Clinical pharmacokinetic study of tiazofurin administered as a 1-hour infusion

H. N. Jayaram, E. Lapis, G. Tricot, P. Kneebone, E. Paulik, W. Zhen, G. P. Engeler, R. Hoffman, G. Weber

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Abstract

Tiazofurin, 2-β-D-ribofuranosylthiazole-4-carboxamide, is cytotoxic to murine and human tumor cells. In earlier Phase-I/-II trials performed in other centers in patients with solid tumors, the drug was given mainly as a 10-min bolus or as a continuous i.v. infusion for 5 days. These protocols were associated with serious side effects, including neurotoxicity, pleuropericarditis, and occasional myelosuppression. In our study, 26 patients with end-stage leukemia were treated with tiazofurin with 1-hr daily i.v. infusions, resulting in lower incidence and less severity of side effects. In this group, 7 attained complete remission and 7 showed hematologic responses. Out of 12 evaluable patients with myeloid blast crisis of chronic granulocytic leukemia, 10 (83%) responded to therapy, with 6 attaining complete response. We present pharmacokinetic parameters of our clinical study and examine some of the reasons for the lower toxicity found in our trials. In leukemic patients during and after infusion at doses of 1,100, 2,200 and 3,300 mg/m2 tiazofurin peak plasma concentrations were 245, 441 and 736 μM, respectively, values one-half of those calculated from other reports with a 10-min bolus administration. In our 1-hr infusion method, biphasic pharmacokinetics were noted with αt( 1/2 ) and βt( 1/2 ) of 0.5 and 6.2 hr, and tiazofurin was eliminated at a faster rate than in previous trials with continuous infusion. The area under the curve with our 1-hr infusion was 52% of that reported for the same dose given by continuous infusion. Our 1-hr infusion method and prompt and effective treatment of side effects enabled us to administer higher doses and larger total amounts of tiazofurin in longer treatment cycles than in any previous trials elsewhere. Tiazofurin therapy using 1-hr infusion may be feasible for other carefully selected types of malignancies.

Original languageEnglish
Pages (from-to)182-188
Number of pages7
JournalInternational Journal of Cancer
Volume51
Issue number2
DOIs
StatePublished - 1992

Fingerprint

tiazofurin
Pharmacokinetics
Blast Crisis
Neoplasms
Pericarditis
Therapeutics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Clinical Studies
Area Under Curve
Leukemia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Jayaram, H. N., Lapis, E., Tricot, G., Kneebone, P., Paulik, E., Zhen, W., ... Weber, G. (1992). Clinical pharmacokinetic study of tiazofurin administered as a 1-hour infusion. International Journal of Cancer, 51(2), 182-188. https://doi.org/10.1002/ijc.2910510204

Clinical pharmacokinetic study of tiazofurin administered as a 1-hour infusion. / Jayaram, H. N.; Lapis, E.; Tricot, G.; Kneebone, P.; Paulik, E.; Zhen, W.; Engeler, G. P.; Hoffman, R.; Weber, G.

In: International Journal of Cancer, Vol. 51, No. 2, 1992, p. 182-188.

Research output: Contribution to journalArticle

Jayaram, HN, Lapis, E, Tricot, G, Kneebone, P, Paulik, E, Zhen, W, Engeler, GP, Hoffman, R & Weber, G 1992, 'Clinical pharmacokinetic study of tiazofurin administered as a 1-hour infusion', International Journal of Cancer, vol. 51, no. 2, pp. 182-188. https://doi.org/10.1002/ijc.2910510204
Jayaram, H. N. ; Lapis, E. ; Tricot, G. ; Kneebone, P. ; Paulik, E. ; Zhen, W. ; Engeler, G. P. ; Hoffman, R. ; Weber, G. / Clinical pharmacokinetic study of tiazofurin administered as a 1-hour infusion. In: International Journal of Cancer. 1992 ; Vol. 51, No. 2. pp. 182-188.
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AU - Lapis, E.

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AU - Kneebone, P.

AU - Paulik, E.

AU - Zhen, W.

AU - Engeler, G. P.

AU - Hoffman, R.

AU - Weber, G.

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