A phase I study of DHP107, a mucoadhesive lipid form of oral paclitaxel, in patients with advanced solid tumors: Crossover comparisons with intravenous paclitaxel

Hong, Yong Sang; Kim, Kyu-Pyo; Lim, Hyeong‐Seok; Bae, Kyun‐Seop; Ryu, Min‐Hee; Lee, Jae‐Lyun; Chang, Heung Moon; Kang, Yoon‐Koo; 김혜연,; Kim, Tae Won

doi:10.1007/s10637-012-9841-7

Cited by 19 publications

(24 citation statements)

References 20 publications

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“…CrEL is a well-documented risk factor of hypersensitivity reactions, and CrEL-free formulations do not cause hypersensitivity reactions [3,21,22]. Oral paclitaxel and HM30181A did not induce hypersensitivity reactions without premedication, similar to the other CrEL-free paclitaxel formulations.…”

Section: Discussionmentioning

confidence: 87%

“…The potential advantages of oral formulation include the following: lack of hypersensitivity, convenience for patients, and potential continuous exposure to paclitaxel. Some oral forms of paclitaxel have been developed and exhibited promising results in phase 1 studies [2,3]; however, none of these agents have been fully developed. The major obstacle in developing oral paclitaxel has been poor oral bioavailability that originates from high affinity for P-glycoprotein (P-gp), which is abundant in the gastrointestinal mucosa [4].…”

Section: Introductionmentioning

confidence: 99%

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A Phase I Study of Oral Paclitaxel with a Novel P-Glycoprotein Inhibitor, HM30181A, in Patients with Advanced Solid Cancer

et al. 2014

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PurposeThe purpose of this study is to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and recommended phase II dose of an oral drug composed of paclitaxel and HM30181A, which is an inhibitor of P-glycoprotein, in patients with advanced cancers.Materials and MethodsPatients with advanced solid tumors received standard therapy were given the study drug at escalating doses, using a 3+3 design. The study drug was orally administered on days 1, 8, and 15, with a 28-day cycle of administration. The dose of paclitaxel was escalated from 60 to 420 mg/m2, and the dose of HM30181A was escalated from 30-210 mg/m2.ResultsA total of twenty-four patients were enrolled. Only one patient experienced a doselimiting toxicity—a grade 3 neutropenia that persisted for more than 2 weeks, at 240 mg/m2 of paclitaxel. MTD was not reached. The maximum plasma concentration was obtained at a dose level of 300 mg/m2 and the area under the curve of plasma concentration- time from 0 to the most recent plasma concentration measurement of paclitaxel was reached at a dose level of 420 mg/m2. The absorption of paclitaxel tends to be limited at doses that exceed 300 mg/m2. The effective plasma concentration of paclitaxel was achieved at a dose of 120 mg/m2. Responses of 23 patients were evaluated; 8 (34.8%) had stable disease and 15 (65.2%) had progressive disease.ConclusionThe study drug appears to be well tolerated, and the effective plasma concentration of paclitaxel was achieved. The recommended phase II dose for oral paclitaxel is 300 mg/m2.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

A Phase I Study of Oral Paclitaxel with a Novel P-Glycoprotein Inhibitor, HM30181A, in Patients with Advanced Solid Cancer

et al. 2014

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“…More recently, a novel oral formulation of paclitaxel called DHP107 was developed that does not require co-administration of Cyclosporine A. DHP107 is a mucoadhesive formulation of paclitaxel, created by dissolving paclitaxel in a mixture of monoolein, tricarprylin and Tween ® 80 [5]. One Phase I crossover study has been completed using DHP107 in patients with advanced solid tumor malignancies who had failed standard therapies [6]. In total, 33 patients were enrolled and given DHP107 once and then subsequently received iv.…”

Section: Novel Oral Formulations Of Paclitaxel and Docetaxelmentioning

confidence: 99%

“…Pharmacokinetics showed that inter-patient variability increased greatly above doses of 250 mg/m 2 and the authors of the study recommended this as the maximum dose for future studies. Another Phase I trial of DHP107 using a weekly dosing schedule is in progress [6]…”

Section: Novel Oral Formulations Of Paclitaxel and Docetaxelmentioning

confidence: 99%

Novel oral taxane therapies: recent Phase I results

Flores¹,

Saif²

2013

Clinical Investigation

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“…In a previous first-in-human study, a single escalating dose of oral DHP107 was shown to be safe and feasible, with no doselimiting toxicity when administered at up to 600 mg/m 2 in patients with advanced solid tumors [21,22] . In a phase I study, the recommended oral dose of DHP107 has been reported to…”

Section: Introductionmentioning

confidence: 99%

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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A phase I study of DHP107, a mucoadhesive lipid form of oral paclitaxel, in patients with advanced solid tumors: Crossover comparisons with intravenous paclitaxel

Abstract: DHP107 was safe and feasible in patients with advanced malignancies. As exposure of paclitaxel plateau among patients receiving more than 250 mg/m(2) of DHP107, the dose escalation of DHP107 may be limited to 250 mg/m(2) in further clinical trials.

Cited by 19 publications

References 20 publications

A Phase I Study of Oral Paclitaxel with a Novel P-Glycoprotein Inhibitor, HM30181A, in Patients with Advanced Solid Cancer

A Phase I Study of Oral Paclitaxel with a Novel P-Glycoprotein Inhibitor, HM30181A, in Patients with Advanced Solid Cancer

Novel oral taxane therapies: recent Phase I results

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

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