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Clinical pharmacology of UCN-01: initial observations and comparison to preclinical models

E A Sausville1, R D Lush, D Headlee

  • 1DTP Clinical Trials Unit, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD, USA. sausville@dtpax2.ncifcrf.gov

Cancer Chemotherapy and Pharmacology
|September 28, 1998
PubMed

Insights

UCN-01, a protein kinase antagonist, showed promise in preclinical models for renal carcinoma. Clinical trials revealed higher human tolerance and a longer half-life than initially predicted, necessitating real-time data analysis.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • UCN-01 (7-hydroxystaurosporine) is a protein kinase antagonist with preclinical efficacy in renal carcinoma xenografts.
  • Initial studies suggested a 72-hour continuous infusion schedule for UCN-01.
  • Preclinical toxicity studies in rats and dogs indicated maximum tolerated doses yielding peak plasma concentrations of 0.2-0.3 microM.

Purpose of the Study:

  • To evaluate the clinical pharmacology of UCN-01 in human subjects.
  • To compare human tolerance and pharmacokinetic profiles with preclinical data.
  • To inform real-time adjustments during Phase I clinical trials.

Main Methods:

  • Phase I clinical trial administration of UCN-01.
  • Pharmacokinetic analysis of UCN-01 plasma concentrations and half-life (T1/2).
  • Assessment of UCN-01 binding to human alpha1-acidic glycoprotein.

Main Results:

  • Humans tolerated UCN-01 concentrations approximately 10-fold greater than those found in preclinical models.
  • UCN-01 exhibited a markedly prolonged elimination half-life in humans compared to preclinical species.
  • Specific binding of UCN-01 to human alpha1-acidic glycoprotein was confirmed.

Conclusions:

  • Clinical pharmacology data for UCN-01 in humans differs significantly from preclinical predictions.
  • The prolonged half-life and higher tolerance in humans necessitate careful monitoring and adaptive dosing strategies.
  • Real-time analysis of clinical pharmacology data is crucial for optimizing UCN-01 therapy during early-phase trials.

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