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A Phase I Bioavailability and Pharmacokinetic Study of Hexamethylene Bisacetamide (NSC 95580) Administered via Nasogastric Tube¹

Hematology-Oncology Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC 20307 [F. T. W., F. A. L., R. B. W.], and Laboratory of Medicinal Chemistry, Developmental Therapeutics Program [J. A. K., J. S. R.] and Investigational Drug Branch, Cancer Therapy Evaluation Program [B. L-J., H. G. C.], Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

A Phase I clinical trial and pharmacological study of nasogastrically administered hexamethylene bisacetamide, a polar-planar compound with in vitro differentating activity, was conducted in 14 adult patients with refractory cancer. Hexamethylene bisacetamide was administered as a 5% (w/v) solution via a nasogastric or gastrostomy tube every 4 h for 5 days, followed in 21 days by a 5-day continuous i.v. infusion at the same daily dose. Parenteral drug administration was then continued at the same interval in the absence of disease progression or unacceptable toxicity. Three patients each were treated at doses of 12 and 24 g/m²/day, while eight patients received a dose of 30 g/m²/day. Toxicity was comparable for both routes of drug administration at the above doses. Nasogastrically administered hexamethylene bisacetamide was well tolerated at the lower doses, whereas neurotoxicity and nausea and vomiting were the major, but manageable, toxicities at 30 g/m²/day. Metabolic acidosis, renal dysfunction, mucositis, and thrombocytopenia were the other commonly observed drug toxicities at this dose. No objective tumor responses were observed. Hexamethylene bisacetamide was rapidly absorbed from the gastrointestinal tract with a mean measured bioavailability of 99 ± 15%. Pharmacokinetic parameters for hexamethylene bisacetamide and plasma concentrations of the two major metabolites, N-acetyl-1,6-diaminohexane and 6-acetamidohexanoic acid, were similar for either route of administration in individual patients. Hexamethylene bisacetamide exhibited apparent monoexponential plasma elimination after either nasogastric or parenteral administration with 27 to 60% of the administered dose being excreted in the urine as parent compound. Based on its demonstrated complete bioavailability and tolerability, nasogastric administration of hexamethylene bisacetamide can be directly and safely substituted for the comparable i.v. dose.

¹ The opinion or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the view of the Department of the Army or the Department of Defense.

² To whom requests for reprints should be addressed, at Division of Neoplastic Diseases, Department of Medicine, New York Medical College, Valhalla, NY 10595.

Received 9/ 7/90. Accepted 1/14/91.