Cancer Chemotherapy and Pharmacology

, Volume 31, Issue 1, pp 37–45 | Cite as

Approaches to optimal dosing of hexamethylene bisacetamide

  • Barbara A. Conley
  • Merrill J. Egorin
  • Victoria Sinibaldi
  • Gerald Sewack
  • Curtis Kloc
  • Lynelle Roberts
  • Eleanor G. Zuhowski
  • Alan Forrest
  • David A. Van Echo
Original Articles Hexamethylene Bisacetamide Pharmacokinetics Pharmacodynamic

Summary

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 HMBAcss value to <2mm, which is at the lower limit of effective in vitro concentrations. When HMBAcss values have been maintained at 1–2mm, 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 targetcss 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 HMBAcss values to >2mm. HMBA was given as a 5-day CI to 14 patients (26 courses) at 2 target HMBAcss 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 HMBAcss value of 1.5–2.0mm in the absence of concurrent alkalinization and at acss level of >2mm, regardless of alkalinization. No neurotoxicity was seen at target HMBAcss values of 1.5–2.0mm 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 HMBAcss having thus been defined at 1.5–2.0mm, 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 acss 1.5–2.0mm 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 HMBAcss of 1–2mm) 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 >7.5mm x day, the use of any concomitant narcotic analgesics, and a mean plasma HMBA level of >1.5mm or a peak plasma concentration of ≥1.75mm correlated significantly with grade 3 neurotoxicity (P<0.001), whereas concomitant alkalinization and a mean plasma HMBA concentration of <1.5mm were associated with a lack of neurotoxicity (P<0.001). An AUC value of >7.5mm x day, a mean or peak plasma HMBA level of >1.5mm, 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 theCcr value showed any correlation with these toxicities in this patient population. These results imply that HMBA may be given for individualized durations at acss of 1.5mm 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 >7.5mm x day will be tolerated during simultaneous maintenance of acss value of >1.0mm.

Keywords

Acute Toxicity Sodium Bicarbonate Peak Plasma Hexamethylene Narcotic Analgesic 

Abbreviations

HMBA

hexamethylene bisacetamide

css

plasma steadystate concentration

CI

continuous infusion

ME

mean error

PLT

platelet count

AUC

area under the concentration-time curve

Ccr

creatinine clearance

DMSO

dimethylsulfoxide

NMF

N-methylformamide

UMCC

University of Maryland Cancer Center

ECOG

Eastern Cooperative Oncology Group

WBC

white-blood-cell count

CBC

complete blood count

EKG

electrocardiogram

AG

anion gap

Vmax

predicted maximal nonrenal HMBA elimination rate

Km

predicted concentration of HMBA at which the nonrenal elimination rate is half of the Vmax value

SLOPE

predicted slope relating the renal clearance of HMBA toCcr

Ra

new infusion rate

Hct

hematocrit

6AcHA

6-acetamidohexanoic acid

NADAH

N-acetyl-1,6-diaminohexane

DAH

1,6-diaminohexane

6AmHA

6-aminohexanoic acid

MAO

monoamine oxidase

MAP

maximum a priori

MAE

mean absolute error

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Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Barbara A. Conley
    • 1
    • 2
  • Merrill J. Egorin
    • 1
    • 2
  • Victoria Sinibaldi
    • 1
  • Gerald Sewack
    • 1
  • Curtis Kloc
    • 1
  • Lynelle Roberts
    • 1
  • Eleanor G. Zuhowski
    • 1
  • Alan Forrest
    • 1
  • David A. Van Echo
    • 1
    • 2
  1. 1.Divisions of Developmental Therapeutics (BAC, MJE, GS, CK, LR, EGZ, AF) and Medical Oncology (BAC, DAVE, VS)University of Maryland Cancer CenterBaltimoreUSA
  2. 2.Division of Medical Oncology, Department of MedicineUniversity of Maryland School of Medicine (BAC, MJE, DAVE)USA

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