Approaches to optimal dosing of hexamethylene bisacetamide.
HMBA is a potent differentiating agent capable of causing > 95% morphological differentiation in cell lines in vitro. The induction of differentiation is dependent on both the concentration of and the duration of exposure to HMBA. However, acute toxicities (neurotoxicity and acidosis) have limited the maximal HMBA css value to < 2 mM, which is at the lower limit of effective in vitro concentrations. When HMBA css values have been maintained at 1-2 mM, thrombocytopenia has limited the duration of HMBA infusion to < or = 10 days. The present studies were performed to determine whether exposure to HMBA could be individualized and maximized without resulting in intolerable toxicity to patients and to determine which factors would predispose a patient to the development of acute toxicity during treatment with HMBA. For these investigations, patients were given HMBA at a target css using an adaptive-feedback-control method rather than at a set dose. Because HMBA administration produces large anion gaps, a simple maneuver such as alkalinization might enable the escalation of plasma HMBA css values to > 2 mM. HMBA was given as a 5-day CI to 14 patients (26 courses) at 2 target HMBA css levels near the maximal tolerated value in the presence or absence of concurrent alkalinization with sodium bicarbonate. Symptomatic acidosis occurred in one patient who did not receive bicarbonate. Neurotoxicity proved to be dose-limiting at the target HMBA css value of 1.5-2.0 mM in the absence of concurrent alkalinization and at a css level of > 2 mM, regardless of alkalinization. No neurotoxicity was seen at target HMBA css values of 1.5-2.0 mM in patients who did receive concurrent alkalinization. Alkalinization was not associated with any detectable changes in plasma HMBA metabolites. With the maximal tolerable 5-day HMBA css having thus been defined at 1.5-2.0 mM, we attempted to maximize exposure to HMBA by defining a tolerable duration of infusion. Individualization of the duration of HMBA infusion to a target nadir PLT was performed in patients who had received an initial 5-day CI of HMBA at a css 1.5-2.0 mM along with concurrent alkalinization. The AUC achieved and the thrombocytopenia produced during this first course were used to predict the duration of infusion that each patient would subsequently tolerate (at an HMBA css of 1-2 mM) to achieve a nadir PLT of 75,000-100,000/microliters.(ABSTRACT TRUNCATED AT 400 WORDS)
Conley
B A
BA
Division of Developmental Therapeutics, University of Maryland Cancer Center.
Egorin
M J
MJ
Sinibaldi
V
V
Sewack
G
G
Kloc
C
C
Roberts
L
L
Zuhowski
E G
EG
Forrest
A
A
Van Echo
D A
DA
D000081:Acetamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000138:Acidosis / Q000139:chemically induced / Q000517:prevention & control; D000328:Adult; D000368:Aged; D001639:Bicarbonates / Q000494:pharmacology; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006397:Hematinics / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D009422:Nervous System Diseases / Q000139:chemically induced; D012964:Sodium / Q000494:pharmacology; D017693:Sodium Bicarbonate
D000081:Acetamides; D001639:Bicarbonates; D006397:Hematinics; D017693:Sodium Bicarbonate; D012964:Sodium; C014026:hexamethylene bisacetamide