Abstract | BACKGROUND:
ONT-093 is an orally bioavailable inhibitor of P-glycoprotein (P-gp). In pre-clinical studies, ONT-093 could inhibit P-gp and reverse multidrug resistance at nM concentrations with no effect on paclitaxel pharmacokinetics. Phase I trials of ONT-093 in normal human volunteers showed no dose-limiting toxicities at serum concentrations associated with biologic activity achieved with doses ranging from 300 to 500 mg. METHODS: Phase I pharmacokinetic trial of ONT-093 in doses from 300 to 500 mg administered before and after intravenous paclitaxel doses of 150 to 175 mg/m(2) repeated every 21 days. All patients received paclitaxel alone on cycle 1. RESULTS: 18 patients were enrolled onto 4 dose levels. Toxicity of the combination included neutropenia, arthralgia, myalgia, and peripheral neuropathy. Four of 6 patients receiving 500 mg doses of ONT-093 and paclitaxel at 175 mg/m(2) (dose level 4) had higher-grade neutropenia with cycle 2, with 1 patient experiencing febrile neutropenia. Plasma pharmacokinetic parameters of paclitaxel were unchanged between cycle 1 and 2 for dose levels 1 to 3, but at dose level 4, 45-65% increases in paclitaxel AUC were observed in 4 of the 6 patients. Mean C(max) of ONT-093 was 9 microM (range 5-15 microM) which were 3- to 5-fold higher than in single agent studies of ONT-093. CONCLUSIONS:
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Authors | Kim N Chi, Stephen K Chia, Ross Dixon, Michael J Newman, Vince J Wacher, Branimir Sikic, Karen A Gelmon |
Journal | Investigational new drugs
(Invest New Drugs)
Vol. 23
Issue 4
Pg. 311-5
(Aug 2005)
ISSN: 0167-6997 [Print] United States |
PMID | 16012790
(Publication Type: Clinical Trial, Clinical Trial, Phase I, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Antineoplastic Agents
- Antineoplastic Agents, Phytogenic
- Imidazoles
- OC 144-093
- cremophor
- Polyethylene Glycols
- Paclitaxel
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Topics |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(antagonists & inhibitors)
- Adult
- Aged
- Alopecia
(chemically induced)
- Antineoplastic Agents
(administration & dosage, adverse effects, pharmacokinetics)
- Antineoplastic Agents, Phytogenic
(administration & dosage, adverse effects, pharmacokinetics)
- Arthralgia
(chemically induced)
- Dose-Response Relationship, Drug
- Drug Therapy, Combination
- Female
- Humans
- Imidazoles
(administration & dosage, pharmacokinetics)
- Male
- Middle Aged
- Neoplasms
(drug therapy)
- Neutropenia
(chemically induced)
- Paclitaxel
(administration & dosage, pharmacokinetics)
- Polyethylene Glycols
(administration & dosage, adverse effects)
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