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•Phospholipid complexation with drug has been employed for enhancing the solubility and thereby bioavailability of BCS class II drugs.•Tamoxifen and phospholipid are reported to be ...held by van der Waals forces and other hydrophobic interactions in the complex.•Increase solubility of tamoxifen phospholipid complex leads to its enhanced dissolution rate.•The complex forms a colloidal dispersion in water thereby increasing the solubility of tamoxifen and leading to its enhanced bioavailability.
In the present study, tamoxifen-phospholipid complex (TMX-PLC) was developed and evaluated for its impact on solubility and bioavailability of tamoxifen. TMX-PLC was prepared by solvent evaporation method and characterized. FTIR revealed the disappearance of the characteristic peaks of TMX in the complex, which can be due to weakening, removal or shielding by the phospholipid molecule. This phenomenon could be due to packing of TMX in the hydrophobic cavity of phospholipid and being held by van der Waals forces and hydrophobic interactions. This observation was confirmed by DSC and PXRD. TMX-PLC exhibited increased solubility, dissolution rate with decreased distribution coefficient indicating its increased hydrophilicity. Oral bioavailability of TMX and TMX-PLC were evaluated in Sprague-Dawley (SD) rats. TMX-PLC exhibited considerable enhancement in the bioavailability with an increase in Cmax (0.85 vs. 0.40μg/mL), t1/2 (22.47 vs. 13.93h), and AUC0–∞ (15.29 vs. 8.62μgh/mL) with 212.25% relative bioavailability. This enhancement can be attributed to the improvement of the aqueous solubility of the complex and a probable decrease in its extent of intestinal and hepatic metabolism. Thus, phospholipid complexation holds a promising potential for increasing oral bioavailability of TMX.
Aims
A prospectively enrolled patient cohort was used to assess whether the prediction of CYP2D6 phenotype activity from genotype data could be improved by reclassification of diplotypes or alleles.
...Methods
Three hundred and fifty‐five patients receiving tamoxifen 20 mg were genotyped for CYP2D6 and tamoxifen metabolite concentrations were measured. The endoxifen : N‐desmethly‐tamoxifen metabolic ratio, as a surrogate of CYP2D6 activity, was compared across four diplotypes (EM/IM, EM/PM, IM/IM, IM/PM) that are typically collapsed into an intermediate metabolizer (IM) phenotype. The relative metabolic activity of each allele type (UM, EM, IM, and PM) and each EM and IM allele was estimated for comparison with the activity scores typically assigned, 2, 1, 0.5 and 0, respectively.
Results
Each of the four IM diplotypes have distinct CYP2D6 activity from each other and from the EM and PM phenotype groups (each P < 0.05). Setting the activity of an EM allele at 1.0, the relative activities of a UM, IM and PM allele were 0.85, 0.67 and 0.52, respectively. The activity of the EM alleles were statistically different (P < 0.0001), with the CYP2D6*2 allele (scaled activity = 0.63) closer in activity to an IM than an EM allele. The activity of the IM alleles were also statistically different (P = 0.014).
Conclusion
The current systems for translating CYP2D6 genotype into phenotype are not optimally calibrated, particularly in regards to IM diplotypes and the *2 allele. Additional research is needed to improve the prediction of CYP2D6 activity from genetic data for individualized dosing of CYP2D6 dependent drugs.
Breast cancer is a heterogeneous disease affecting thousands of people every year. Multiple factors are responsible in causing breast cancer while a number of treatment options are also available for ...the disease. Tamoxifen is the most widely used anti-estrogen for the treatment of hormone-dependent breast cancer. The specific drug is used as a hormonal therapy for patients who exhibit estrogen receptor positive breast cancer. The pharmacological activity of Tamoxifen is dependent on its conversion to its active metabolite, endoxifen, by CYP2D6. Tamoxifen reduces the risk of recurrence and death from breast cancer when given as adjuvant therapy and provides effective palliation for patients with metastatic breast cancer. In this review we focus on the role of Tamoxifen in breast cancer treatment including mechanisms and side-effects. Finally, we discuss in detail the exciting prospects that lie ahead.
Abstract The present investigation reports on the conditions for preparation of tamoxifen loaded PLGA nanoparticles (Tmx-NPs) for oral administration. Tmx-NPs with >85% entrapment efficiency and ...165.58 ± 3.81 nm particle size were prepared and freeze dried. Freeze dried Tmx-NPs were found to be stable in various simulated GIT media (pH 1.2, pH 3.5, pH 6.8, SGF & SIF). No significant changes in characteristics of Tmx-NPs were observed after 3 months accelerated stability studies. The cell viability in C127I cells was found to be relatively lower in Tmx-NP treated cells as compared to free Tmx treated cells. CLSM imaging reveled that nanoparticles were efficiently localized into the nuclear region of C127I cells. Oral bioavailability of Tmx was increased by 3.84 and 11.19 times as compared to the free Tmx citrate and Tmx base respectively, when formulated in NPs. In vivo oral antitumor efficacy of Tmx-NPs was carried out in DMBA induced breast tumor model and tumor size was reduced up to 41.56% as compared to untreated groups which showed an increase in tumor size up to 158.66%. Finally, Tmx-NPs showed the marked reduction in hepatotoxicty when compared with free Tmx citrate as evidenced by histopathological examination of liver tissue as well as AST, ALT and MDA levels. Therefore Tmx-NPs could have the significant value for the oral chronic breast cancer therapy with reduced hepatotoxicity.
Summary Background As trials of 5 years of tamoxifen in early breast cancer mature, the relevance of hormone receptor measurements (and other patient characteristics) to long-term outcome can be ...assessed increasingly reliably. We report updated meta-analyses of the trials of 5 years of adjuvant tamoxifen. Methods We undertook a collaborative meta-analysis of individual patient data from 20 trials (n=21 457) in early breast cancer of about 5 years of tamoxifen versus no adjuvant tamoxifen, with about 80% compliance. Recurrence and death rate ratios (RRs) were from log-rank analyses by allocated treatment. Findings In oestrogen receptor (ER)-positive disease (n=10 645), allocation to about 5 years of tamoxifen substantially reduced recurrence rates throughout the first 10 years (RR 0·53 SE 0·03 during years 0–4 and RR 0·68 0·06 during years 5–9 both 2p<0·00001; but RR 0·97 0·10 during years 10–14, suggesting no further gain or loss after year 10). Even in marginally ER-positive disease (10–19 fmol/mg cytosol protein) the recurrence reduction was substantial (RR 0·67 0·08). In ER-positive disease, the RR was approximately independent of progesterone receptor status (or level), age, nodal status, or use of chemotherapy. Breast cancer mortality was reduced by about a third throughout the first 15 years (RR 0·71 0·05 during years 0–4, 0·66 0·05 during years 5–9, and 0·68 0·08 during years 10–14; p<0·0001 for extra mortality reduction during each separate time period). Overall non-breast-cancer mortality was little affected, despite small absolute increases in thromboembolic and uterine cancer mortality (both only in women older than 55 years), so all-cause mortality was substantially reduced. In ER-negative disease, tamoxifen had little or no effect on breast cancer recurrence or mortality. Interpretation 5 years of adjuvant tamoxifen safely reduces 15-year risks of breast cancer recurrence and death. ER status was the only recorded factor importantly predictive of the proportional reductions. Hence, the absolute risk reductions produced by tamoxifen depend on the absolute breast cancer risks (after any chemotherapy) without tamoxifen. Funding Cancer Research UK, British Heart Foundation, and Medical Research Council.
At 8 years of follow-up, premenopausal women with breast cancer had higher rates of disease-free and overall survival with the addition of ovarian suppression to antiestrogen therapy and a higher ...rate of hormonal side effects than with tamoxifen alone.
Tamoxifen is widely prescribed as adjuvant therapy in patients with early-stage breast cancer. It has been postulated that concentrations of endoxifen, the active metabolite of tamoxifen, are a ...better predictor of tamoxifen efficacy than CYP2D6 genotypes. Although in a retrospective study, an endoxifen threshold of 5.9 ng/mL for efficacy was described, confirmation based on prospective studies is lacking. The objective of the prospective CYPTAM (The Netherlands National Trial Register: NTR1509) study was to associate endoxifen concentrations and CYP2D6 genotypes with clinical outcome in patients with early-stage breast cancer receiving tamoxifen.
From February 2008 to December 2010, patients with breast cancer treated with adjuvant tamoxifen were included. Patients could be enrolled up to a maximum of 12 months after tamoxifen initiation. Blood samples were retrieved for CYP2D6 genotyping and endoxifen measurements by Amplichip (Roche Diagnostics, Indianapolis, IN) and high-performance liquid chromatography-tandem mass spectrometry, respectively. Endoxifen concentrations were analyzed as a continuous variable, classifying patients into quartiles and using an endoxifen threshold of 5.9 ng/mL. Endoxifen concentrations and CYP2D6 genotypes were associated with relapse-free survival (censored at the time of tamoxifen discontinuation; RFSt) by Cox regression analysis.
A total of 667 pre- and postmenopausal patients were enrolled and had received tamoxifen for a median time of 0.37 years (range, 0.23 to 0.6 years) before study entry. No association was found between endoxifen concentrations and RFSt (adjusted hazard ratio, 0.991; 95% CI, 0.946 to 1.038; P = .691). Also, neither categorizing endoxifen concentrations into quartiles nor using 5.9 ng/mL as threshold altered these results. In addition, no association was found between CYP2D6 genotype and RFSt (adjusted hazard ratio, 0.929; 95% CI, 0.525 to 1.642; P = .799).
This prospective clinical study shows no association between endoxifen concentrations or CYP2D6 genotypes and clinical outcome in patients with early-stage breast cancer receiving adjuvant tamoxifen.
We explored whether breast cancer outcomes are associated with endoxifen and other metabolites of tamoxifen and examined potential correlates of endoxifen concentration levels in serum including ...cytochrome P450 2D6 (CYP2D6) metabolizer phenotype and body mass index (BMI). Concentration levels of tamoxifen, endoxifen, 4‐hydroxytamoxifen (4OH‐tamoxifen), and N‐desmethyltamoxifen (ND‐tamoxifen) were measured from samples taken from 1,370 patients with estrogen receptor (ER)‐positive breast cancer who were participating in the Women's Healthy Eating and Living (WHEL) Study. We tested these concentration levels for possible associations with breast cancer outcomes and found that breast cancer outcomes were not associated with the concentration levels of tamoxifen, 4‐hydroxytamoxifen, and ND‐tamoxifen. For endoxifen, a threshold was identified, with women in the upper four quintiles of endoxifen concentration appearing to have a 26% lower recurrence rate than women in the bottom quintile (hazard ratio (HR) = 0.74; 95% confidence interval (CI), (0.55–1.00)). The predictors of this higher‐risk bottom quintile were poor/intermediate metabolizer genotype, higher BMI, and lower tamoxifen concentrations as compared with the mean for the cohort as a whole. This study suggests that there is a minimal concentration threshold above which endoxifen is effective against the recurrence of breast cancer and that ~80% of tamoxifen takers attain this threshold.
Clinical Pharmacology & Therapeutics (2011) 89 5, 718–725. doi:10.1038/clpt.2011.32
Background: Although the use of complementary and alternative medicines is widespread in cancer patients, clinical evidence of their benefits is sparse. Furthermore, while they are often assumed to ...be safe with regard to concurrent use of anticancer therapies, few studies have been carried out to investigate possible interactions. Fucoidans are a group of sulfated carbohydrates, derived from marine brown algae, which have long been used as dietary supplements due to their reported medicinal properties, including anticancer activity. The aim of this study was to investigate the effect of co-administration of fucoidan, derived from Undaria pinnatifida, on the pharmacokinetics of 2 commonly used hormonal therapies, letrozole and tamoxifen, in patients with breast cancer. Methods: This was an open label non-crossover study in patients with active malignancy taking letrozole or tamoxifen (n = 10 for each group). Patients took oral fucoidan, given in the form of Maritech extract, for a 3-week period (500 mg twice daily). Trough plasma concentrations of letrozole, tamoxifen, 4-hydroxytamoxifen, and endoxifen were measured using HPLC-CAD (high-performance liquid chromatography charged aerosol detector), at baseline and after concomitant administration with fucoidan. Results: No significant changes in steady-state plasma concentrations of letrozole, tamoxifen, or tamoxifen metabolites were detected after co-administration with fucoidan. In addition, no adverse effects of fucoidan were reported, and toxicity monitoring showed no significant differences in all parameters measured over the study period. Conclusions: Administration of Undaria pinnatifida fucoidan had no significant effect on the steady-state trough concentrations of letrozole or tamoxifen and was well tolerated. These results suggest that fucoidan in the studied form and dosage could be taken concomitantly with letrozole and tamoxifen without the risk of clinically significant interactions.
Endoxifen is one of the most important metabolites of the prodrug tamoxifen. High interindividual variability in endoxifen steady‐state concentrations (CSS,min ENDX) is observed under tamoxifen ...standard dosing and patients with breast cancer who do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at a 26% higher recurrence risk compared with patients with endoxifen concentrations exceeding this value. In this investigation, 10 clinical tamoxifen studies were pooled (1,388 patients) to investigate influential factors on CSS,min ENDX using nonlinear mixed‐effects modeling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared with postmenopausal patients, premenopausal patients had a 30% higher risk for subtarget CSS,min ENDX at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1–13.8‐fold higher risk for subtarget CSS,min ENDX compared with elderly low‐weight patients. Considering ever‐rising obesity rates and the clinical importance of tamoxifen for premenopausal patients, this subpopulation may benefit most from individualized tamoxifen dosing.
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