A Phase I clinical trial and pharmacological study of nasogastrically administered
hexamethylene bisacetamide, a polar-planar compound with in vitro differentiating 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.