A novel self-microemulsifying formulation of paclitaxel for oral administration to patients with advanced cancer

Veltkamp, Stephan A.; Thijssen, Bram; Garrigue, Jean-Sébastien; Lambert, Grégory; Lallemand, Frédéric; Binlich, Florence; Huitema, Alwin D. R.; Nuijen, Bastiaan; Nol, A.; Beijnen, Jos H.; Schellens, Jan H.M.

doi:10.1038/sj.bjc.6603312

Cited by 42 publications

(17 citation statements)

References 23 publications

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“…Firstly, the median time to peak concentration of paclitaxel following oral Genetaxyl at 60 mg/m 2 was 1.5 hours, consistent with prior results showing that this parameter is lower when paclitaxel is administered in a formulation with lower concentrations of CrEL (1.5-2.9 versus 3.3-4.1 hours) [11,21]. This suggest that paclitaxel is absorbed more rapidly when the formulation contains no or less CrEL; it is possible that the rate of absorption of paclitaxel is affected by concentration-dependent entrapment of paclitaxel in CrEL micelles, thereby preventing paclitaxel from crossing the gastrointestinal membrane.…”

Section: Discussionsupporting

confidence: 78%

“…These results indicate that CrEL may play a more important role in affecting the initial rate of gastrointestinal absorption than processes taking place subsequently. Indeed, it is possible that the micellar effects of CrEL limit the absorption of paclitaxel in a timedependent fashion, and that these effects are diminished with time due to enzymatic and/or chemical hydrolysis of the excipients within the gastrointestinal tract, as suggested previously [11].…”

Section: Discussionmentioning

confidence: 91%

“…However, development of oral paclitaxel is hampered by poor bioavailability [5], which is due to extensive first-pass metabolism by the cytochrome P450 isoforms CYP2C8 and CYP3A4 [6] and, to a lesser extent, to paclitaxel's affinity for efflux transporters expressed in the gastrointestinal tract and liver, such as ABCB1 (P-glycoprotein) [5] and ABCC2 (cMOAT; MRP2) [7]. Strategies used to improve the oral bioavailability of paclitaxel include coadministration of enzyme/transporter inhibitors such as cyclosporin A (CsA) with paclitaxel, and, more recently, the development of alternative formulations of paclitaxel on the basis of mixed micelles, nanoemulsions, or lipid nanocapsules [8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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“…Oral chemotherapy can enable the development of dosing regimens as well resulting in prolonged periods of plasma concentration above pharmacologically relevant levels. 2 Lastly, oral chemotherapy will be important for patients who may have personal dislike to repeated needle-sticks or have poor venous access.…”

Section: Introductionmentioning

confidence: 99%

Curcumin Enhances Oral Bioavailability and Anti-Tumor Therapeutic Efficacy of Paclitaxel upon Administration in Nanoemulsion Formulation

Ganta

Devalapally

Amiji

2010

Journal of Pharmaceutical Sciences

111

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“…The formulation needs optimization to increase the systemic exposure upon oral administration of indibulin. This is a common problem in the development of oral formulations of taxanes such as paclitaxel [13][14][15]. Several clinical studies were described with new oral paclitaxel formulations, however, so far no clinically applicable oral paclitaxel formulation has been developed [13][14][15].…”

Section: Discussionmentioning

confidence: 98%

Dose-finding and pharmacokinetic study of orally administered indibulin (D-24851) to patients with advanced solid tumors

et al. 2009

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Indibulin (ZIO-301/D-24851) is an orally applied small molecule with antitumor activity based upon destabilization of microtubule polymerization. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) as well as the dose limiting toxicity (DLT), the pharmacokinetics, safety and tolerability of orally administered indibulin as capsule formulation in patients with advanced solid tumors. Patients received a single dose of indibulin. Seven dose-levels were evaluated: 100 mg, 150 mg, 250 mg, 350 mg and 600 mg once daily (QD), 450 mg and 600 mg twice daily (BID). After a washout period, patients received indibulin at the pre-defined daily dose for 14 days every 3 weeks (multiple dose part). A total of 28 patients entered the study. Indibulin administered as capsules was generally well tolerated. The MTD was not reached. There was a disproportionate increase of the area under the plasma concentration-time curve (AUC) with dose, with declining AUC corrected for dose starting at the 250 mg dose-level. There was no significant difference in AUC of indibulin after multiple dosing (day 1-14) compared to single administration (day-4). Inter-patient variability in AUC (102% CV) was high. A plateau in drug exposure was observed prior to reaching the MTD. Continued dose-escalation was unlikely to yield any increase in exposure of indibulin. The formulation needs optimization to increase the systemic exposure upon oral administration.

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A novel self-microemulsifying formulation of paclitaxel for oral administration to patients with advanced cancer

Cited by 42 publications

References 23 publications

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

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

Curcumin Enhances Oral Bioavailability and Anti-Tumor Therapeutic Efficacy of Paclitaxel upon Administration in Nanoemulsion Formulation

Dose-finding and pharmacokinetic study of orally administered indibulin (D-24851) to patients with advanced solid tumors

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