7),在空白血浆中20,100和800 ng.mL-1浓度的提取回收率分别为79.49%8,7.06%和78.56%。血药浓度测定结果显示,5例皮肤T-细胞淋巴瘤患者口服贝沙罗汀软胶囊300 mg.m-2,服药d 1和连续服药d 28的Cmax分别为366.31和652.44 ng.mL-1;Tmax分别为1.80和1.88 h;t1/2分别为2.56和3.18 h;AUC0～t分别为1 680.96和2 133.34ng.mL-1.h。结论:建立的荧光液相色谱法稳定,敏感性高。皮肤T-细胞淋巴瘤患者口服300 mg.m-2的贝沙...     

贝沙罗汀的合成工艺研究

目的 研究贝沙罗汀的合成工艺。方法 以2,5-二甲基-2,5-己二醇为起始原料,经卤代、Friedel-Crafts烷基化反应、Friedel-Crafts酰化反应、Wittig反应、水解5步反应制得贝沙罗汀。结果与结论 目标化合物的结构经¹H-NMR和MS谱确证,总收率为37.2％。改进后的工艺操作简便,有利于工业化生产。     

Bexarotene therapy for mycosis fungoides and Sézary syndrome

Background Bexarotene (Targretin^®) is a synthetic retinoid which is licensed for the treatment of advanced refractory cutaneous T‐cell lymphoma (CTCL). Objectives To summarize our experience with bexarotene for patients with CTCL with the aim of assessing efficacy and safety. Methods A retrospective study of 66 patients (44 male, 22 female) with mycosis fungoides (40 patients) or Sézary syndrome (26 patients) who were commenced on bexarotene prior to August 2007 was carried out. Nineteen patients had early‐stage (IB–IIA) refractory mycosis fungoides and 47 patients had advanced‐stage CTCL (IIB–IVB). Results Fifty‐two out of 66 (79%) patients completed over 1 month of therapy with an intention‐to‐treat response rate of 44% (29/66). Of the patients, six (9%) had a complete response, 23 (35%) had a partial response, 15 (23%) had stable disease and eight (12%) had progressive disease. Median time to maximal response was 3 months (1–9 months). Median response duration was 8 months (1 to > 48 months). Median time to progression was 9 months (3–44 months). Fourteen patients (21%) did not complete a month of bexarotene therapy. Adverse effects of the whole group included central hypothyroidism in 100% (all grade II and managed with thyroid replacement) and hyperlipidaemia in 100% (all managed with lipid‐lowering therapy ± dose reduction). Responses were seen in all stages and were higher in advanced stages: 26% (five of 19) with early‐stage and 51% (24/47) of advanced‐stage disease. Responses were seen in skin, blood and lymph nodes. Twenty‐eight out of 66 patients were treated with bexarotene monotherapy and the remainder were on one or more additional anti‐CTCL therapies. Conclusions Our data demonstrate that bexarotene is well tolerated in most patients and responses are seen in almost half of patients with all disease stages. However partial responses were not graded and would include any improvement seen in the skin, blood and lymph node.     

Sézary syndrome associated with granulomatous lesions during treatment with bexarotene

Sézary syndrome (SS) is a leukaemic variant of cutaneous T-cell lymphoma (CTCL). We report a patient with SS who developed granulomatous lesions. These lesions broke out during treatment with bexarotene when the disease had appeared to stabilize. After a partial clinical remission the disease showed rapid progression and finally led to the patient's death. This contradicts the initial assessment, which considered the granulomatous inflammation as a good prognostic factor in CTCL.     

The optimal use of bexarotene in cutaneous T-cell lymphoma

The management goal in cutaneous T-cell lymphomas (CTCLs) is to improve symptoms and induce remission. Early-stage disease is generally treated with skin-directed therapies. However, if these do not control the disease, systemic therapy becomes necessary. Bexarotene, a novel rexinoid, is an oral, noncytotoxic drug that has been approved in Europe for the treatment of refractory advanced-stage CTCL and in the U.S.A. for refractory CTCL. We provide guidance on the use of bexarotene in the management of CTCL, based on data from phase II/III clinical trials and the authors' clinical experience, and suggest how the potential of the drug can be maximized. The clinical trial results with bexarotene are reviewed, especially in comparison with interferon-alpha, which is the other commonly used noncytotoxic systemic therapy for CTCL. A treatment algorithm for bexarotene in refractory CTCL is suggested. As bexarotene may take time to achieve a maximum response, this algorithm recommends that therapy should be continued for a sufficient period to allow for a delayed onset of action. In addition, possible combination therapies with bexarotene are discussed. We conclude that bexarotene is effective in the management of CTCL, and has the advantage of oral administration. An on-going randomized clinical trial comparing psoralen plus ultraviolet A (PUVA) with PUVA plus bexarotene will provide valuable information about this combination regimen in early-stage disease, but further data are needed on the relative efficacies of other combination therapies with bexarotene in CTCL.     

Synergistic effect of a retinoid X receptor-selective ligand bexarotene (LGD1069, Targretin) and paclitaxel (Taxol) in mammary carcinoma

We have previously shown that the retinoid X receptor (RXR) ligand bexarotene (LGD1069, Targretin) is efficacious as a chemopreventive and chemotherapeutic agent in rat N-nitroso-N-methylurea (NMU)-induced mammary carcinomas (Cancer Res 58: 479–484, 1998). To determine additional role for bexarotene in breast cancer treatment, we evaluated the effect of bexarotene on the efficacy of paclitaxel (Taxol) treatment in a rat NMU-derived mammary tumor cell line, NMU-417,in vitro and in rat NMU-induced mammary tumors in vivo. Our growth inhibition results showed that the bexarotene/paclitaxel combination produced a concentration-dependent synergy in NMU-417 tumor cell line. Synergistic growth inhibition by the combination was associated with an increase in cell death induced by both agents. In rat NMU-induced mammary tumor model in vivo, the benefit of combination therapy was observed as early as 1week after treatment and increased as treatment continued. At the end of 6weeks of treatment, the bexarotene/paclitaxel combination produced an overall objective response rate of 94% compared with a rate of 12% in paclitaxel-treated and 58% in bexarotene-treated animals, an effect that was more than the additive effects produced by single agents. Although both bexarotene alone and the bexarotene/paclitaxel combination reduced tumor multiplicity to similar extent, the combination regimen produced a statistically significant decrease in total tumor burden compared to single agents and untreated controls (two-tailed, p>0.05). Combination therapy did not further alter body weight nor increase toxicity when compared to single agents. In summary, our results demonstrated the potential of using a RXR selective ligand in combination with chemotherapy for the treatment of breast cancer.