Intrathecal 6-Mercaptopurine: Preclinical Pharmacology, Phase I/II Trial, and Pharmacokinetic Study

Peter C. Adamson, Frank M. Balis, Carola A.S. Arndt, Robert F. Murphy, Andrea J. Gillespie, David G. Poplack

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

For over 30 years, oral 6-mercaptopurine (6-MP) has been a mainstay of systemic maintenance therapy for acute lymphoblastic leukemia. De spite its efficacy as an antileukemic agent, 6-MP has not been previously administered by the intrathecal (IT) route. In anticipation of a clinical trial of IT 6-MP, preclinical cytotoxicity and pharmacology studies were performed to define a safe, effective dose. The optimal concentration (>1 fiM) and duration of exposure (>12 h) to 6-MP required for cytotoxicity were determined in vitro using human leukemia cell lines. The dose required to achieve the desired cerebrospinal fluid concentrations in humans was derived from pharmacokinetic parameters determined in rhesus monkeys. A phase I/II study was then performed in pediatrie patients with refractory meningea! leukemia. Nine patients (aged 3.5 to 16 years) with chronic meningea! leukemia (2 to 6 central nervous system relapses) were entered onto the study. All had previously failed, at a minimum, IT methotrexate, IT cytarabine, and cranial (±spinal) radia tion. A 10-mg IT dose of 6-MP (calculated to produce cytotoxic cerebro spinal fluid levels for 12 h) was administered twice weekly for 4 weeks. There were four complete responses and three partial responses. The duration of complete responses ranged from 7 to 22 weeks. Observed toxicities were not dose limiting and included mild headache (three patients) and minimal nausea (two patients). Pharmacokinetic studies performed in patients confirmed that cerebrospinal fluid concentrations of 6-MP were >1 /UMfor 12 h. These results indicate that the IT administration of 6-MP is feasible, is not associated with significant toxicity, and has definite activity in patients with refractory meningea! leukemia.

Original languageEnglish (US)
Pages (from-to)6079-6083
Number of pages5
JournalCancer Research
Volume51
Issue number22
StatePublished - 1991
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Fingerprint Dive into the research topics of 'Intrathecal 6-Mercaptopurine: Preclinical Pharmacology, Phase I/II Trial, and Pharmacokinetic Study'. Together they form a unique fingerprint.

  • Cite this

    Adamson, P. C., Balis, F. M., Arndt, C. A. S., Murphy, R. F., Gillespie, A. J., & Poplack, D. G. (1991). Intrathecal 6-Mercaptopurine: Preclinical Pharmacology, Phase I/II Trial, and Pharmacokinetic Study. Cancer Research, 51(22), 6079-6083.