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 c_ss value to <2 mm, which is at the lower limit of effective in vitro concentrations. When HMBA c_ss values have been maintained at 1-2 mm, thrombocytopenia has limited the duration of HMBA infusion to ≤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 c_ss 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 c_ss values to >2 mm. HMBA was given as a 5-day CI to 14 patients (26 courses) at 2 target HMBA c_ss 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 c_ss value of 1.5-2.0 mm in the absence of concurrent alkalinization and at a c_ss level of >2 mm, regardless of alkalinization. No neurotoxicity was seen at target HMBA c_ss 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 c_ss 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 c_ss 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 c_ss of 1-2 mm) to achieve a nadir PLT of 75,000-100,000/μl. The observed percentage changes in PLT matched the predicted percentage change in PLT, with the mean error (ME) being -8.9%. For a better determination as to which factors may contribute to neurotoxicity or acidosis in patients receiving HMBA, 98 courses of HMBA given as 5- to 10-day CIs to 56 patients were analyzed (multifactorial logistic regression). An HMBA AUC value of >7.5 mm x day, the use of any concomitant narcotic analgesics, and a mean plasma HMBA level of >1.5 mm or a peak plasma concentration of ≥1.75 mm correlated significantly with grade 3 neurotoxicity (P<0.001), whereas concomitant alkalinization and a mean plasma HMBA concentration of <1.5 mm were associated with a lack of neurotoxicity (P<0.001). An AUC value of >7.5 mm x day, a mean or peak plasma HMBA level of >1.5 mm, and an age of >70 years correlated with the likelihood of a large anion gap (P<0.03). With the above factors being accounted for, neither the duration of infusion nor the C_cr value showed any correlation with these toxicities in this patient population. These results imply that HMBA may be given for individualized durations at a c_ss of 1.5 mm in the presence or absence of concomitant alkalinization and that narcotic analgesics should not be given to patients receiving this agent. However, due to the resultant acute neurotoxicity, it is unlikely that AUCs of >7.5 mm x day will be tolerated during simultaneous maintenance of a c_ss value of >1.0 mm.