In vivo bioavailability and pharmacokinetics of a c-MYC antisense phosphorodiamidate morpholino oligomer, AVI-4126, in solid tumors

Gayathri R. Devi, Tomasz M. Beer, Christopher L. Corless, Vikram Arora, Doreen L. Weller, Patrick L. Iversen

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

Phosphorodiamidate morpholino oligomers (PMO) inhibit targeted gene expression by preventing ribosomal assembly, thereby preventing mRNA translation. AVI-4126, a PMO targeted against c-MYC, has been extensively characterized in multiple cancer and other disease models and is currently in human clinical trials. A phase I clinical study was conducted to address the issue of PMO bioavailability in malignant tumors surgically excised from patients with adenocarcinoma of prostate and breast 1 day after i.v. administration of a single dose of 90 mg AVI-4126 PMO. The study objectives were to evaluate safety, to determine AVI-4126 concentration in tissue samples of the tumors, and to examine the distribution of AVI-4126 (margin versus tumor core). Significant concentrations of intact PMO similar to the animal models were detected in both human prostate and breast tumor tissues with increased distribution in the tumor core for the vascular breast tumors. No serious adverse events (graded according to National Cancer Institute Common Toxicity Criteria) were reported. Another phase I study was conducted in normal human volunteers to assess AVI-4126 plasma pharmacokinetics following single i.v. administration of 90 mg AVI-4126. Data from both human studies indicated similar plasma concentration-time profile. These studies show PMO bioavailability in tumor tissue and establish the feasibility of using PMO targeting specific genes in human cancer clinical trials.

Original languageEnglish (US)
Pages (from-to)3930-3938
Number of pages9
JournalClinical Cancer Research
Volume11
Issue number10
DOIs
StatePublished - May 15 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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