Weekly oral paclitaxel as first-line treatment in patients with advanced gastric cancer

Kruijtzer, C. M. F.; Boot, H.; Beijnen, Jos H.; Lochs, H.; Parnis, Francis; Planting, A. S. T.; Pelgrims, J.; Williams, R.; Mathôt, Ron A. A.; Rosing, Hilde; Schot, Margaret; Tinteren, Harm van; Schellens, Jan H.M.

doi:10.1093/annonc/mdg078

Cited by 37 publications

(30 citation statements)

References 27 publications

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“…A decrease in paclitaxel absorption after repeated dosing has also been reported in previous studies [20,[25][26][27] . Moreover, paclitaxel is known to be a substrate of P-gp and is metabolized mainly by CYP3A4 and CYP2C8, and increased P-gp and CYP expression after oral paclitaxel administration has been demonstrated and confirmed by observations that paclitaxel absorption increases after co-administration with P-gp inhibitors [25][26][27] . To evaluate whether the expression levels of P-gp, CYP3A4, and CYP2C8 were enhanced by oral paclitaxel administration, we performed Western blot analysis of these proteins in the livers and small intestines of mice collected up to 7 d after a single dose of oral DHP107 at 50 mg/kg ( Figure 5).…”

Section: Western Blottingsupporting

confidence: 82%

“…Paclitaxel has a low oral bioavailability, owing to the multidrug efflux pump P-gp in the intestine and to hepatic and intestinal first-pass elimination by CYPs [25][26][27] . In this study, we evaluated the effects of P-gp and CYPs by administering F109 instead of DHP107 as the first dose.…”

Section: Discussionmentioning

confidence: 99%

“…Such b.i.d. dosing has also been attempted in one of the first clinical trials of another oral paclitaxel formulation [25][26][27] and has been reported to be effective when oral paclitaxel (Paxene ® or Paxoral ® ) is administered with cyclosporine A [25][26][27] . Repeated dosing studies of DHP107 have also been performed in animal models, and DHP107 has been used in metronomic therapy in a mouse model of ovarian cancer [20] .…”

Section: Original Articlementioning

confidence: 99%

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Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase

et al. 2016

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Paclitaxel is a most widely used anticancer drug with low oral bioavailability, thus it is currently administered via intravenous infusion. DHP107 is a lipid-based paclitaxel formulation that can be administered as an oral solution. In this study, we investigated the mechanism of paclitaxel absorption after oral administration of DHP107 in mice and rats by changing the dosing interval, and evaluated the influence of bile excretion. DHP107 was orally administered to mice at various dosing intervals (2, 4, 8, 12, 24 h) to examine how residual DHP107 affected paclitaxel absorption during subsequent administration. Studies with small-angle X-ray diffraction (SAXS) and cryo-transmission electron microscopy (cryo-TEM) showed that DHP107 formed a lipidic sponge phase after hydration. The AUC values after the second dose were smaller than those after the first dose, which was correlated to the induction of expression of P-gp and CYP in the livers and small intestines from 2 h to 7 d after the first dose. The smaller AUC value observed after the second dose was also attributed to the intestinal adhesion of residual formulation. The adhered DHP107 may have been removed by ingested food, thus resulting in a higher AUC. In ex vivo and in vivo mucoadhesion studies, the formulation adhered to the villi for up to 24 h, and the amount of DHP107 that adhered was approximately half that of monoolein. The paclitaxel absorption after administration of DHP107 was not affected by bile in the cholecystectomy mice. The dosing interval and food intake affect the oral absorption of paclitaxel from DHP107, which forms a mucoadhesive sponge phase after hydration. Bile excretion does not affect the absorption of paclitaxel from DHP107 in vivo.

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Section: Western Blottingsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Original Articlementioning

confidence: 99%

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Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase

et al. 2016

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“…A phase II trial of orally administered paclitaxel and cyclosporine in 23 patients with previously treated NSCLC resulted in an overall response rate of 26%, a median time to progression of 3.5 months, and an overall survival of 6 months, results that are in accordance with other single agent drugs given intravenously [82]. A similar trial in 24 untreated gastric cancer patients found an overall response rate of 32% and a median time to progression of 16 weeks [83]. Evidence also exists for enhanced intestinal absorption for chemotherapy drugs, such as etoposide, when administered in combination with P-gp inhibitors [84].…”

Section: Role Of P-gp Inhibitorsmentioning

confidence: 66%

The Role of ABC Transporters in Clinical Practice

2003

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Drug resistance remains one of the primary causes of suboptimal outcomes in cancer therapy. ATP-binding cassette (ABC) transporters are a family of transporter proteins that contribute to drug resistance via ATPdependent drug efflux pumps. P-glycoprotein (P-gp), encoded by the MDR1 gene, is an ABC transporter normally involved in the excretion of toxins from cells. It also confers resistance to certain chemotherapeutic agents. P-gp is overexpressed at baseline in chemotherapy-resistant tumors, such as colon and kidney cancers, and is upregulated after disease progression following chemotherapy in malignancies such as leukemia and breast cancer. Other transporter proteins mediating drug resistance include those in the multidrug-resistance-associated protein (MRP) family, notably MRP1, and ABCG2. These transporters are also involved in normal physiologic functions. The expressions of MRP family members and ABCG2 have not been well worked out in cancer.Increased drug accumulation and drug resistance reversal with P-gp inhibitors have been well documented in vitro, but only suggested in clinical trials. Limitations in the design of early resistance reversal trials contributed to disappointing results. Despite this, three randomized trials have shown statistically significant benefits with the use of a P-gp inhibitor in combination with chemotherapy. Improved diagnostic techniques aimed at the selection of patients with tumors that express P-gp should result in more successful outcomes. Further optimism is warranted with the advent of potent, nontoxic inhibitors and new treatment strategies, including the combination of new targeted therapies with therapies aimed at the prevention of drug resistance. The Oncologist 2003;8:411-424

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“…CsA is an efficacious inhibitor of CYP3A4 [13], ABCB1 [14], and ABCC2 [15], and the feasibility of co-administering CsA with oral paclitaxel to increase systemic exposure has been demonstrated in various Phase 1 [16][17][18] and Phase II clinical trials [19,20]. However, the apparent bioavailability of oral paclitaxel is still relatively low (about 30%), which is partly due to the presence of high concentrations (50%, v/v) of the formulation excipient Cremophor EL (CrEL), which limits drug absorption through the formation of micelles that entrap paclitaxel [21].…”

Section: Introductionmentioning

confidence: 99%

Oral bioavailability of a novel paclitaxel formulation (Genetaxyl) administered with cyclosporin A in cancer patients

et al. 2008

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The formulation excipient Cremophor EL (CrEL) is known to limit absorption of oral paclitaxel given together with cyclosporin A (CsA). We hypothesized that the use of oral Genetaxyl, a paclitaxel formulation containing only 20% CrEL would have an improved oral bioavailability. Cohorts of 6 patients were treated with oral Genetaxyl at a dose of 60, 120, or 180 mg/m 2 and 10 mg/kg of oral CsA in cycle 1. In cycle 2, patients received intravenous (i.v.) Genetaxyl (175 mg/m 2 , 3-hour infusion). Three additional patients received one dose of generic i.v. paclitaxel (Genaxol, containing 50% CrEL; 175 mg/m 2 , 3-hour infusion). The median area under the plasma concentration-time curve (AUC) and peak concentration of total paclitaxel following i.v. Genetaxyl were lower than those for i.v. Genaxol, as a result of significantly increased clearance (P = 0.017), and the AUC ratio for unbound to total paclitaxel for i.v. Genetaxyl was about 2 times higher than that for i.v. Genaxol (P = 0.0077). After oral administration of Genetaxyl at doses of 60, 120, and 180 mg/m 2 , the median total paclitaxel AUCs were 1.29, 1.60, and 1.85 µg×h/mL, respectively, suggesting a less than proportional increase in systemic exposure with increasing doses. The corresponding median values for the apparent bioavailability of oral Genetaxyl were similar when calculated either based on data for total paclitaxel (30.1%) or unbound paclitaxel (30.6%) when compared to i.v. Genetaxyl.

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Weekly oral paclitaxel as first-line treatment in patients with advanced gastric cancer

Abstract: Oral paclitaxel in combination with CsA is both active and safe in chemonaïve patients with advanced gastric cancer. Toxicities were mainly gastrointestinal.

Cited by 37 publications

References 27 publications

Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase

Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase

The Role of ABC Transporters in Clinical Practice

Oral bioavailability of a novel paclitaxel formulation (Genetaxyl) administered with cyclosporin A in cancer patients

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