Biomedical subjects

Ellen Stokvis

Publications and source records attributed to Ellen Stokvis.

8 recordsLinked to original sources

PubMed2006

A simple and sensitive assay for the quantitative analysis of paclitaxel and metabolites in human plasma using liquid chromatography/tandem mass spectrometry.

A sensitive and specific LC-MS/MS assay for the determination of paclitaxel and its 3'p- and 6-alpha-hydroxy metabolites is presented. A 200 microL plasma aliquot was spiked with a 13C6-labeled paclitaxel internal standard and extracted with 1.0 mL tert-butylmethylether. Dried extracts were reconstituted in 0.1 M ammonium acetate-acetonitrile (1:1, v/v) and 25 microL volumes were injected onto the HPLC system. Separation was performed on a 150 x 2.1 mm C18 column using an alkaline eluent (10 mm ammonium hydroxide-methanol, 30:70, v/v). Detection was performed by positive ion electrospray followed by tandem mass spectrometry. The assay quantifies a range for paclitaxel from 0.25 to 1000 ng/mL and metabolites from 0.25 to 100 ng/mL using 200 microL human plasma samples. Validation results demonstrate that paclitaxel and metabolite concentrations can be accurately and precisely quantified in human plasma. This assay is now used to support clinical pharmacologic studies with paclitaxel.

Antineoplastic Agents, Phytogenic↗

PubMed2005

Phase I clinical and pharmacokinetic study of kahalalide F in patients with advanced androgen refractory prostate cancer.

PURPOSE: The purpose is to determine the maximum tolerated dose, profile of adverse events, and dose-limiting toxicity of Kahalalide F (KF) in patients with androgen refractory prostate cancer. Furthermore, the pharmacokinetics after KF administration and preliminary antitumor activity were evaluated. KF is a dehydroaminobutyric acid-containing peptide isolated from the marine herbivorous mollusk, Elysia rufescens. EXPERIMENTAL DESIGN: Adult patients with advanced or metastatic androgen refractory prostate cancer received KF as an i.v. infusion over 1 hour, during five consecutive days every 3 weeks. The starting dose was 20 microg per m(2) per day. Clinical pharmacokinetics studies were done in all patients using noncompartmental analysis. Prostate-specific antigen levels were evaluated as a surrogate marker for activity against prostate cancer. RESULTS: Thirty-two patients were treated at nine dose levels (20-930 microg per m(2) per day). The maximum tolerated dose on this schedule was 930 microg per m(2) per day. The dose-limiting toxicity was reversible and asymptomatic Common Toxicity Criteria grade 3 and 4 increases in transaminases. The recommended dose for phase II studies is 560 microg per m(2) per day. Pharmacokinetics analysis revealed dose linearity up to the recommended dose. Thereafter, a more than proportional increase was observed. Elimination was rapid with a mean (SD) terminal half-life (t(1/2)) of 0.47 hour (0.11 hour). One patient at dose level 80 microg per m(2) per day had a partial response with a prostate-specific antigen decline by at least 50% for > or =4 weeks. Five patients showed stable disease. CONCLUSIONS: KF can be given safely as a 1-hour i.v. infusion during five consecutive days at a dose of 560 microg per m(2) per day once every 3 weeks.

Aged↗

PubMed2005

Stable isotopically labeled internal standards in quantitative bioanalysis using liquid chromatography/mass spectrometry: necessity or not?

It appears to be a general belief that stable isotopically labeled (SIL) internal standards yield better assay performance results for quantitative bioanalytical liquid chromatography/mass spectrometry (LC/MS) assays than does any other internal standard. In this article we describe our experiences with structural analogues and SIL internal standards and their merits and demerits. SIL internal standards are the first choice, but deuterium-labeled compounds may demonstrate unexpected behavior, such as different retention times or recoveries, than the analyte. In addition, a SIL internal standard with identical chemical properties as the analyte may cover up assay problems with stability, recovery, and ion suppression. Since SIL internal standards are not always available or are very expensive, structural analogues can be used, however, with consideration of several issues, which are usually displayed during method validation.

Acetamides↗

PubMed2004

A more sensitive MS detector does not obviously lead to a more sensitive assay: experiences with ES-285.

In this paper the transfer of an existing method for the quantitative determination of the anticancer agent ES-285 in human plasma using liquid chromatography tandem mass spectrometry on an API 365 to an API 3000 mass spectrometer is described. The transfer appeared not to be straightforward. Problems arose resulting from carry-over and interferences. In addition, due to the expansion of the calibration range, data ought to be weighted with a different factor to increase the accuracy of the lower concentrations. After finding appropriate solutions for these problems, the lower limit of quantitation could be lowered from 10 to 1 ng/mL for ES-285 in human plasma. The usefulness and necessity of the modified assay was demonstrated by analysis of plasma samples from a patient receiving a low dosage of the drug.

Alkanes↗

PubMed2004

Quantitative analysis of the P-glycoprotein inhibitor Elacridar (GF120918) in human and dog plasma using liquid chromatography with tandem mass spectrometric detection.

A liquid chromatographic/tandem mass spectrometric (LC/MS/MS) method for the determination of the P-glycoprotein and breast cancer resistance protein inhibitor Elacridar in human and dog plasma is described. The internal standard was stable isotopically labelled Elacridar. Sample pretreatment involved liquid-liquid extraction with tert-butyl methyl ether. Analysis of Elacridar and internal standard was performed by reversed-phase LC on a basic stable minibore analytical column with an eluent consisting of acetonitrile and aqueous ammonia. An API-2000 triple-quadrupole mass spectrometer with an electrospray ion source was used in the positive-ion multiple reaction monitoring mode. The run time per sample was only 6 min. The method is sensitive and specific, with a dynamic range from 1 to 500 ng ml(-1) from 100 microl of human or dog plasma. The accuracy of the method was within 15% bias and the precision was lower than 15% for all tested concentration levels and in both matrices. The method is simple and the liquid-liquid extraction produces clean samples. This method was successfully applied to support the pharmacokinetics of a clinical trial in which orally applied Elacridar was used as a bioavailability enhancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Quantitative analysis of D-24851, a novel anticancer agent, in human plasma and urine by liquid chromatography coupled with tandem mass spectrometry.

The development of a liquid chromatography/tandem mass spectrometric assay for the quantitative analysis of the novel tubulin inhibitor D-24851 in human plasma and urine is described. D-24851 and the deuterated internal standard were extracted from 250 microL of plasma or urine using hexane/ether (1:1, v/v). Subsequently, 10-microL aliquots of reconstituted extracts were injected onto an Inertsil ODS analytical column (50 x 2.0 mm i.d., 5 microm particle size). An eluent consisting of methanol/5 mM ammonium acetate, 0.004% formic acid in water (80:20, v/v) was pumped at a flow rate of 0.2 mL/min. An API 365 triple quadrupole mass spectrometer was used in the multiple reaction monitoring mode for sensitive detection. For human plasma a dynamic range of 1-1000 ng/mL was validated, and for human urine a range of 0.25-50 ng/mL. Validation was performed according to the most recent FDA guidelines and all results were within requirements. The assay has been successfully applied to support a phase I clinical trial with orally administered D-24851.

Acetamides↗

PubMed2002

Clinical pharmacokinetics, pharmacodynamics and metabolism of the novel matrix metalloproteinase inhibitor ABT-518.

PURPOSE: To investigate the pharmacokinetics, pharmacodynamics and metabolism of the novel matrix metalloproteinase (MMP) inhibitor ABT-518. METHODS: Plasma and urine samples were obtained from six patients included in a phase I trial in which ABT-518 was given once daily via the oral route. Samples were analyzed by LC-MS/MS, ELISA and immunocapture assay. The pharmacokinetics of the parent compound and of detectable metabolites were calculated. RESULTS: After a single dose of ABT-518 peak plasma levels were reached within 4-8 h. ABT-518 had an estimated clearance (Cl/F) of approximately 3 l/h, an estimated volume of distribution (V/F) of over 70 l and a terminal half-life (T(1/2)) of 20 h. At least six different metabolites were formed. Pharmacodynamic analysis for angiogenic growth factors (bFGF and VEGF) showed plasma and urine levels in the picogram range and for total MMP-9 and MMP-2 or MMP-9 activity showed plasma and urine levels in the nanogram range. CONCLUSIONS: The MMP inhibitor ABT-518 is extensively metabolized in humans. No significant correlations between pharmacokinetics and pharmacodynamics could be established.

Adult↗

PubMedDate not supplied

Liquid chromatography-mass spectrometry for the quantitative bioanalysis of anticancer drugs.

The monitoring of anticancer drugs in biological fluids and tissues is important during both pre-clinical and clinical development and often in routine clinical use. Traditionally, liquid chromatography (LC) in combination with ultraviolet (UV), fluorescence, or electrochemical detection is employed for this purpose. The successful hyphenation of LC and mass spectrometry (MS), however, has dramatically changed this. MS detection provides better sensitivity and selectivity than UV detection and, in addition, is applicable to a significantly larger group of compounds than fluorescence or electrochemical detection. Therefore, LC-MS has now become the method of first choice for the quantitative bioanalysis of many anticancer agents. There are still, however, a lot of new developments to be expected in this area, such as the introduction of more sensitive and robust mass spectrometers, high-throughput analyses, and further optimization of the coupled LC systems. Many articles have appeared in this field in recent years and are reviewed here. We conclude that LC-MS is an extremely powerful tool for the quantitative analysis of anticancer drugs in biological samples.

Animals↗