Single-dose pharmacokinetics of thalidomide in human immunodeficiency virus-infected patients

Piscitelli, Stephen C.; Figg, William D.; Hahn, Barbara; Kelly, Gerald D.; Thomas, Steven; Walker, Robert

doi:10.1128/aac.41.12.2797

Cited by 41 publications

(22 citation statements)

References 15 publications

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“…21 The mean elimination halflife, volume of distribution, and total body clearance of thalidomide reported here, assuming complete oral absorption of the drug, were, however, similar to those reported previously in both healthy and diseased states. 21,[24][25][26][27] Our data also indicate that thalidomide would not be expected to accumulate in the body after daily dosing with either 100-or 200-m g doses, as the expected steady state accum ulation ratio was calculated to be about 1.10. This is in agreement with an actual value of 1.20 reported for a group of healthy female volunteers receiving 200 mg of thalidomide daily for 21 days.…”

Section: Discussionmentioning

confidence: 92%

“…24 Studies of healthy volunteers using different oral preparations of thalidomide have reported considerably higher 25 or lower 21 dose-adjusted C m ax coupled with a significantly higher T m ax of 6.4 hr 25-27 and 4.4 hr, 21 although these differences are likely due to the poor solubility of the unspecified preparations used. 21 The mean elimination halflife, volume of distribution, and total body clearance of thalidomide reported here, assuming complete oral absorption of the drug, were, however, similar to those reported previously in both healthy and diseased states.…”

Section: Discussionmentioning

confidence: 97%

“…Subjects remained in a fasted state for a further 4 hr postdosing. Blood samples, for drug analysis, were taken at the following times: predose (up to 30 min prior to dosing); every half-hour for 3 hr; then at 4,5,6,8,10,12,16,20,24, and 48 hr postdose. To prevent any spontaneous hydrolysis of the drug, blood samples were placed immediately in ice and all subsequent processing was carried out at 4°C.…”

Section: Subjects and Study Outlinementioning

confidence: 99%

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Pharmacokinetics and Hemodynamic Effects of Single Oral Doses of Thalidomide in Asymptomatic Human Immunodeficiency Virus-Infected Subjects

Noormohamed

Youle²,

Higgs³

et al. 1999

AIDS Research and Human Retroviruses

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Thalidomide (alpha-N-phthalimidoglutarimide), a potent inhibitor of tumor necrosis factor alpha (TNF-alpha), is proving to be a promising drug in the treatment of a number of inflammatory, autoimmune, and HIV-associated disorders. The pharmacokinetics and hemodynamic effects of two single oral doses of thalidomide (100 and 200 mg) were investigated, using a randomized, two-period crossover design, in a group of asymptomatic, male HIV-seropositive subjects. Thalidomide pharmacokinetics were linear at the doses studied, and were best described by a one-compartment model with first-order absorption and elimination processes. The drug was rapidly absorbed, with a mean absorption half-life of 0.95 hr (range, 0.16-2.49 hr) and 1.19 hr (range, 0.33-3.53 hr) after 100- and 200-mg doses, respectively. The corresponding mean Cmax values were 1.15+/-0.24 microg/ml (100 mg) and 1.92+/-0.47 microg/ml (200 mg; p<0.001), which were achieved (Tmax) at 2.5+/-1.5 h and 3.3+/-1.4 hr, respectively. Plasma concentrations of thalidomide declined thereafter, in a log-linear manner, with elimination half-lives of 4.6+/-1.2 hr (100 mg) and 5.3+/-2.2 hr (200 mg). The apparent volumes of distribution (Vdss/F) were 69.9+/-15.6 liters (100 mg) and 82.7+/-34.9 liters (200 mg) while total body clearances (Cl/F) were 10.4+/-2.1 and 10.8+/-1.7 liters/hr, respectively. Significant dose-dependent decreases in supine systolic and diastolic blood pressures were seen for up to 2 hr postdosing; somnolence, headache, dizziness, and confusion were also reported more frequently at the higher dose of thalidomide.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 97%

Section: Subjects and Study Outlinementioning

confidence: 99%

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Pharmacokinetics and Hemodynamic Effects of Single Oral Doses of Thalidomide in Asymptomatic Human Immunodeficiency Virus-Infected Subjects

Noormohamed

Youle²,

Higgs³

et al. 1999

AIDS Research and Human Retroviruses

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“…Chen et al 28 reported the pharmacokinetics of thalidomide after oral dosing in healthy male volunteers. The disposition of thalidomide in these patients was characterized by an elimination half-life of approximately 9 h, a clearance of 10 L/h, and an apparent volume of distribution of nearly 121 L. Piscitelli et al 22 reported the pharmacokinetics of thalidomide in HIV-infected patients after a single oral dose. Thalidomide pharmacokinetics in these patients was characterized by slow absorption, with a mean t max of 3.4 h, an elimination half-life of approximately 6 h, an oral clearance of approximately 8.5 L/h, and an apparent volume of distribution of approximately 85 L. For both the studies, the dose was no more than 300 mg. Our study reported nearly identical values for the low-dose arm (200 mg), but the apparent volume of distribution and the halflife were significantly different for the high-dose arm (800 mg test dose and then dose escalations every 2 weeks).…”

Section: Discussionmentioning

confidence: 98%

Pharmacokinetics of thalidomide in an elderly prostate cancer population

Figg¹,

Raje²,

Bauer³

et al. 1999

Journal of Pharmaceutical Sciences

109

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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 dose 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.

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“…To date, evaluation of the pharmacokinetics of the drug in HIVinfected persons has been restricted primarily to single-dose studies that do not provide data on the pharmacokinetics of the most recent and widely used formulation of the drug (Celgene) under multiple dose conditions in HIV-infected patients [9,10]. Furthermore, some concern exists as to whether thalidomide may induce its own metabolism following chronic dosing [11].…”

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confidence: 99%

Safety, Tolerability, and Pharmacokinetic Effects of Thalidomide in Patients Infected with Human Immunodeficiency Virus: AIDS Clinical Trials Group 267

et al. 2002

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Thalidomide is used to treat human immunodeficiency virus (HIV)-associated conditions, including aphthous ulcers and wasting syndrome. The safety, tolerability, and pharmacokinetics of a formulation of thalidomide with improved bioavailability in HIV-infected persons was examined in a placebo-controlled, dose-escalating phase 1 study. Subjects with CD4 cell counts of 200-500 cells/mm(3) were enrolled and randomized 3:1 in groups of 12 to receive 50, 100, or 150 mg of thalidomide or matching placebo. Two subjects who received 150 mg of drug and 2 subjects assigned placebo experienced dose-limiting toxicity. Concentrations of thalidomide in the blood increased with escalating dose, but the time to maximum concentration and clearance did not differ across dose cohorts. Previous suggestions of autoinduction of drug metabolism were not confirmed by this study. At the doses studied, thalidomide was tolerated well and had linear pharmacokinetics.

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Single-dose pharmacokinetics of thalidomide in human immunodeficiency virus-infected patients

Cited by 41 publications

References 15 publications

Pharmacokinetics and Hemodynamic Effects of Single Oral Doses of Thalidomide in Asymptomatic Human Immunodeficiency Virus-Infected Subjects

Pharmacokinetics and Hemodynamic Effects of Single Oral Doses of Thalidomide in Asymptomatic Human Immunodeficiency Virus-Infected Subjects

Pharmacokinetics of thalidomide in an elderly prostate cancer population

Safety, Tolerability, and Pharmacokinetic Effects of Thalidomide in Patients Infected with Human Immunodeficiency Virus: AIDS Clinical Trials Group 267

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