Biomedical subjects

Jos H Beijnen

Publications and source records attributed to Jos H Beijnen.

At least 19 recordsLinked to original sources

PubMed2026

Development and validation of an LC-MS/MS method for the quantification of the KRASG12C inhibitor divarasib.

Divarasib is a newly developed covalent KRASG12C inhibitor, currently under clinical investigation in a phase 3 trial in patients with non-small cell lung cancer (NSCLC). At the moment, very limited pharmacokinetic data are publicly known. However, obtaining more insight into the pharmacokinetic properties of divarasib is important, since this may provide a better understanding of its efficacy and safety risks. Pre-clinical studies have been performed in mouse models to evaluate the effect of drug transporters and drug-metabolizing enzymes on the plasma exposure and tissue distribution of divarasib. Therefore, a reliable quantification method is required. To our knowledge, no bioanalytical assay of divarasib has been published yet. Therefore, in this study we developed and validated an assay to quantify divarasib in human plasma and in eight different mouse-related matrices, and partially in mouse plasma, using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method was initially evaluated over a concentration range of 1-10,000 nM. However, due to carry-over observed at 10,000 nM, the validated calibration range was established at 1-2000 nM, with matrix-dependent LLOQs of 1-10 nM. Erlotinib was used as an internal standard and acetonitrile was utilized to perform protein precipitation as sample pretreatment. Divarasib demonstrated stability in human plasma and in mouse plasma and tissue homogenates under various experimental conditions. A pilot in vivo study showed the applicability of our validated LC-MS/MS method. Ongoing clinical trials may collect plasma samples, and this developed method enables quantification of divarasib in both mouse and human plasma samples.

Animals↗

PubMed2007

In vitro characterization of the human biotransformation pathways of aplidine, a novel marine anti-cancer drug.

Aplidine is a potent marine anti-cancer drug and is currently being investigated in phase II clinical trials. However, the enzymes involved in the biotransformation of aplidine and thus its pharmacokinetics are not known yet. To assess the biotransformation pathways of aplidine and their potential implications for human pharmacology and toxicology, the in vitro metabolism of aplidine was characterized using incubations with human plasma, liver preparations, cytochrome P450 (CYP) and uridine diphosphoglucuronosyl transferase (UGT) supersomes in combination with HPLC analysis and cytotoxicity assays with cell lines. Aplidine was metabolised by carboxyl esterases in human plasma. Using CYP supersomes and liver microsomes, it was shown that aplidine was metabolised mainly by CYP3A4 and also by CYP2A6, 2E1 and 4A11. Four metabolites were observed after incubation with human liver microsomes, one formed by CYP2A6 (C-demethylation) and three by CYP3A4 (hydroxylation and/or C-dealkylation). No conjugation was observed in human liver S9 fraction. However, the aplidine metabolites formed by CYP were further conjugated by the phase II enzymes UGT, GST and SULT. In accordance with the findings in microsomes and CYP supersomes, a significant effect of specific CYP2A6, 2E1, 3A4 and 4A11 inhibitors on the cytotoxicity of aplidine in Hep G2 and IGROV-1 cells could be observed. These results provide evidence that CYP3A4 has a major role in metabolising aplidine in vitro with additional involvement of CYP2A6, 2E1, and 4A11. Further, the metabolites formed by CYPs can be conjugated by UGT, SULT and GST. These findings could help interpret the in vivo pharmacokinetics of aplidine.

Antineoplastic Agents↗

PubMed2007

Trabectedin (ET-743, Yondelis) is a substrate for P-glycoprotein, but only high expression of P-glycoprotein confers the multidrug resistance phenotype.

Trabectedin (ET-743, Yondelis) is a novel anticancer drug currently undergoing phase II and III investigations. There are various and conflicting reports whether trabectedin is a substrate for P-glycoprotein (P-gp), an important factor in drug disposition and multi-drug resistance (MDR). We have now unambiguously shown that trabectedin is a P-gp substrate by investigating vectorial transport over monolayers of LLC-PK1 pig kidney and Madine-Darby Canine kidney (MDCK) cells and the mdr1a and/or MDR1 transfected subclones. We further characterized the cytotoxic effects and cellular accumulation of trabectedin in these cell lines as well as in a panel of other cell lines with high or moderate expression levels of P-gp. Trabectedin displayed the typical MDR phenotype only in highly P-gp expressing cell lines, but not in cell lines with expression levels more closely conforming to clinical samples, suggesting that P-gp will not confer resistance to trabectedin in cancer patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

The effect of hydroxyurea on P-glycoprotein/BCRP-mediated transport and CYP3A metabolism of imatinib mesylate.

PURPOSE: It has been reported that the combination therapy of imatinib mesylate, a tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, is associated with remarkable antitumor activity in patients with recurrent glioblastoma multiforme. However, the mechanism of the added activity of hydroxyurea to imatinib is not known. The purpose of this study was to investigate in vitro, whether hydroxyurea could enhance the central nervous system penetration of imatinib, by inhibition of the ATP-dependent transporter proteins P-glycoprotein (ABCB1; MDR1; Pgp) and Breast Cancer Resistance Protein (ABCG2; BCRP), or by inhibition of cytochrome P450 3A (CYP3A) metabolism of imatinib. METHODS: The effect of hydroxyurea on the Pgp and BCRP mediated transport of imatinib was investigated by the sulforhodamine-B (SRB) drug cytotoxicity assay and transepithelial transport assay. In vitro biotransformation studies with supersomes expressing human CYP3A4 were performed to investigate whether hydroxyurea inhibited CYP3A4. RESULTS: In both in vitro cytotoxicity and transport assays, hydroxyurea did not affect Pgp and BCRP mediated transport of imatinib. In a biotransformation assay, hydroxyurea had no influence on the metabolic degradation of imatinib either. CONCLUSION: The results indicate that hydroxyurea does not interact with imatinib by inhibition of Pgp and BCRP mediated transport or by CYP3A4 mediated metabolism of imatinib.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Multidrug transporter ABCG2/breast cancer resistance protein secretes riboflavin (vitamin B2) into milk.

The multidrug transporter breast cancer resistance protein (BCRP/ABCG2) is strongly induced in the mammary gland during pregnancy and lactation. We here demonstrate that BCRP is responsible for pumping riboflavin (vitamin B(2)) into milk, thus supplying the young with this important nutrient. In Bcrp1(-/-) mice, milk secretion of riboflavin was reduced >60-fold compared to that in wild-type mice. Yet, under laboratory conditions, Bcrp1(-/-) pups showed no riboflavin deficiency due to concomitant milk secretion of its cofactor flavin adenine dinucleotide, which was not affected. Thus, two independent secretion mechanisms supply vitamin B(2) equivalents to milk. BCRP is the first active riboflavin efflux transporter identified in mammals and the first transporter shown to concentrate a vitamin into milk. BCRP activity elsewhere in the body protects against xenotoxins by reducing their absorption and mediating their excretion. Indeed, Bcrp1 activity increased excretion of riboflavin into the intestine and decreased its systemic availability in adult mice. Surprisingly, the paradoxical dual utilization of BCRP as a xenotoxin and a riboflavin pump is evolutionarily conserved among mammals as diverse as mice and humans. This study establishes the principle that an ABC transporter can transport a vitamin into milk and raises the possibility that other vitamins and nutrients are likewise secreted into milk by ABC transporters.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2006

Flat dosing of carboplatin is justified in adult patients with normal renal function.

PURPOSE: The Calvert formula is a widely applied algorithm for the a priori dosing of carboplatin based on patients glomerular filtration rate (GFR) as accurately measured using the 51Cr-EDTA clearance. Substitution of the GFR in this formula by an estimate of creatinine clearance or GFR as calculated by formulae using serum creatinine (SCR; Cockcroft-Gault, Jelliffe, and Wright) is, however, routine clinical practice in many hospitals. The goal of this study was to validate this practice retrospectively in a large heterogeneous adult patient population. EXPERIMENTAL DESIGN: Concentration-time data of ultrafilterable platinum of 178 patients (280 courses, 3,119 samples) with different types of cancer receiving carboplatin-based chemotherapy in conventional and high doses were available. Data were described with a linear two-compartment population pharmacokinetic model. Relations between SCR-based formulae for estimating renal function and carboplatin clearance were investigated. RESULTS: None of the tested SCR-based estimates of renal function were relevantly related to the pharmacokinetic variables of carboplatin. Neither SCR (median, 51; range, 18-124 micromol/L) nor the estimated GFR using the three different formulae was related to carboplatin clearance. CONCLUSIONS: Our data do not support the application of modifications of the Calvert formula by estimating GFR from SCR in the a priori dosing of carboplatin in patients with relatively normal renal function (creatinine clearance, >50 mL/min). For targeted carboplatin exposures, the original Calvert formula, measuring GFR using the 51Cr-EDTA clearance, remains the method of choice. Alternatively, in patients with normal renal function, a flat dose based on the mean population carboplatin clearance should be administered.

Adolescent↗

PubMed2006

Multidrug resistance protein 2 is an important determinant of paclitaxel pharmacokinetics.

PURPOSE: P-glycoprotein (P-gp; ABCB1) efficiently transports lipophilic amphipathic drugs, including the widely used anticancer drug paclitaxel (Taxol). We found previously that human multidrug resistance protein 2 (MRP2; ABCC2) also transports paclitaxel in vitro, and although we expected that paclitaxel pharmacokinetics would be dominated by P-gp, the effect of Mrp2 was tested in vivo. EXPERIMENTAL DESIGN: We generated and characterized Mdr1a/1b/Mrp2(-/-) mice, allowing assessment of the distinct roles of Mrp2 and Mdr1a/1b P-gp in paclitaxel pharmacokinetics. RESULTS: Surprisingly, the effect of Mrp2 on i.v. administration of paclitaxel was as great as that of P-gp. The area under plasma concentration-time curve (AUC)i.v. in both Mrp2(-/-) and Mdr1a/1b(-/-) mice was 1.3-fold higher than in wild-type mice, and in Mdr1a/1b/Mrp2(-/-) mice, a 1.7-fold increase was found. In spite of this similar effect, Mrp2 and P-gp had mostly complementary functions in paclitaxel elimination. Mrp2 dominated the hepatobiliary excretion, which was reduced by 80% in Mrp2(-/-) mice. In contrast, P-gp dominated the direct intestinal excretion, with a minor role for Mrp2. The AUCoral of paclitaxel was 8.5-fold increased by Mdr1a/1b deficiency but not affected by Mrp2 deficiency. However, in the absence of Mdr1a/1b P-gp, additional Mrp2 deficiency increased the AUCoral another 1.7-fold. CONCLUSIONS: Thus far, Mrp2 was thought to mainly affect organic anionic drugs in vivo. Our data show that Mrp2 can also be a major determinant of the pharmacokinetic behavior of highly lipophilic anticancer drugs, even in the presence of other efficient transporters. Variation in MRP2 activity might thus directly affect the effective exposure to paclitaxel, on i.v. administration, but also on oral administration, especially when P-gp activity is inhibited.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2006

The effect of low pH on breast cancer resistance protein (ABCG2)-mediated transport of methotrexate, 7-hydroxymethotrexate, methotrexate diglutamate, folic acid, mitoxantrone, topotecan, and resveratrol in in vitro drug transport models.

Some cellular uptake systems for (anti)folates function optimally at acidic pH. We have tested whether this also applies to efflux from cells by breast cancer resistance protein (BCRP; ABCG2), which has been reported to transport folic acid, methotrexate, and methotrexate di- and triglutamate at physiological pH. Using Spodoptera frugiperda-BCRP membrane vesicles, we showed that the ATP-dependent vesicular transport of 1 muM methotrexate by BCRP is 5-fold higher at pH 5.5 than at physiological pH. The transport of methotrexate was saturable at pH 5.5, with apparent Km and Vmax values of 1.3 +/- 0.2 mM and 44 +/- 2.5 nmol/mg of protein/min, respectively, but was linear with drug concentration at pH 7.3 up to 6 mM methotrexate. In contrast to recent reports, we did not detect transport of methotrexate diglutamate at physiological pH, but we did find transport at pH 5.5. We also found that 7-hydroxy-methotrexate, the major metabolite of methotrexate, is transported by BCRP both at physiological pH and (more efficiently) at low pH. The pH effect was also observed in intact BCRP-overexpressing cells: we found a 3-fold higher level of resistance to both methotrexate and the prototypical BCRP substrate mitoxantrone at pH 6.5 as at physiological pH. Furthermore, with MDCKII-BCRP monolayers, we found that resveratrol, which is a neutral compound at pH < or = 7.4, is efficiently transported by BCRP at pH 6.0, whereas we did not detect active transport at pH 7.4. We conclude that BCRP transports substrate drugs more efficiently at low pH, independent of the dissociation status of the substrate.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2006

Pharmacogenetic screening of CYP3A and ABCB1 in relation to population pharmacokinetics of docetaxel.

PURPOSE: Despite the extensive clinical experience with docetaxel, unpredictable interindividual variability in efficacy and toxicity remain important limitations associated with the use of this anticancer drug. Large interindividual pharmacokinetic variability has been associated with variation in toxicity profiles. Genetic polymorphisms in drug-metabolizing enzymes and drug transporters could possibly explain the observed pharmacokinetic variability. The aim of this study was therefore to investigate the influence of polymorphisms in the CYP3A and ABCB1 genes on the population pharmacokinetics of docetaxel. EXPERIMENTAL DESIGN: Whole blood samples were obtained from patients with solid tumors and treated with docetaxel to quantify the exposure to docetaxel. DNA was collected to determine polymorphisms in the CYP3A and ABCB1 genes with DNA sequencing. A population pharmacokinetic analysis of docetaxel was done using nonlinear mixed-effect modeling. RESULTS: In total, 92 patients were assessable for pharmacokinetic analysis of docetaxel. A three-compartmental model adequately described the pharmacokinetics of docetaxel. Several polymorphisms in the CYP3A and ABCB1 genes were found, with allele frequencies of 0.54% to 48.4%. The homozygous C1236T polymorphism in the ABCB1 gene (ABCB1*8) was significantly correlated with a decreased docetaxel clearance (-25%; P = 0.0039). No other relationships between polymorphisms and pharmacokinetic variables reached statistical significance. Furthermore, no relationship between haplotypes of CYP3A and ABCB1 and the pharmacokinetics could be identified. CONCLUSIONS: The polymorphism C1236T in the ABCB1 gene was significantly related to docetaxel clearance. Our current finding may provide a meaningful tool to explain interindividual differences in docetaxel treatment in daily practice.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2006

Clinical and pharmacologic study of the farnesyltransferase inhibitor tipifarnib in cancer patients with normal or mildly or moderately impaired hepatic function.

PURPOSE: This study explored the feasibility of treating patients with impaired hepatic function with tipifarnib. The safety profile, pharmacokinetics, and relationship between the pharmacokinetics and toxicities were evaluated. PATIENTS AND METHODS: Patients with mildly or moderately impaired hepatic function (Child-Pugh classification) were treated with tipifarnib bid on days 1 to 5 of cycle 1. Further dosing was based on the individual day 5 pharmacokinetic data and absolute neutrophil count. For patients with normal hepatic function, tipifarnib was dosed on days 1 to 14, followed by 1 week of rest. For all patients, in subsequent cycles, tipifarnib was administered for 21 consecutive days out of every 28 days. RESULTS: Twenty-eight patients were included in the normal (n = 16), mild (n = 9), and moderate (n = 3) impairment groups. The most important grade 3 to 4 hematologic toxicity was leukocytopenia/neutropenia, which was mostly observed in patients with moderate impairment. Common nonhematologic toxicities were fatigue, nausea, and vomiting. The pharmacokinetic data showed higher plasma concentrations of tipifarnib in patients with liver impairment compared with patients with normal hepatic function. CONCLUSION: In patients with mildly impaired hepatic function, tipifarnib can be administered safely at a starting dose of 200 mg bid, but it is not safe to treat patients with moderate hepatic impairment.

Adult↗

PubMed2006

ABCB1 genotypes and haplotypes in patients with dementia and age-matched non-demented control patients.

Amyloid beta is an in vitro substrate for P-glycoprotein (P-gp), an efflux pump at the blood brain barrier (BBB). The Multi Drug Resistance (ABCB1) gene, encoding for P-gp, is highly polymorphic and this may result in a changed function of P-gp and may possibly interfere with the pathogenesis of Alzheimer's disease. This study investigates to what extent ABCB1 Single Nucleotide Polymorphisms (SNPs; C1236T in exon 12, G2677T/A in exon 21 and C3435T in exon 26) and inferred haplotypes exist in an elderly population and if these SNPs and haplotypes differ between patients with dementia and age-matched non-demented control patients. ABCB1 genotype, allele and haplotype frequencies were neither significantly different between patients with dementia and age-matched controls, nor between subgroups of different types of dementia nor age-matched controls. This study shows ABCB1 genotype frequencies to be comparable with described younger populations. To our knowledge this is the first study on ABCB1 genotypes in dementia. ABCB1 genotypes are presently not useful as a biomarker for dementia, as they were not significantly different between demented patients and age-matched control subjects.

Journal Article↗

PubMed2006

Metabolism of trabectedin (ET-743, Yondelis) in patients with advanced cancer.

PURPOSE: Trabectedin (ET-743, Yondelis) is a novel anti-cancer drug currently undergoing phase II-III evaluation, that has shown remarkable activity in pre-treated patients with soft tissue sarcoma. Despite extensive pharmacokinetic studies, the human disposition and metabolism of trabectedin remain largely unknown. We aimed to determine the metabolic profile of trabectedin and to identify its metabolites in humans. METHODS: We analysed urine and faeces (the major excretory route) from eight cancer patients after a 3 or 24 h intravenous administration of [14C]trabectedin. Using liquid chromatography with tandem quadrupole mass spectrometric detection (LC-MS/MS) and radiochromatography with off-line radioactivity detection by liquid scintillation counting (LC-LSC), we characterised the metabolic profile in 0-24 h urine and 0-120 h faeces. RESULTS: By radiochromatography, a large number of trabectedin metabolites were detected. Incubation with beta-glucuronidase indicated the presence of a glucuronide metabolite in urine. Trabectedin, ET-745, ET-759A, ETM-259, ETM-217 (all available as reference compounds) and a proposed new metabolite coined ET-731 were detected using LC-MS/MS. The inter-individual differences in radiochromatographic profiles were small and did not correlate with polymorphisms in drug-metabolising enzymes (CYP2C9, 2C19, 2D6, 2E1, 3A4, GST-M1, P1, T1 and UGT1A1 2B15) as determined by genotyping. CONCLUSIONS: Trabectedin is metabolically converted to a large number of compounds that are excreted in both urine and faeces. In urine and faeces we have confirmed the presence of trabectedin, ET-745, ET-759A, ETM-259, ETM-217 and ETM-204. In addition we have identified a putative new metabolite designated ET-731. Future studies should be aimed at further identification of possible metabolites and assessment of their activity.

Antineoplastic Agents, Alkylating↗

PubMed2006

A semi-physiological population pharmacokinetic model describing the non-linear disposition of indisulam.

The pharmacokinetic profile of the anti-cancer agent indisulam is non-linear. In addition to non-linear clearance, this may partially be explained by saturable distribution to red blood cells and saturable plasma protein binding. The aims of this study were to develop a semi-physiological population pharmacokinetic model of indisulam and to examine the impact of protein binding and distribution to red blood cells. Indisulam concentrations in plasma, plasma ultrafiltrate and in red blood cells from multiple phase I studies in Caucasian and Japanese patients were used to develop a pharmacokinetic model using NONMEM. This model comprised four physiological compartments: plasma, red blood cells, interstitial fluid and tissue. A simulation study was performed to examine the contribution of physiological processes in indisulam pharmacokinetics. Plasma albumin concentrations were predictive for the maximal protein binding capacity and considerably influenced total plasma concentrations of indisulam, whereas free plasma concentrations remained relatively unaffected. The maximal specific red blood cell binding capacity was 64.0 ( +/-5.9) mg/L and corresponded to the typical red blood cell carbonic anhydrase concentration. Simulation studies demonstrated that the hematocrit does not have a clinically relevant impact on indisulam disposition. This semi-physiological model allowed adequate prediction of the time profiles of indisulam concentrations in all monitored compartments for a large range of dose levels and several treatment regimens. The model has elucidated the mechanism and the role of saturable plasma protein binding and saturable distribution to red blood cells in indisulam pharmacokinetics and provides a basis for rationale PK-PD relationships.

Algorithms↗

PubMed2006

Treatment of ovarian cancer using intraperitoneal chemotherapy with taxanes: from laboratory bench to bedside.

The combination of a taxane, paclitaxel or docetaxel, and a platinum compound has become the systemic chemotherapy of choice for primary ovarian cancer and has demonstrated high efficacy. However, ultimately most patients will die from this disease. Hence, there is a need for even more effective systemic chemotherapy or different treatment strategies. Intraperitoneal chemotherapy with taxanes is such an alternative treatment option. Ovarian cancer is theoretically an attractive malignancy for this regional treatment, because the disease remains largely confined to the peritoneal cavity. The choice of taxanes for this kind of chemotherapy is rational, because of its high activity against ovarian cancer cells and expected favourable pharmacokinetics because of limited absorption from the peritoneal cavity due to their large molecular weight and first-pass effect in the liver. In animal model and human pharmacokinetic studies, very high intraperitoneal drug concentrations and exposure and high peritoneal tumour concentrations were achieved, while systemic drug levels were low. The combination of intraperitoneal chemotherapy with hyperthermia enhances the penetration and cytotoxic activity of many drugs. Although data concerning thermal enhancement of taxane cytotoxicity are inconsistent, experimental studies show that at high locoregional concentrations there seems to be such an effect. Recently, feasibility and efficacy of this treatment have evidently been demonstrated in various clinical studies. A large randomized trial revealed improvement of outcome by intraperitoneal instillation chemotherapy with paclitaxel and cisplatin as first-line treatment. Moreover, promising results have been observed after intraoperative hyperthermic intraperitoneal chemotherapy with docetaxel for recurrent disease.

Animals↗

PubMed2006

Stability experiments in human urine with EO9 (apaziquone): a novel anticancer agent for the intravesical treatment of bladder cancer.

EO9 (apaziquone) is a novel, promising anticancer agent, which is currently being investigated for the intravesical treatment of bladder cancer. EO9 contains a highly reactive aziridine ring in its structure that limits its chemical stability in acidic aqueous solutions. The stability of the pharmaceutically formulated EO9 in human urine, including the effects of several parameters such as temperature, buffer strength and pH have been investigated. Urine extracts were analyzed by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry (HPLC-MS/MS) using a TurboIonspray interface and positive-ion multiple reaction monitoring. EO9 was unstable in urine at 43 degrees C during the instillation for longer than 1 h. However, the drug was stable in human urine for 3 h at 37 degrees C. EO9 is stable in urine stabilized with TRIS buffer (pH 9.0; 5 mM) for up to three freeze/thaw cycles at -20 and -70 degrees C and 3 months of storage at -70 degrees C. The results also illustrated that with the lower pH in urine, EO9 became more unstable. Furthermore, a new degradation product of EO9 was discovered and successfully identified as EO9-Cl. The outcomes of these stability experiments will be implemented to insure proper sample handling at the clinical sites, transport, storage, and sample handling during analysis in the forthcoming preclinical studies of EO9 in superficial bladder cancer, supported by bioanalysis and pharmacokinetic monitoring.

Antineoplastic Agents↗

PubMed2006

Phase I and pharmacokinetic study of combined treatment with perifosine and radiation in patients with advanced solid tumours.

PURPOSE: Perifosine is an orally applicable, membrane-targeted alkylphosphocholine analogue with antitumour activity and radiosensitising properties in preclinical models. The purpose of this phase I study was to determine the feasibility and tolerability of concurrent daily perifosine and radiation in patients with advanced cancer. PATIENTS AND METHODS: Starting dose of perifosine was 50 mg/day; dose escalation was in steps of 50mg. Daily administration commenced 2 days before radiotherapy and was continued throughout the radiation treatment. At least three patients were entered at each dose level; at the 150 mg/day level 10 patients were included. Pharmacokinetic sampling was performed weekly pre-dosing. Twenty-one patients were entered. Tumour types included NSCLC (n=17), prostate, oesophageal, colon and bladder cancer. Most patients (16/21) had received prior chemotherapy; none radiotherapy. Median number of daily perifosine administrations was 31 (range 24-53). Mean radiation dose (BED(10)) was 59.8 Gy (range 50.7-87.5 Gy in 13-28 fractions). RESULTS: Major drug-related toxicities according to CTC criteria were nausea in 57%, fatigue in 48%, vomiting in 38%, diarrhoea in 38% and anorexia in 19%. No bone marrow toxicity was observed. DLT (nausea/vomiting) was encountered in two of five patients at the 200mg/day dose level. Dose-dependent steady-state plasma levels were reached after 1 week. Major radiotherapy-related acute toxicity consisted of dysphagia in 38% and pneumonitis in 29%. CONCLUSION: Perifosine can be safely combined with fractionated radiotherapy. A dosage of 150 mg/day, to be started at least 1 week prior to radiotherapy, is recommended for phase II evaluation.

Adult↗

PubMed2006

Dose-finding phase I clinical and pharmacokinetic study of orally administered irinotecan in patients with advanced solid tumors.

PURPOSE: The aim of this study was to determine the daily maximum tolerated dose (MTD) and the dose-limiting toxicity for the following administration schedules: oral irinotecan given over 14 days every 3 weeks (part I) and oral irinotecan administered concomitantly with capecitabine over 14 days every 3 weeks (part II). In total, 42 patients (17 male and 25 female) with solid tumors refractory to standard therapy entered the study. EXPERIMENTAL DESIGN: Treatment in part I consisted of irinotecan administered orally as semisolid matrix capsules at doses of 25, 30, and 35 mg/m(2) once daily to confirm the MTD of our earlier study. In part II treatment, dose levels for irinotecan combined with capecitabine were 20/1,600, 25/1,600, 30/1,600, and 30/2,000 mg/m(2)/d. RESULTS: The median number of cycles administered per patient was 2.0 (range, 1-12) in part I and 2.0 (range, 1-13) in study part II. Gastrointestinal toxicities (grade 3 nausea, grades 3 and 4 vomiting, and grades 3 and 4 diarrhea) were dose limiting in both parts of the study. There were no grade 3 or 4 hematologic toxicities. The MTD was 30 mg/m(2)/d for irinotecan single agent and 30/1,600 mg/m(2)/d for the combination with capecitabine. Absorption of irinotecan was rapid, and peak concentrations of irinotecan and metabolite SN-38 were reached within 0 to 3 and 1.5 to 4.0 hours, respectively. CONCLUSIONS: In conclusion, oral irinotecan and capecitabine is feasible and well tolerated, and the recommended dose for phase II studies is 30/1,600 mg/m(2)/d administered daily for 14 days every 3 weeks.

Administration, Oral↗

PubMed2006

Quantification of farnesylmethylcysteine in lysates of peripheral blood mononuclear cells using liquid chromatography coupled with electrospray tandem mass spectrometry: pharmacodynamic assay for farnesyl transferase inhibitors.

Biological effectiveness is an important parameter in determining optimal dosages of molecular targeted drugs, such as farnesyl transferase inhibitors. To determine concentration-effect relationships, robust and quantitative biological assays are a prerequisite. Here, we present a novel assay for protein farnesylation that is based on generation of the biomarker farnesylmethylcysteine (FmC). Quantification was performed with liquid chromatography coupled to tandem mass spectrometry. The assay has been validated based on the most recent FDA guidelines for bioanalytical validation, and all results were within requirements. FmC is formed under the action of an endogenous protease that is activated upon cell lysis. The biomarker could be detected in A549 human lung cancer cells as well as in human peripheral blood mononuclear cells. Incubation of A549 cells with AZD3409, a novel prenyl transferase inhibitor, resulted in a significant decrease of the FmC concentration in the lysates. These findings provide a very good starting point for use of this assay in preclinical and clinical dose finding studies with FTIs.

Biological Assay↗