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1.
Drug Metab Dispos ; 50(4): 327-340, 2022 04.
Article in English | MEDLINE | ID: mdl-35042701

ABSTRACT

Lurbinectedin is a novel and potent selective inhibitor of active transcription of protein-coding genes, triggering apoptosis of cancerous cells. It has been approved for the treatment of patients with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy. Studies exploring the disposition and metabolism of lurbinectedin were performed in vitro and in vivo (by intravenous administration of lurbinectedin). Low blood cell partitioning for lurbinectedin in rats, nonhuman primates (NHP), and humans was determined as 23.4%, 29.8%, and 9.8%, respectively. Protein binding was very high (>95%) in total plasma (rat, NHP, and human), albumin, and α-1-acid glycoprotein (both human). In vitro, lurbinectedin underwent intense liver microsome-mediated metabolism-in 10 minutes, 80% of the compound is metabolized in human-with CYP3A4 being the isoform involved in that metabolism. Results also showed NHPs being the nonclinical species which, metabolically, most closely resembles humans. Mass balance studies performed in rats (both genders), NHPs (male only), and patients (both genders) demonstrated that the principal route of excretion of 14C-lurbinectedin-related radioactivity was through the feces (88.7% ± 10.1% in patients), with only a minor fraction recovered from the urine (5.6% ± 2.0% in patients). In plasma samples, the majority of lurbinectedin-related radioactivity was attributed to unchanged compound (95% ± 3.1% and 70.2% ± 10.9% in NHPs and humans, respectively). Plasma metabolic profiling demonstrated the major (% compared with unchanged compound) circulating metabolites were N-Desmethyl-lurbinectedin (0.4% ± 0.2% and 10.4% ± 2.2% in NHPs and patients, respectively) and 1',3'-Desmethylene-lurbinectedin (0.9% ± 0.7% and 14.3% ± 10.4% in NHP and patients, respectively). SIGNIFICANCE STATEMENT: Lurbinectedin is a novel and potent selective inhibitor of active transcription of protein-coding genes, triggering apoptosis of cancerous cells, and was recently approved for the treatment of patients with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy. The present study provides a complete set of information on the pharmacokinetics, biotransformation, and elimination of 14C-lurbinectedin and its metabolites, following a single intravenous administration to nonclinical species (rats and nonhuman primates) and patients.


Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , Animals , Carbolines/pharmacology , Carbolines/therapeutic use , Feces , Female , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Male , Rats , Small Cell Lung Carcinoma/chemically induced , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/pathology
2.
J Pharm Biomed Anal ; 173: 169-175, 2019 Sep 05.
Article in English | MEDLINE | ID: mdl-31146172

ABSTRACT

Galunisertib is an anti-cancer drug currently evaluated in phase I and II clinical trials. This study describes the development and validation of a bioanalytical assay to quantify galunisertib in human plasma using HPLC-MS/MS. Stable isotope labelled galunisertib was added as internal standard and the analyte and internal standard were extracted from the matrix by protein precipitation using acetonitrile-methanol (50:50, v/v). Final extracts were injected onto a C18 column, gradient elution was applied for chromatographic separation and detection was performed using a triple quadrupole mass spectrometer operating in the positive ion mode. The assay was linear over the range 0.05-10 ng/mL, with acceptable accuracy (bias ranging from -6.1 to 3.1%) and precision (below 5.7% C.V.) values. The applicability of the assay was demonstrated in a pharmacokinetic experiment in mice.


Subject(s)
Protein Kinase Inhibitors/blood , Pyrazoles/blood , Quinolines/blood , Tandem Mass Spectrometry/methods , Administration, Oral , Animals , Chromatography, High Pressure Liquid/methods , Drug Screening Assays, Antitumor , Humans , Male , Mice , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/administration & dosage , Pyrazoles/pharmacokinetics , Quinolines/administration & dosage , Quinolines/pharmacokinetics , Reproducibility of Results , Sensitivity and Specificity , Transforming Growth Factor beta/antagonists & inhibitors
3.
Cancer Chemother Pharmacol ; 82(3): 441-455, 2018 09.
Article in English | MEDLINE | ID: mdl-29974200

ABSTRACT

PURPOSE: Plitidepsin absorption, distribution, metabolism and excretion characteristics were investigated in a mass balance study, in which six patients received a 3-h intravenous infusion containing 7 mg 14C-plitidepsin with a maximum radioactivity of 100 µCi. METHODS: Blood samples were drawn and excreta were collected until less than 1% of the administered radioactivity was excreted per matrix for two consecutive days. Samples were pooled within-patients and between-patients and samples were screened for metabolites. Afterwards, metabolites were identified and quantified. Analysis was done using Liquid Chromatography linked to an Ion Trap Mass Spectrometer and offline Liquid Scintillation Counting (LC-Ion Trap MS-LSC). RESULTS: On average 4.5 and 62.4% of the administered dose was excreted via urine over the first 24 h and in faeces over 240 h, respectively. Most metabolites were found in faeces. CONCLUSION: Plitidepsin is extensively metabolised and it undergoes dealkylation (demethylation), oxidation, carbonyl reduction, and (internal) hydrolysis. The chemical formula of several metabolites was confirmed using high resolution mass data.


Subject(s)
Depsipeptides/metabolism , Neoplasms/metabolism , Carbon Radioisotopes , Chromatography, Liquid , Clinical Trials, Phase I as Topic , Depsipeptides/administration & dosage , Depsipeptides/blood , Depsipeptides/urine , Feces , Humans , Neoplasms/blood , Neoplasms/drug therapy , Neoplasms/urine , Peptides, Cyclic , Tandem Mass Spectrometry
4.
J Pharm Biomed Anal ; 158: 160-165, 2018 Sep 05.
Article in English | MEDLINE | ID: mdl-29883879

ABSTRACT

Lurbinectedin is a novel highly selective inhibitor of RNA polymerase II triggering caspase-dependent apoptosis of cancerous cells. This article describes the development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay to quantify lurbinectedin in human plasma and urine. Plasma samples were pre-treated with 1 M aqueous ammonia after which they were brought onto supported liquid extraction (SLE) columns. Lurbinectedin was eluted from the columns using tert-butyl methyl ether (TBME). Urine was first diluted in plasma and lurbinectedin was extracted from this matrix by liquid-liquid extraction using TBME. Samples were measured by LC-MS/MS in the positive electron ion spray mode. The method was linear over 0.1-100 ng/mL and 1-1000 ng/mL in plasma and urine, respectively, with accuracies and precisions within ±15% (20% for LLOQ) and below 15% (20% for LLOQ), respectively. The method was developed to support a mass balance study in which patients received a dose of 5 mg lurbinectedin.


Subject(s)
Antineoplastic Agents/analysis , Carbolines/analysis , Heterocyclic Compounds, 4 or More Rings/analysis , Lung Neoplasms/drug therapy , Small Cell Lung Carcinoma/drug therapy , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Carbolines/pharmacokinetics , Carbolines/therapeutic use , Chromatography, High Pressure Liquid/instrumentation , Chromatography, High Pressure Liquid/methods , Clinical Trials, Phase III as Topic , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Humans , Limit of Detection , Liquid-Liquid Extraction , Lung Neoplasms/blood , Lung Neoplasms/urine , RNA Polymerase II/antagonists & inhibitors , Reproducibility of Results , Sensitivity and Specificity , Small Cell Lung Carcinoma/blood , Small Cell Lung Carcinoma/urine , Tandem Mass Spectrometry/instrumentation , Tandem Mass Spectrometry/methods , Time Factors
5.
Cancer Chemother Pharmacol ; 81(1): 39-46, 2018 01.
Article in English | MEDLINE | ID: mdl-29043410

ABSTRACT

INTRODUCTION: Niraparib (Zejula™) is a poly(ADP-ribose) polymerase inhibitor recently approved by the US Food and Drug Administration for the maintenance treatment of patients with recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. The pivotal phase III clinical trial has shown improved progression-free survival in patients receiving niraparib compared with those receiving placebo. PURPOSE: Since niraparib is administered orally, it is of interest to investigate the oral bioavailability (F po) of this novel compound, which is the aim of this study. METHODS: Six patients received an oral therapeutic dose of 300 mg niraparib, followed by a 15-min intravenous infusion of 100 µg 14C-niraparib with a radioactivity of approximately 100 nCi. The niraparib therapeutic dose was measured in plasma using a validated liquid chromatography-tandem mass spectrometry method, whereas the total 14C-radioactivity and 14C-niraparib plasma levels were measured by accelerator mass spectrometry and a validated high performance liquid chromatography assay with AMS. RESULTS: The F po of niraparib was determined to be 72.7% in humans.


Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Breast Neoplasms/drug therapy , Carbon Radioisotopes/metabolism , Fallopian Tube Neoplasms/drug therapy , Indazoles/administration & dosage , Indazoles/pharmacokinetics , Ovarian Neoplasms/drug therapy , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage , Poly(ADP-ribose) Polymerase Inhibitors/pharmacokinetics , Administration, Oral , Adult , Aged , Antineoplastic Agents/blood , Antineoplastic Agents/therapeutic use , Area Under Curve , Biological Availability , Breast Neoplasms/metabolism , Chromatography, High Pressure Liquid , Fallopian Tube Neoplasms/metabolism , Female , Humans , Indazoles/blood , Indazoles/therapeutic use , Infusions, Intravenous , Middle Aged , Ovarian Neoplasms/metabolism , Piperidines/blood , Piperidines/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Progression-Free Survival , Radioactive Tracers , Tandem Mass Spectrometry
6.
Cancer Chemother Pharmacol ; 81(1): 47, 2018 01.
Article in English | MEDLINE | ID: mdl-29181573

ABSTRACT

The article ''Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients'', written by L. van Andel, H. Rosing, Z. Zhang, L. Hughes, V. Kansra, M. Sanghvi, M. M. Tibben, A. Gebretensae, J. H. M. Schellens and J. H. Beijnen, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 17th October 2017 without open access.

7.
J Pharm Biomed Anal ; 145: 137-143, 2017 Oct 25.
Article in English | MEDLINE | ID: mdl-28662481

ABSTRACT

Plitidepsin is an anti-cancer drug currently evaluated in phase I/II/III clinical trials. This article describes the development and validation of a bioanalytical assay to quantify plitidepsin in human plasma, urine and whole blood using HPLC-MS/MS. The analyte was extracted from the matrix by liquid-liquid extraction using tert-butyl methyl ether. Final extracts were injected onto a C18 column, gradient elution was applied for chromatographic separation and detection was performed on a triple quadrupole mass spectrometer operating in the positive ion mode. The assay was linear over the range 0.1-100ng/mL, with acceptable accuracy and precision values. This is the first reported bioanalytical assay quantifying plitidepsin using a stable isotopically labelled standard, achieving a lower limit of quantification of 0.1ng/mL in all three matrices, allowing the quantification of trace levels of plitidepsin, and accomplishing this in an analysis time of two minutes only. The presented method was successfully applied in a mass balance study with plitidepsin in patients with advanced cancer.


Subject(s)
Depsipeptides/blood , Depsipeptides/urine , Chromatography, High Pressure Liquid , Humans , Methyl Ethers , Peptides, Cyclic , Reproducibility of Results , Tandem Mass Spectrometry
8.
Invest New Drugs ; 35(6): 751-765, 2017 12.
Article in English | MEDLINE | ID: mdl-28303528

ABSTRACT

Niraparib is an investigational oral, once daily, selective poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor. In the pivotal Phase 3 NOVA/ENGOT/OV16 study, niraparib met its primary endpoint of improving progression-free survival (PFS) for adult patients with recurrent, platinum sensitive, ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to platinum-based chemotherapy. Significant improvements in PFS were seen in all patient cohorts regardless of biomarker status. This study evaluates the absorption, metabolism and excretion (AME) of 14C-niraparib, administered to six patients as a single oral dose of 300 mg with a radioactivity of 100 µCi. Total radioactivity (TRA) in whole blood, plasma, urine and faeces was measured using liquid scintillation counting (LSC) to obtain the mass balance of niraparib. Moreover, metabolite profiling was performed on selected plasma, urine and faeces samples using liquid chromatography - tandem mass spectrometry (LC-MS/MS) coupled to off-line LSC. Mean TRA recovered over 504 h was 47.5% in urine and 38.8% in faeces, indicating that both renal and hepatic pathways are comparably involved in excretion of niraparib and its metabolites. The elimination of 14C-radioactivity was slow, with t1/2 in plasma on average 92.5 h. Oral absorption of 14C-niraparib was rapid, with niraparib concentrations peaking at 2.49 h, and reaching a mean maximum concentration of 540 ng/mL. Two major metabolites were found: the known metabolite M1 (amide hydrolysed niraparib) and the glucuronide of M1. Based on this study it was shown that niraparib undergoes hydrolytic, and conjugative metabolic conversions, with the oxidative pathway being minimal.


Subject(s)
Breast Neoplasms/metabolism , Carbon Radioisotopes/analysis , Colorectal Neoplasms/metabolism , Indazoles/analysis , Ovarian Neoplasms/metabolism , Piperidines/analysis , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly(ADP-ribose) Polymerases/chemistry , Adult , Aged , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Carbon Radioisotopes/pharmacology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Female , Follow-Up Studies , Humans , Indazoles/pharmacology , Middle Aged , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Piperidines/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/analysis , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Prognosis
9.
Invest New Drugs ; 35(5): 589-598, 2017 10.
Article in English | MEDLINE | ID: mdl-28111728

ABSTRACT

Plitidepsin (Aplidin®) is a marine-derived anticancer compound currently investigated in phase III clinical trials. This article describes the distribution, metabolism and excretion of this novel agent and it mainly aims to identify the major routes of elimination. Six subjects were enrolled in a mass balance study during which radiolabelled plitidepsin was administered as a 3-h intravenous infusion. Blood samples were taken and urine and faeces were collected. Total radioactivity (TRA) analysis using Liquid Scintillation Counting (LSC) was done to determine the amount of radioactivity excreted from the body and plitidepsin concentrations in whole blood, plasma and urine were determined by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays. In total, a mean of 77.4% of the administered radioactivity was excreted over a time period of 20 days, of which 71.3% was recovered in faeces and 6.1% was found in urine. The majority excreted in urine was accounted for by unchanged plitidepsin, with only 1.5% of the total administered dose explained by metabolites in urine. Faeces, on the other hand contained low levels of parent compound, which means that most of the TRA excreted in faeces was accounted for by metabolites. TRA levels were 3.7 times higher in whole blood compared to plasma. Plitidepsin was widely distributed and plasma clearance was low. This study shows that red blood cells are a major distribution compartment and that the biliary route is the main route of total radioactivity excretion.


Subject(s)
Carbon Radioisotopes/pharmacokinetics , Depsipeptides/pharmacokinetics , Neoplasms/metabolism , Administration, Oral , Aged , Feces/chemistry , Female , Humans , Infusions, Intravenous/methods , Male , Middle Aged , Peptides, Cyclic , Tissue Distribution
10.
Article in English | MEDLINE | ID: mdl-27898364

ABSTRACT

Niraparib (MK-4827) is a novel poly(ADP-Ribose) polymerase (PARP) inhibitor currently investigated in phase III clinical trials to treat cancers. The development of a new drug includes the characterisation of absorption, metabolism and excretion (AME) of the compound. AME studies are a requirement of regulatory agencies and for this purpose bioanalytical assays are essential. This article describes the development and validation of a bioanalytical assay for niraparib and its carboxylic acid metabolite M1 in human plasma and urine using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Sample pre-treatment involved protein precipitation for plasma and dilution of urine samples using acetonitrile-methanol (50:50, v/v). Final extracts were injected onto a SunFire C18 column and gradient elution using 20mM ammonium acetate (mobile phase A) and formic acid:acetonitrile:methanol (0.1:50:50, v/v/v) (mobile phase B) was applied. Detection was performed on an API5500 tandem mass spectrometer operating in the positive electrospray ionisation mode applying multiple reaction monitoring (MRM). The assay was successfully validated in accordance with the Food and Drug Administration and latest European Medicines Agency guidelines on bioanalytical method validation and can therefore be applied in pharmacological clinical studies.


Subject(s)
Chromatography, High Pressure Liquid/methods , Indazoles/blood , Indazoles/urine , Piperidines/blood , Piperidines/urine , Poly(ADP-ribose) Polymerase Inhibitors/blood , Poly(ADP-ribose) Polymerase Inhibitors/urine , Tandem Mass Spectrometry/methods , Humans , Indazoles/metabolism , Limit of Detection , Piperidines/metabolism , Poly(ADP-ribose) Polymerase Inhibitors/metabolism
11.
Invest New Drugs ; 33(6): 1197-205, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26362459

ABSTRACT

BACKGROUND: Lapatinib has proven efficacy as monotherapy and in combination with capecitabine in patients with metastatic breast cancer (MBC) overexpressing HER2 and/or EGFR. Gemcitabine also has anti-tumor activity in MBC and a favourable toxicity profile. In this phase I study lapatinib and gemcitabine were combined. METHODS: Female patients with advanced BC were given lapatinib once daily (QD) in 28-day cycles with gemcitabine administered on day 1, 8 and 15. Physical examinations, vital signs and blood sampling for hematology, clinical chemistry and pharmacokinetics (PK) and radiological assessments of disease were performed at regular intervals. RESULTS: In total, 33 patients were included. Six dose-limiting toxicities were observed, mostly grade 3 increases in liver function tests. Most common toxicities were fatigue (73%), nausea (70%), diarrhea (58%), increases in ALAT and ASAT (55 and 52%, respectively) and rash (46%). The maximum tolerated dose was lapatinib 1250 mg QD with gemcitabine 1000 mg/m(2). Lapatinib and gemcitabine PK did not appear to be influenced by each other. Anti-tumor activity was observed with one patient (4%) showing complete response and six (23%) partial response. CONCLUSION: Despite a slightly increased toxicity profile compared to their respective monotherapies, lapatinib and gemcitabine can be safely combined while showing signs of anti-tumor activity.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Deoxycytidine/analogs & derivatives , Quinazolines/administration & dosage , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Breast Neoplasms/diagnosis , Breast Neoplasms/metabolism , Cohort Studies , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/pharmacokinetics , Disease Progression , Dose-Response Relationship, Drug , Fatigue/chemically induced , Female , Humans , Lapatinib , Middle Aged , Quinazolines/adverse effects , Quinazolines/pharmacokinetics , Gemcitabine
12.
Anal Bioanal Chem ; 391(2): 577-85, 2008 May.
Article in English | MEDLINE | ID: mdl-18385987

ABSTRACT

We present a highly sensitive method for the determination of platinum (Pt) in DNA extracts of peripheral blood mononuclear cells (PBMCs) and tissue samples from patients treated with cisplatin. The method is based on the measurement of Pt by inductively coupled plasma mass spectrometry (ICP-MS) and allows quantification of Pt-DNA adducts in PBMCs isolated from 10 mL blood and 1 mg tissue. The lower limit of quantification is 0.75 pg Pt or 7.5 fg Pt µg(-1) DNA when using 100 µg DNA. The method proved to be accurate and precise. The results obtained using the ICP-MS method were in good agreement with results from the alternative (32)P-postlabelling assay. The ICP-MS method was, however, more sensitive and proved to be less laborious. The advantages of the presented ICP-MS technique were demonstrated by the analysis of PBMCs, normal gastric tissue, and gastric tumour tissue of patients treated with cisplatin.


Subject(s)
Antineoplastic Agents/blood , Cisplatin/blood , DNA Adducts/analysis , Leukocytes, Mononuclear/chemistry , Mass Spectrometry/methods , Platinum/analysis , Stomach Neoplasms/blood , Antineoplastic Agents/therapeutic use , Cisplatin/therapeutic use , Humans , Isotopes , Stomach Neoplasms/drug therapy
13.
Br J Cancer ; 98(8): 1320-6, 2008 Apr 22.
Article in English | MEDLINE | ID: mdl-18414469

ABSTRACT

This dose escalation study was designed to determine the recommended dose of the multi-targeted cell cycle inhibitor indisulam in combination with capecitabine in patients with solid tumours and to evaluate the pharmacokinetics of the combination. Thirty-five patients were treated with indisulam on day 1 of each 21-day cycle. Capecitabine was administered two times daily (BID) on days 1-14. Plasma concentrations of indisulam, capecitabine and its three metabolites were determined for pharmacokinetic analysis. The main dose-limiting toxicity was myelosuppression. Hand/foot syndrome and stomatitis were the major non-haematological toxicities. The recommended dose was initially established at indisulam 700 mg m(-2) and capecitabine 1250 mg m(-2) BID. However, during cycle 2 the recommended dose was poorly tolerated in three patients. A dose of indisulam 500 mg m(-2) and capecitabine 1250 mg m(-2) BID proved to be safe at cycle 1 and 2 in nine additional patients. Indisulam pharmacokinetics during cycle 1 were consistent with pharmacokinetic data from phase I mono-therapy studies. However, exposure to indisulam was remarkably increased at cycle 2 due to a drug-drug interaction between capecitabine and indisulam. Partial response was confirmed in two patients, one with colon carcinoma and the other with pancreatic carcinoma. Seventeen patients had stable disease. Indisulam (700 mg m(-2)) in combination with capecitabine (1250 mg m(-2) BID) was well tolerated during the first cycle. A dose of indisulam 500 mg m(-2) and capecitabine 1250 mg m(-2) BID was considered safe in multiple treatment cycles. The higher incidence of toxicities observed during cycle 2 can be explained by a time-dependent pharmacokinetic drug-drug interaction.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Deoxycytidine/analogs & derivatives , Fluorouracil/analogs & derivatives , Sulfonamides/administration & dosage , Adult , Aged , Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors , Capecitabine , Cytochrome P-450 CYP2C9 , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/blood , Drug Administration Schedule , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Fluorouracil/blood , Humans , Male , Middle Aged , Sulfonamides/adverse effects , Sulfonamides/blood
14.
J Mass Spectrom ; 41(9): 1186-94, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16929560

ABSTRACT

We present a highly sensitive, rapid method for the determination of platinum originating from the anticancer agents cisplatin, carboplatin, and oxaliplatin in human plasma ultrafiltrate. The method is based on the quantification of platinum by inductively coupled plasma mass spectrometry and allows quantification of 7.50 ng l-1 platinum in only 150 microl of matrix. Sample pretreatment involves dilution of samples with 1% HNO3. Validation fulfilled the most recent FDA guidelines for bioanalytical method validation. Validated ranges of quantification were 7.50 ng l-1 to 1.00x10(5) ng l-1 in plasma ultrafiltrate for all three platinum compounds. The assay is now successfully used to support pharmacokinetic studies in cancer patients treated with cisplatin, carboplatin, or oxaliplatin.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Carboplatin/pharmacokinetics , Cisplatin/pharmacokinetics , Organoplatinum Compounds/pharmacokinetics , Platinum/blood , Antineoplastic Agents/blood , Calibration , Carboplatin/blood , Cisplatin/blood , Humans , Indicators and Reagents , Mass Spectrometry , Organoplatinum Compounds/blood , Oxaliplatin , Quality Control , Reference Standards , Reproducibility of Results , Ultrafiltration
15.
Anal Bioanal Chem ; 382(7): 1484-90, 2005 Aug.
Article in English | MEDLINE | ID: mdl-15952001

ABSTRACT

A method for sensitive determination of the anti-cancer agent oxaliplatin in human plasma and human plasma ultrafiltrate (pUF) is presented. The method is based on the quantification of platinum by graphite-furnace atomic-absorption spectrometry, with Zeeman correction and an atomisation temperature of 2,700 degrees C. Sample pretreatment involves dilution of the samples with a solution containing 0.15 mol L(-1) NaCl and 0.20 mol L(-1) HCl in water. Validation was performed in accordance with the most recent FDA guidelines for bioanalytical method validation. All results were within requirements. The validated ranges of quantification were 0.10-400 micromol L(-1) for human pUF and 0.50-400 micromol L(-1) for plasma. The assay is now successfully used to support pharmacokinetic studies of cancer patients treated with oxaliplatin.


Subject(s)
Antineoplastic Agents/blood , Graphite/chemistry , Organoplatinum Compounds/blood , Spectrophotometry, Atomic/methods , Calibration , Humans , Molecular Structure , Oxaliplatin , Reference Standards , Reproducibility of Results , Sensitivity and Specificity , Ultrafiltration
16.
Anal Bioanal Chem ; 373(4-5): 233-6, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12110973

ABSTRACT

AP5280 is an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer to which are linked tetrapeptide side chains containing bioactive platinum complexes at their C-terminal sides. We have developed and validated a rapid and sensitive analytical assay for the determination of total platinum concentrations in plasma, and free platinum of an AP5280 origin in plasma ultrafiltrate (PUF), of subjects dosed with AP5280. The total platinum levels were determined by use of graphite-furnace atomic-absorption spectrometry (GF-AAS) with Zeeman correction after appropriate dilution of the plasma sample with plasma-hydrochloric acid 0.2 mol L(-1) (1:5) as diluent. The limit of quantitation of this assay is 0.25 micromol L(-1) platinum in plasma. Linear calibration curves were obtained over the concentration range 0.25-5.0 micromol L(-1). Accuracy was between 87.7% and 104.2% and precision was 15.3% at the lowest concentration and less than 14% for all other levels tested. Accuracy and precision were thus in accordance with generally accepted criteria for analytical methods. Analysis of samples obtained from patients receiving AP5280 demonstrated the applicability of the described assay. Analysis of free platinum in PUF was performed by use of a previously validated and reported assay from our institute in which the same instrumental method is used.


Subject(s)
Acrylamides/administration & dosage , Organoplatinum Compounds/administration & dosage , Platinum/blood , Acrylamides/pharmacokinetics , Calibration , Drug Delivery Systems/standards , Hemofiltration , Humans , Organoplatinum Compounds/pharmacokinetics , Platinum/pharmacokinetics , Reproducibility of Results , Sensitivity and Specificity , Spectrophotometry, Atomic
17.
Ann Oncol ; 13(3): 374-84, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11996467

ABSTRACT

BACKGROUND: High-dose chemotherapy in combination with peripheral blood progenitor cell transplantation is widely used in the treatment of several malignancies. The use of high-dose chemotherapy can be complicated by the occurrence of severe and sometimes life threatening toxicity. A wide interpatient variability in toxicity is encountered, which may be caused by variability in the pharmacokinetics of the agents. The aim of this study was to establish the pharmacokinetics of cyclophosphamide, thiotepa, carboplatin and all relevant metabolites in a widely used high-dose combination and to study possible relationships between the pharmacokinetics and toxicity. PATIENTS AND METHODS: Blood samples were collected from patients treated with modifications of the CTCb regimen consisting of cyclophosphamide (1000-1500 mg/m2/day), carboplatin (265-400 mg/m2/day) and thiotepa (80-120 mg/m2/day) as short infusions for four consecutive days. Thiotepa and its main metabolite tepa, ultrafilterable carboplatin, cyclophosphamide and its activated metabolites 4-hydroxycyclophosphamide and phosphoramide mustard were determined. Pharmacokinetics were assessed with the use of population pharmacokinetic analyses. Relationship between the area under the concentration-time curves (AUCs) of these compounds and toxicity were tested. RESULTS: A total of 46 patients (83 courses of chemotherapy) was included. Relationships were identified between elevation of transaminases and the thiotepa and tepa AUC, mucositis and the tepa AUC and ototoxicity and the carboplatin AUC. A strong trend between the 4-hydroxycyclophosphamide AUC and veno-occlusive disease was found. CONCLUSIONS: The complex pharmacokinetics of the different agents and their metabolites have been established and several relationships between the pharmacokinetics and toxicity were identified. These findings may form the basis for further treatment optimisation and dose-individualisation in this high-dose chemotherapy combination.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Breast Neoplasms/metabolism , Carboplatin/administration & dosage , Carboplatin/pharmacokinetics , Cyclophosphamide/administration & dosage , Cyclophosphamide/pharmacokinetics , Neoplasms, Germ Cell and Embryonal/metabolism , Ovarian Neoplasms/metabolism , Thiotepa/administration & dosage , Thiotepa/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Area Under Curve , Breast Neoplasms/drug therapy , Carboplatin/adverse effects , Cyclophosphamide/adverse effects , Dose-Response Relationship, Drug , Female , Half-Life , Humans , Male , Middle Aged , Neoplasms, Germ Cell and Embryonal/drug therapy , Ovarian Neoplasms/drug therapy , Thiotepa/adverse effects , Tissue Distribution
18.
J Pharmacokinet Pharmacodyn ; 28(3): 211-30, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11468938

ABSTRACT

Cyclophosphamide (CP) is widely used in high-dose chemotherapy regimens in combination with thioTEPA. CP is a prodrug and is activated by cytochrome P450 to 4-hydroxycyclophosphamide (HCP) which yields the final cytotoxic metabolite phosphoramide mustard (PM). The metabolism of CP into HCP exhibits autoinduction but is inhibited by thioTEPA. The aim of this study was to develop a population pharmacokinetic model for the bioactivation route of CP incorporating the phenomena of both autoinduction and the drug-drug interaction between CP and thioTEPA. Plasma samples were collected from 34 patients who received high-dose CP, thioTEPA and carboplatin in short infusions during 4 consecutive days. Elimination of CP was described by a noninducible route and an inducible route leading to HCP. The latter route was mediated by a hypothetical amount of enzyme. Autoinduction leads to a zero-order increase in amount of this enzyme during treatment. Inhibition by thioTEPA was modeled as a reversible, competitive, concentration-dependent inhibition. PM pharmacokinetics were described by first-order formation from HCP and first-order elimination. The final models for CP, HCP, and PM provided an adequate fit of the experimental data. The volume of distribution, noninducible and initial inducible clearances of CP were 31.0 L, 1.58 L/hr and 4.76 L/hr, respectively. The enzyme amount increased with a zero-order rate constant of 0.041 amount * hr-1. After each thioTEPA infusion, however, approximately 80% of the enzyme was inhibited. This inhibition was reversible with a half-life of 6.5 hr. The formation and elimination rate constants of PM were 1.58 and 0.338 hr-1, respectively. The developed model enabled the assessment of the complex pharmacokinetics of CP in combination with thio TEPA. This model provided an adequate description of enzyme induction and inhibition and can be used for treatment optimization in this combination.


Subject(s)
Antineoplastic Agents, Alkylating/pharmacokinetics , Cyclophosphamide/pharmacokinetics , Cytochrome P-450 Enzyme System/metabolism , Models, Chemical , Thiotepa/pharmacokinetics , Adolescent , Adult , Antineoplastic Agents, Alkylating/chemistry , Cyclophosphamide/chemistry , Drug Interactions/physiology , Female , Humans , Male , Middle Aged , Nonlinear Dynamics , Phosphoramide Mustards/metabolism
19.
J Chromatogr B Biomed Sci Appl ; 757(2): 349-57, 2001 Jun 15.
Article in English | MEDLINE | ID: mdl-11417881

ABSTRACT

Cyclophosphamide (CP) is one of the most frequently used anticancer agents. It is a prodrug requiring activation before exerting cytotoxicity. CP is deactivated to 2-dechloroethylcyclophosphamide (2-DCECP) with formation of an equimolar amount of chloroacetaldehyde. The aim of this study was to develop and validate a sensitive and simple assay for 2-DCECP in plasma of patients treated with CP. Sample pre-treatment consisted of solid-phase extraction of 500 microl of plasma over OASIS HLB (1 ml) cartridges with trofosfamide as internal standard. Separation and detection of underivatized 2-DCECP was performed with capillary gas chromatography with nitrogen/phosphorous selective detection. Extraction recovery of 2-DCECP exceeded 87%. No interference from endogenous compounds, other metabolites of CP and frequently coadministered drugs was detected. The assay was linear in the range of 5-5000 ng/ml in plasma. Accuracy, within-day and between-day precision were less than 11% for the complete concentration range. In plasma, 2-DCECP was stable for at least 1 month when kept at -70 degrees C. Analysis of samples from patients treated with CP demonstrated the applicability of the assay. In conclusion, a sensitive and simple assay for 2-DCECP in plasma, which meets the current requirements for bioanalytical assays, was developed.


Subject(s)
Antineoplastic Agents, Alkylating/blood , Chromatography, Gas/methods , Cyclophosphamide/blood , Cyclophosphamide/analogs & derivatives , Humans , Reproducibility of Results , Sensitivity and Specificity
20.
Fresenius J Anal Chem ; 369(5): 442-5, 2001 Mar 01.
Article in English | MEDLINE | ID: mdl-11270226

ABSTRACT

NAMI-A is a novel ruthenium-containing experimental anticancer agent. We have developed and validated a rapid and sensitive analytical method to determine NAMI-A in human plasma, plasma ultrafiltrate and urine using atomic absorption spectrometry with Zeeman correction. The sample pretreatment procedure is straightforward, involving only dilution with an appropriate hydrochloric acid buffer-solution. Because the response signal of the spectrometer depended on the composition of the sample matrix, in particular on the amount of human plasma in the sample, all unknown samples were diluted to match the matrix composition in which the standard line was prepared (plasma-buffer 1:10 v/v). This procedure enabled the measurement of samples of different biological matrices in a single run. The validated range of determination was 1.1-220 microM NAMI-A for plasma and urine, and 0.22-44 microM for plasma ultrafiltrate. The lower limit of detection was 0.85 microM in plasma and urine and 0.17 microM in plasma ultrafiltrate. The lower limit of quantitation was 1.1 and 0.22 microM, respectively. The performance of the method, in terms of precision and accuracy was according to the generally accepted criteria for validation of analytical methodologies. The applicability of the method was demonstrated in a patient who was treated in a pharmacokinetic phase I trial with intravenous NAMI-A.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Dimethyl Sulfoxide/pharmacokinetics , Organometallic Compounds/pharmacokinetics , Spectrophotometry, Atomic , Antineoplastic Agents/blood , Antineoplastic Agents/urine , Buffers , Dimethyl Sulfoxide/analogs & derivatives , Dimethyl Sulfoxide/blood , Dimethyl Sulfoxide/urine , Humans , Hydrochloric Acid , Organometallic Compounds/blood , Organometallic Compounds/urine , Ruthenium/pharmacokinetics , Ruthenium Compounds
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