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

Abstract

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.

DHP23002 as a next generation oral paclitaxel formulation for pancreatic cancer therapy

“…The reason for the paclitaxel persistence in tumors remains unclear; however, based on the mechanism of DHP107, we can make a few assumptions regarding DHP23002. DHP23002 can prolong the release of paclitaxel in the intestine to enhance the absorption and stability of the drug in the tumor and can evade the action of P-glycoproteins [17–18]. In a PK experiment conducted on large animals, DHP23002 showed similar PK patterns, and it was confirmed that an effective paclitaxel concentration was maintained in blood for a prolonged period even when low doses were administered (S2 Fig).…”

HM30181A, a potent P-glycoprotein inhibitor, potentiates the absorption and <i>in vivo</i> antitumor efficacy of paclitaxel in an orthotopic brain tumor model

“…In addition, mice with intra-cerebrally implanted tumor cells show increased apoptosis of tumor cells in brain tumors after co-oral administration of HM and PTX. A recent phase I clinical study investigating the use of an oral drug containing PTX and HM for the treatment of advanced solid tumors, such as cancers of the breast, pancreas, and gallbladder, has suggested the relative safety of HM PTX co-treatment in clinical practice 28 .…”

Carbon nano-onion-mediated dual targeting of P-selectin and P-glycoprotein to overcome cancer drug resistance

“…This can be done by using inhibitor to block the P-gp efflux. Indeed, coadministration of the therapeutic agents and P-gp inhibitors in their free forms may reduce the expulsion of the agents by P-gp and increase the intracellular drug concentration 15 , 16 . Nevertheless, P-gp pumps also play a crucial physiological role in protecting tissues from poisonous xenobiotics and endogenous metabolites that are widely distributed throughout the body 17 – 19 .…”