Phase I and Pharmacokinetic Evaluation of Intravenous Hyaluronic Acid in Combination with Doxorubicin or 5-Fluorouracil

• BACKGROUND: Pre-clinically, hyaluronan (HA) has been demonstrated to systemically target chemotherapeutic drugs to tumours while ameliorating treatment toxicities. This study is a preliminary clinical investigation to determine if HA could be safely used in combination with 5-fluorouracil (5-FU) and doxorubicin (DOX). METHODS: Thirty patients with metastatic cancer were intravenously administered 500 mg/m2 HA in combination with escalating doses of DOX (30-60 mg/m2) or 5-FU (cumulative dose of 1,350-2,250 mg/m2 per cycle). The effect of pre-administration of 20 mg/m2 of folinic acid on HA/5-FU chemotherapy was also investigated. Patients were randomized to receive either HA/chemotherapy or chemotherapy alone in their first treatment cycle and vice versa for the second cycle. Patients received HA and chemotherapy in all subsequent cycles. RESULTS: Treatment was well tolerated, tumour responses were observed and the co-administration of HA did not alter the pharmacokinetics of clinically relevant doses of 5-FU or DOX. CONCLUSION: High doses of intravenous high-molecular-weight HA can be safely co-administered with clinical doses of chemotherapy without significantly altering the toxicity or pharmacokinetics of the drugs or HA.

Nyckelord

Adjuvants; Immunologic/administration & dosage/adverse effects/*pharmacokinetics

Adult

Aged

Antineoplastic Agents/administration & dosage/adverse effects/*pharmacokinetics

Comparative Study

Dose-Response Relationship; Drug

Doxorubicin/administration & dosage/adverse effects/*pharmacokinetics

Drug Therapy; Combination

Female

Fluorouracil/administration & dosage/adverse effects/*pharmacokinetics

Humans

Hyaluronic Acid/administration & dosage/adverse effects/*pharmacokinetics

Infusions; Intravenous

Leucovorin/pharmacology

Male

Middle Aged

Neoplasm Metastasis

Neoplasms/*drug therapy/pathology

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