Pharmacokinetics and toxicity of 120-hour continuous-infusion hydroxyurea in patients with advanced solid tumors

Edward M. Newman, Mary Carroll, Steven A. Akman, Warren Chow, Paul Coluzzi, Victor Hamasaki, Lucille A. Leong, Kim A. Margolin, Robert J. Morgan, James W. Raschko, Stephen Shibata, George Somlo, Merry Tetef, Yun Yen, Chul W. Ahn, James H. Doroshow

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Abstract

A group of 18 patients with advanced cancer were entered on a phase I study of a 120-h continuous intravenous infusion of hydroxyurea. The dose of hydroxyurea was escalated in cohorts of patients from 1 to 2 to 3.2 g/m2 per day. The primary dose-limiting toxicity was neutropenia, often accompanied by leukopenia, thrombocytopenia and generalized skin rash. Prophylactic treatment of patients with dexamethasone and diphenhydramine hydrochloride prevented the skin rash, but not the hematopoietic toxicities. The pharmacokinetics of hydroxyurea were studied in all patients. The steady-state concentrations of hydroxyurea were linearly correlated with the dose (R2 = 0.71, n = 18, P < 0.0001). The mean ± SE concentrations were 93 ± 16, 230 ± 6 and 302 ± 27 μM at 1, 2 and 3.2 g/m2 per day, respectively. The mean ± SE renal and nonrenal clearances of hydroxyurea were 2.14 ± 0.18 and 3.39 ± 0.28 l/h per m2 (n = 16), neither of which correlated with the dose. The concentration of hydroxyurea in plasma decayed monoexponentially with a mean ± SE half-life of 3.25 ± 0.18 h (n = 17). The steady-state concentration of hydroxyurea was >200 μM in all nine patients treated at 2 g/m2 per day, a dose which was well tolerated for 5 days. We recommend this dose for phase II trials in combination with other antineoplastic agents.

Original languageEnglish
Pages (from-to)254-258
Number of pages5
JournalCancer Chemotherapy and Pharmacology
Volume39
Issue number3
DOIs
Publication statusPublished - Jan 1 1997
Externally publishedYes

Fingerprint

Pharmacokinetics
Hydroxyurea
Toxicity
Tumors
Neoplasms
Skin
Exanthema
Diphenhydramine
Antineoplastic Agents
Dexamethasone
Leukopenia
Neutropenia
Intravenous Infusions
Thrombocytopenia

Keywords

  • Drug therapy
  • Human
  • Hydroxyurea
  • Pharmacokinetics
  • Toxicity

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Newman, E. M., Carroll, M., Akman, S. A., Chow, W., Coluzzi, P., Hamasaki, V., ... Doroshow, J. H. (1997). Pharmacokinetics and toxicity of 120-hour continuous-infusion hydroxyurea in patients with advanced solid tumors. Cancer Chemotherapy and Pharmacology, 39(3), 254-258. https://doi.org/10.1007/s002800050569

Pharmacokinetics and toxicity of 120-hour continuous-infusion hydroxyurea in patients with advanced solid tumors. / Newman, Edward M.; Carroll, Mary; Akman, Steven A.; Chow, Warren; Coluzzi, Paul; Hamasaki, Victor; Leong, Lucille A.; Margolin, Kim A.; Morgan, Robert J.; Raschko, James W.; Shibata, Stephen; Somlo, George; Tetef, Merry; Yen, Yun; Ahn, Chul W.; Doroshow, James H.

In: Cancer Chemotherapy and Pharmacology, Vol. 39, No. 3, 01.01.1997, p. 254-258.

Research output: Contribution to journalArticle

Newman, EM, Carroll, M, Akman, SA, Chow, W, Coluzzi, P, Hamasaki, V, Leong, LA, Margolin, KA, Morgan, RJ, Raschko, JW, Shibata, S, Somlo, G, Tetef, M, Yen, Y, Ahn, CW & Doroshow, JH 1997, 'Pharmacokinetics and toxicity of 120-hour continuous-infusion hydroxyurea in patients with advanced solid tumors', Cancer Chemotherapy and Pharmacology, vol. 39, no. 3, pp. 254-258. https://doi.org/10.1007/s002800050569
Newman, Edward M. ; Carroll, Mary ; Akman, Steven A. ; Chow, Warren ; Coluzzi, Paul ; Hamasaki, Victor ; Leong, Lucille A. ; Margolin, Kim A. ; Morgan, Robert J. ; Raschko, James W. ; Shibata, Stephen ; Somlo, George ; Tetef, Merry ; Yen, Yun ; Ahn, Chul W. ; Doroshow, James H. / Pharmacokinetics and toxicity of 120-hour continuous-infusion hydroxyurea in patients with advanced solid tumors. In: Cancer Chemotherapy and Pharmacology. 1997 ; Vol. 39, No. 3. pp. 254-258.
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