Uterine fibroids, also known as leiomyomas, uterine myomas or fibroleiomyomas, are benign, encapsulated uterine tumors consisting of smooth muscle fibers of the uterus and connective tissue, the most common in the female genital tract. They affect 20 to 25% of women of childbearing age and are 3 to 9 times more common in black women than in white women, and nearly 70% of those close to 50 years of age. Uterine myomas are a real public health problem. The cost of treating them is expensive and the only treatment deemed effective is surgery. The rapid progression of leiomyomas during the childbearing years and regression after menopause indicate that estrogen plays a key role as a growth factor for these tumors. To contribute to the knowledge of the etiological factors involved in the tumor process of uterine fibroids, the study of the Cytochrome P-450c17α gene (CYP17α), involved in the hydroxylation of estrogen, has been carried out. Our study population consisted of 57 patients with uterine fibroids. After sampling (tumour tissue and peripheral blood), molecular analysis were done (DNA extraction, PCR-sequencing). Raw data were submitted to Mutation Surveyor 5.0.1 for mutation identification and AlamutVisual 2.12 software. The pathogenicity of each non-synonymous mutation was evaluated using Polyphen-2, Mutation Taster and SIFT. After cleaning, correction and alignment of sequences with BioEdit 7.0.8.0, genetic diversity, genetic differentiation and polymorphism of the gene CYP17α in correlation with epidemiological factors were determined with DNASP 5.10.01, MEGA 7.0.14, Arlequin 3.5.3.1 and the statistical software RStudio 3.5.1. Our results showed 84 mutations characterizing a high rate of tumor tissue polymorphism but also a genetic difference between tumor and peripheral blood. The mutation c.-34T>C which is located in the 5' promoter region at 34 bp upstream of the translation initiation site was found in patients with uterine fibroids. No genetic structuring of the CYP17α gene according to clinico-pathological parameters was observed. In conclusion, the cytochrome P450 enzymes responsible for highly specific reactions in the steroid biosynthesis pathway are gaining interest as molecular targets, given their role cléF in the formation of various very potent endogenous steroid hormones. Indeed, current treatments for tumors, particularly fibroids, are mainly surgical and expensive. It is therefore essential to develop and evaluate alternatives to surgical procedures.
Background Dovitinib (TKI258) is an oral receptor tyrosine kinase inhibitor targeting kinases involved in tumor cell proliferation and survival, including FGFR, VEGFR, PDGFR, c-KIT, and FLT3. A phase 3 study in renal cell carcinoma used a capsule (cap) formulation of dovitinib. However, the planned commercial formulation is a tablet (tab). Therefore, this study evaluated the bioequivalence of the tab and cap formulations using a crossover design. Methods Patients (pts) ≥ 18 years of age with advanced solid tumors (excluding breast cancer) were randomized to receive caps or tabs (500 mg po once daily, 5 days on/2 days off) for 3 weeks, followed by the same dose and schedule of the other formulation for 1 week. Following the bioequivalence phase, pts could continue to receive dovitinib caps (500 mg once a day, 5 days on/2 days off). Blood samples for dovitinib plasma concentrations were collected before and after the fifth dose in weeks 3 and 4. The pharmacokinetic (PK) analysis set (PAS) comprised pts with ≥ 2 evaluable PK profiles following cap and tab administration, who did not vomit ≤ 4 hours after dosing on blood collection days and received ≥ 7 of the first 10 doses and 4 consecutive days of dosing prior to blood collection. A linear mixed-effects model was fitted to log-transformed parameters (area under the curve [AUClast] and maximal concentration [Cmax]). Results A total of 173 pts were randomized to receive the cap/tab sequence (n = 88) or the tab/cap sequence (n = 85). The median age was 60 years, and the most common primary sites of cancer were colon (n = 48), lung (n = 18), and rectum (n = 14). Sixty-nine pts were in the PAS (32 in the cap/tab sequence and 37 in the tab/cap sequence). The most common reason for PAS exclusion was dose interruption due to disease progression or adverse events (AEs). Geometric means of PK parameters were similar for the tab vs cap formulations: AUClast (5379 vs 5705 h·ng/mL), Cmax (247 vs 252 ng/mL), half-life (14.5 vs 15.3 h), oral clearance (89.5 vs 82.5 L/h), and apparent volume of distribution (1876 vs 1823 L). The geometric mean ratios (90% CI) for AUClast and Cmax comparing tab vs cap were 0.95 (0.88-1.01) and 0.98 (0.91-1.05), respectively. In pts who received at least 1 dose of dovitinib throughout the entire study (including the postbioequivalence phase; n = 168), the most common AEs suspected to be related to study drug (any grade) were diarrhea (58.9%), nausea (50.0%), fatigue (42.3%), vomiting (41.7%), and decreased appetite (20.8%). Grade 3/4 AEs were < 5% except for fatigue (11.9%), diarrhea (5.4%), and hypertension (5.4%). Conclusions The tab and cap formulations were bioequivalent. The safety profile was similar to that observed in other dovitinib studies in pts with advanced solid tumors. The tab formulation is used in selected current studies and will be used in future clinical dovitinib studies. Citation Format: John Sarantopoulos, Sanjay Goel, Vincent Chung, Pamela Munster, Shubham Pant, Manish Patel, Jeffrey Infante, Hussein Tawbi, Carlos Becerra, Justine Bruce, Fairooz Kabbinavar, Howard Kaufman, A. Craig Lockhart, Eugene Tan, Shu Yang, Mariama Diallo, Jeffrey Scott, Sunil Sharma. Randomized, phase 1 crossover study assessing the bioequivalence of tablet and capsule formulations of dovitinib (TKI258). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4640. doi:10.1158/1538-7445.AM2014-4640
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