Abstract:
:The authors examined the pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in 17 patients (4 children, 13 adults) with B-lineage lymphoid malignancies, including 12 patients with acute lymphoblastic leukemia (ALL) and 5 patients with non-Hodgkin's lymphoma (NHL). The immunoconjugate was administered intravenously as a 1-hour continuous infusion at a dose level of either 0.1 mg/kg (N = 12) or 0.18 mg/kg (N = 5), and the plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameters. Pharmacokinetic analyses revealed a plasma half-life of 19 +/- 4 hours, mean residence time of 22 +/- 4 hours, and a systemic clearance of 18 +/- 2 mL/h/kg. The average (mean +/- SEM) values for the maximum plasma concentration Cmax, volume of distribution at steady state (Vss), and area under curve (AUC) were 1092 +/- 225 ng/ml, 291 +/- 37 mL/kg, and 9987 +/- 2021 micrograms x h/L, respectively. The AUC values were higher at the 0.18 mg/kg dose level than at the 0.1 mg/kg dose level (16,848 +/- 5118 micrograms x h/L vs. 7128 +/- 1156 micrograms x h/L, p = 0.009). Patients with ALL had a significantly larger volume of distribution at steady state (332 +/- 47 mL/kg vs. 191 +/- 12 mL/kg, p = 0.04), faster clearance (21 +/- 3 mL/h/kg vs. 11 +/- 2 mL/h/kg, p = 0.03), and lower dose-corrected AUC than patients with NHL (6010 +/- 836 micrograms x h/L vs. 12,044 +/- 2707 micrograms x h/L, p = 0.006). There was a trend toward faster clearance rates (23 +/- 4 mL/h/kg vs. 16 +/- 3 mL/h/kg, p = 0.1), shorter elimination half-lives (5.7 +/- 3.6 hours vs. 13 +/- 8.8 hours, p = 0.1), and shorter mean residence times (11 +/- 3 hours vs. 25 +/- 5 hours, p = 0.08) for non-Caucasian patients as compared to Caucasian patients. When compared to adult patients, pediatric patients showed a significantly larger volume of distribution at steady state (418 +/- 82 mL/kg vs. 252 +/- 34 mL/kg, p = 0.02) and a longer elimination half-lives (18.4 +/- 13.6 hours vs. 8.7 +/- 6.7 hours, p = 0.04). The pharmacokinetics of B43-Genistein was not affected by the gender of the patients or by bone marrow transplantation in past medical history. Overall, B43-Genistein showed favorable pharmacokinetics in this heavily pretreated leukemia/lymphoma patient population, which is reminiscent of its recently reported favorable pharmacokinetics in cynomolgus monkeys. To our knowledge, this is the first clinical pharmacokinetics study of a tyrosine kinase inhibitor containing immunoconjugate.
journal_name
J Clin Pharmacoljournal_title
Journal of clinical pharmacologyauthors
Chen CL,Levine A,Rao A,O'Neill K,Messinger Y,Myers DE,Goldman F,Hurvitz C,Casper JT,Uckun FMdoi
10.1177/00912709922012051subject
Has Abstractpub_date
1999-12-01 00:00:00pages
1248-55issue
12eissn
0091-2700issn
1552-4604journal_volume
39pub_type
临床试验,杂志文章abstract::The differential diagnosis of idiosyncratic adverse drug reactions (ADRs) is difficult because symptoms are seldom pathognomonic. The authors compared the performance of two new diagnostic aids in the differential diagnosis of 27 cases of skin reactions associated with sulfonamide therapy. One test, the Bayesian Adver...
journal_title:Journal of clinical pharmacology
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doi:10.1002/j.1552-4604.1994.tb04736.x
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abstract::The pharmacokinetics and pharmacodynamics of intravenous famotidine were evaluated in 10 infants ranging from 5 to 19 days of age who had a therapeutic indication for the prophylactic treatment of stress ulceration. After a 0.5-mg/kg infusion of famotidine, timed serum (n = 6), urine (24-hour collection), and repeated...
journal_title:Journal of clinical pharmacology
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abstract::Raltegravir is a novel HIV-1 integrase inhibitor with potent in vitro activity (95% inhibitory concentration = 33 nM in 50% human serum). In vitro characterization of raltegravir inhibition potential was assessed against a panel of cytochrome P450 (CYP) enzymes. An open-label, 2-period study was conducted to assess th...
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abstract::Optimal design has been used in the past mainly to optimize sampling schedules for clinical trials. Optimization on design variables other than sampling times has been published in the literature only once before. This study shows, as an example, optimization on the length of treatment periods to obtain reliable estim...
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doi:10.1177/0091270008329560
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abstract::Renal electrolyte excretion patterns were determined in nonedematous healthy volunteers following bumetanide and furosemide in two separate clinical studies. In study 1, intravenous bumetanide was administered to 24 subjects at four dose levels. In study 2, bumetanide (1 or 2 mg) or furosemide (40 or 80 mg) was admini...
journal_title:Journal of clinical pharmacology
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abstract::Clinical pharmacologists, neurologists, internists, and all health care givers must consider the efficacy, safety, and side effect profile of a given antiepileptic drug (AED) when determining which drug is best for a given patient. The first purpose of this paper is to address whether the "new" AEDs have advantages ov...
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journal_title:Journal of clinical pharmacology
pub_type: 杂志文章,评审
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journal_title:Journal of clinical pharmacology
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journal_title:Journal of clinical pharmacology
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journal_title:Journal of clinical pharmacology
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journal_title:Journal of clinical pharmacology
pub_type: 杂志文章,随机对照试验
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journal_title:Journal of clinical pharmacology
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journal_title:Journal of clinical pharmacology
pub_type: 临床试验,杂志文章
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journal_title:Journal of clinical pharmacology
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journal_title:Journal of clinical pharmacology
pub_type: 临床试验,杂志文章
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更新日期:1994-06-01 00:00:00
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journal_title:Journal of clinical pharmacology
pub_type: 杂志文章,评审
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abstract::Ten years' experience with a system of modifying the scoring of examinations in pharmacology based on feedback comments from students on individual questions are analyzed. Each examination (3 per year for 10 years), approximately 100 items in length, was subjected to rigorous editing by a faculty committee and an inde...
journal_title:Journal of clinical pharmacology
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doi:10.1002/j.1552-4604.1997.tb04315.x
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journal_title:Journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
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journal_title:Journal of clinical pharmacology
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journal_title:Journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
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abstract::To enhance protection of humans exposed to long-duration low-gravity environments such as the Space Shuttle and National Aerospace Plane during re-entry or in the short-duration high(-)+Gz environment of fighter aircraft, the effects of +Gz acceleration on cardiovascular hemodynamics must be understood. This study rep...
journal_title:Journal of clinical pharmacology
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doi:10.1002/j.1552-4604.1994.tb04991.x
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abstract::Lofexidine, an antihypertensive imidazoline derivative, was given to ten hypertensives on both a twice-daily and once-daily regimen, using routine blood pressure measurements and 24-hour Remler recording. Plasma renin activity and catecholamines were measured. After a dose titration with twice-daily doses, the total t...
journal_title:Journal of clinical pharmacology
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