Pharmacokinetics of thalidomide in an elderly prostate cancer population

William D. Figg, Sangeeta Raje, Kenneth S. Bauer, Anne Tompkins, David Venzon, Raymond Bergan, Alice Chen, Michael Hamilton, James Pluda, Eddie Reed

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Abstract

Thalidomide, a glutamic acid derivative, has recently been shown to inhibit in vitro angiogenesis, the process of formation of new blood vessels. This Phase II study examined the pharmacokinetics of thalidomide in patients with clinically progressive hormone-refractory prostate cancer. Patients (aged 55 to 80 years) were randomized to two different arms, low dose versus high dose. Patients in the low-dose group were given 200 mg of thalidomide and patients in the high-dose group received 200 mg of thalidomide, with subsequent dose escalations to 1200 mg. Serial serum or blood samples were obtained for pharmacokinetic assessment after administration of a single oral dose or multiple daily dosing of thalidomide and were assayed by reversed- phase HPLC. Pharmacokinetic parameters for both the single and multiple dosing were calculated with ADAPT II. A one-compartment model best fit the data. After single dosing, the oral clearance and apparent volume of distribution for the low-dose regimen (n = 13) were 7.41 ± 2.05 L/h and 66.93 ± 34.27 L, respectively, whereas for the high-dose regimen (n = 11), these values were 7.21 ± 2.89 L/h and 165.81 ± 84.18 L, respectively. The elimination half-lives for the low and high dose were 6.52 + 3.81 and 18.25 ± 14.08 h, respectively. After the multiple dosing of thalidomide, the oral clearance and apparent volume of distribution for the low-dose group (n = 10) were 6.35 ± 1.64 L/h and 64.63 ± 23.20 L, respectively, whereas for the high-dose group (n = 11), these values were 7.73 ± 2.27 L/h and 167.85 ± 82.08 L, respectively. The elimination half-lives for the low and high close were 7.08 ± 1.87 and 16.19 ± 9.57 h, respectively. For both the single and multiple dosing of thalidomide, the apparent volume of distribution and half- life were significantly higher for the high-dose group than those for the low-dose group. The higher apparent volume of distribution may be attributable to several factors, such as change in absorption, protein binding, etc. A dose-proportional increase in thalidomide steady-state concentrations was seen after multiple daily dosing of thalidomide.

Original languageEnglish (US)
Pages (from-to)121-125
Number of pages5
JournalJournal of Pharmaceutical Sciences
Volume88
Issue number1
DOIs
StatePublished - Jan 1999

ASJC Scopus subject areas

  • Pharmaceutical Science

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    Figg, W. D., Raje, S., Bauer, K. S., Tompkins, A., Venzon, D., Bergan, R., Chen, A., Hamilton, M., Pluda, J., & Reed, E. (1999). Pharmacokinetics of thalidomide in an elderly prostate cancer population. Journal of Pharmaceutical Sciences, 88(1), 121-125. https://doi.org/10.1021/js980172i