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Jaap Verweij

Publications and source records attributed to Jaap Verweij.

At least 73 records · Page 4Linked to original sources
PubMed2004

Flat-fixed dosing of irinotecan: influence on pharmacokinetic and pharmacodynamic variability.

PURPOSE: In a previous analysis, it was shown that body-surface area (BSA) is not a predictor of irinotecan pharmacokinetic parameters. Here, we prospectively evaluated the effects of administering a flat-fixed irinotecan dose to cancer patients, regardless of BSA. EXPERIMENTAL DESIGN: Twenty-six cancer patients (12 females) received a fixed irinotecan dose of 600 mg, given as a 90-min i.v. infusion. Plasma concentrations of irinotecan and its metabolites SN-38 (7-ethyl-10-hydroxycamptothecin) and SN-38G (SN-38 glucuronide) were measured during the first cycle and analyzed using nonlinear mixed-effect modeling. Data were compared with those obtained in 47 cancer patients (19 females) who received irinotecan at a BSA-normalized dose of 350 mg/m(2). RESULTS: The interindividual variability in irinotecan clearance (25.9% versus 25.1%; P = 0.93), in relative extent of conversion to SN-38 (47.8% versus 42.7%; P = 0.24), and in relative extent of SN-38 glucuronidation (71.2% versus 72.4%; P = 0.95) were not significantly different between the two dose groups. Variance differences in irinotecan-mediated hematological side effects were also similar between the 600 mg and 350 mg/m(2) groups (P > 0.14). CONCLUSIONS: These findings suggest that flat-fixed dosing of irinotecan does not result in increased pharmacokinetic/pharmacodynamic variability and could be safely used to supplant current dosing strategies based on BSA.

Adult↗
PubMed2004

Population pharmacokinetics of cisplatin in adult cancer patients.

PURPOSE: To characterize the pharmacokinetics of the anticancer agent cisplatin, and explore the influence of patient covariates and interoccasion variability on drug disposition. METHODS: Data were obtained from 285 patients (519 complete curves; 3483 plasma samples) who received the drug as a 3-h intravenous infusion at a mean dose of 144 mg (range 75-210 mg). The population model was built with the use of NONMEM, performing generalized-additive modeling to identify candidate covariates including body-surface area (BSA), age, sex, height, weight, hematocrit, total protein, albumin, serum creatinine, and creatinine clearance, and using a backward deletion protocol to obtain the final models for clearance (CL) and volume of distribution (V). RESULTS: The final model was a one-compartment linear model with BSA (in meters squared) as the only significant covariate that impacted on both CL and V: TVCL (in liters per hour)=51.7+26.3x(BSA-1.855) and TVV (in liters)=41.1+24.6x(BSA-1.855), where TVCL and TVV are referred to as typical values that could be used a priori in dosage regimen design. The interindividual and interoccasion variability estimates for CL and V were 16.82 and 20.35%, and 13.93 and 22.91%, respectively. CONCLUSION: A population pharmacokinetic model for cisplatin has been developed that incorporates measures of body size to predict clearance. In this patient population, cisplatin pharmacokinetics were not associated with age, sex, or measures of renal dysfunction.

Adult↗
PubMed2004

A phase I pharmacokinetic and pharmacodynamic study of the farnesyl transferase inhibitor BMS-214662 in combination with cisplatin in patients with advanced solid tumors.

PURPOSE: BMS-214662 is a potent and selective inhibitor of the farnesyl transferase enzyme with in vitro and in vivo antitumor activity. The aims of this study were to characterize the toxicities and to determine the pharmacokinetic profiles of BMS-214662 when administered in combination with cisplatin, and to determine the constitutive farnesyltransferase activity as a surrogate pharmacodynamic end point. EXPERIMENTAL DESIGN: Twenty-nine patients with advanced solid malignancy, refractory to conventional therapy, and with adequate hematological, renal, and hepatic function were treated with escalating doses of BMS-214662 administered as a 1-h infusion, followed after an interval of 30 min by 75 mg/m(2) cisplatin administered as a 4-h infusion and repeated every 21 days. Blood and urine samples for pharmacokinetic and pharmacodynamic analyses were collected during the first cycle of treatment only. RESULTS: Dose-limiting toxicities occurred in 4 of 9 patients enrolled at the 225 mg/m(2) BMS-214662 dose cohort, and included elevation of hepatic transaminases, nausea, vomiting, diarrhea, and renal failure. There was no apparent pharmacokinetic interaction between the two drugs at the recommended dose levels, and a dose-dependent inhibition of farnesyltransferase activity was observed, which returned to control levels within 24 h of drug administration. There were no objective responses, but disease stabilization was observed in 15 patients, including 4 patients with stable disease after 6 cycles of treatment. CONCLUSIONS: A dose of 200 mg/m(2) of BMS-214662 administered as a 1-h infusion with 75 mg/m(2) cisplatin over 4 h is the recommended dose for additional studies.

Adult↗
PubMed2004

Phase I and pharmacokinetic study of the polyamine synthesis inhibitor SAM486A in combination with 5-fluorouracil/leucovorin in metastatic colorectal cancer.

PURPOSE: The purpose of our study was to determine the maximum-tolerated dose, dose-limiting toxicity, safety profile, and pharmacokinetics of the polyamine synthesis inhibitor SAM486A given in combination with 5-fluorouracil/leucovorin (5-FU/LV) in cancer patients. EXPERIMENTAL DESIGN: Patients with advanced colorectal cancer were treated with 5-FU [bolus (400 mg/m(2)) followed by a 22-h infusion (600 mg/m(2))] and LV (200 mg/m(2)) and escalating doses of SAM486A, 1-3-h infusion daily for 3 days. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of the combination RESULTS: Twenty-seven patients with metastatic colorectal cancer and 1 with pseudomyxoma peritonei were treated. Twenty-six patients received SAM486A in the combination at doses ranging from 25 to 150 mg/m(2)/day. Dose-limiting toxicity consisting of fatigue grade 3 was seen at 150 mg/m(2)/day. Other adverse events included neutropenia, hand and foot syndrome, nausea, vomiting, diarrhea, and constipation. Fifteen of 26 patients evaluable for best response according to the Southwest Oncology Group criteria achieved a partial response [8 (30%) of 26] or stable disease [9 (35%) of 26]. SAM486A did not influence the pharmacokinetics of 5-FU, and SAM486A clearance was similar to that when used as a single agent. CONCLUSIONS: The novel molecular agent SAM486A is tolerable and safe in combination with a standard 5-FU regimen in patients with advanced colorectal cancer. The dose of SAM486A recommended for additional studies with this combination is 125 mg/m(2)/day. A disease-directed evaluation of SAM486A using this regimen is warranted.

Adult↗
PubMed2004

A phase I and pharmacokinetic study of weekly paclitaxel and carboplatin in patients with metastatic esophageal cancer.

PURPOSE: To determine the maximum-tolerated dose, toxicity profile, and pharmacokinetics of a fixed dose of paclitaxel followed by increasing doses of carboplatin, given weekly to patients with advanced esophageal or gastric junction cancer. EXPERIMENTAL DESIGN: Paclitaxel was administered on day 1 as a 1-h infusion at a fixed dose of 100 mg/m(2) followed by a 1-h infusion of carboplatin targeting an area under the curve (AUC) of 2-5 mg x min/ml, with cycles repeated on days 8, 15, 29, 36, and 43. RESULTS: Forty patients [36 males; median (range) age, 57 (40-74) years] were enrolled. Dose-limiting toxicity was observed at a carboplatin AUC of 5 mg x min/ml and consisted of treatment delay attributable to myelosuppression. No grade 3/4 treatment-related nonhematological toxicity was observed. The highest dose intensity (>95% of the planned dose over time) was achieved with a carboplatin AUC of 4 mg x min/ml. The mean (+/-SD) AUCs of unbound (Cu) and total paclitaxel were 0.662 +/- 0.186 and 7.37 +/- 1.33 micro M x h, respectively. Clearance of Cu was 188 +/- 44.6 liter/h/m(2), which is not significantly different from historical data (P = 0.52). Cremophor EL clearance was 123 +/- 23 ml/h/m(2), similar to previous findings. Of 37 patients evaluable for response, 1 had complete response, 19 had partial response, and 10 had stable disease, accounting for an overall response rate of 54%. CONCLUSIONS: This regimen is very tolerable and effective, and the recommended doses for additional studies are paclitaxel (100 mg/m(2)), with carboplatin targeting an AUC of 4 mg x min/ml.

Adenocarcinoma↗
PubMed2004

Comparative pharmacokinetics of weekly and every-three-weeks docetaxel.

PURPOSE: Weekly administration of docetaxel has demonstrated comparable efficacy together with a distinct toxicity profile with reduced myelosuppression, although pharmacokinetic data with weekly regimens are lacking. The comparative pharmacokinetics of docetaxel during weekly and once every 3 weeks (3-weekly) administration schedules were evaluated. EXPERIMENTAL DESIGN: Forty-six patients received weekly docetaxel (35 mg/m(2)) as a 30-min infusion alone (n = 8) or in combination with irinotecan (n = 12), or in 3-weekly regimens, as a 1-h infusion at 60 mg/m(2) with doxorubicin (n = 10), 75 mg/m(2) alone (n = 9), or 100 mg/m(2) alone (n = 7). Serial blood samples were obtained immediately before and up to 21 days after the infusion. Plasma concentrations were measured by liquid chromatography-mass spectrometry and analyzed by compartmental modeling. RESULTS: Mean +/- SD docetaxel clearance values were similar with weekly and 3-weekly schedules (25.2 +/- 7.7 versus 23.7 +/- 7.9 liter/h/m(2)); half-lives were also similar with both schedules of administration (16.5 +/- 11.2 versus 17.6 +/- 7.4 h). With extended plasma sampling beyond 24 h post-infusion, docetaxel clearance was 18% lower and the terminal half-life was 5-fold longer. At 35 mg/m(2), the mean +/- SD docetaxel concentration on day 8 was 0.00088 +/- 0.00041 microg/ml (1.08 +/- 0.51 nM) at 75 mg/m(2), concentrations on day 8, 15, and 22 were 0.0014 +/- 0.00043 microg/ml (1.79 +/- 0.53 nM), 0.00067 +/- 0.00025 microg/ml (0.83 +/- 0.31 nM), and 0.00047 +/- 0.00008 microg/ml (0.58 +/- 0.099 nM), respectively. CONCLUSION: Docetaxel pharmacokinetics are similar for the weekly and 3-weekly regimens. Prolonged circulation of low nanomolar concentrations of docetaxel may contribute to the mechanism of action of docetaxel through suppression of microtubule dynamics and tumor angiogenesis and enhanced cell radiosensitivity in combined modality therapy.

Adult↗
PubMed2004

Simultaneous analysis of docetaxel and the formulation vehicle polysorbate 80 in human plasma by liquid chromatography/tandem mass spectrometry.

An analytical procedure for the simultaneous determination of the anticancer agent docetaxel (Taxotere) and its formulation vehicle polysorbate 80 (Tween 80) in human plasma samples is described. Sample pretreatment involved a double liquid-liquid extraction step with a mixture of acetonitrile/n-butyl chloride (1/4, v/v). Separation of the compounds of interest, including the internal standard paclitaxel, was achieved on a reversed-phase Waters X-Terra mass spectrometry (MS) column (50 x 2.1mm internal diameter) packed with a 3.5-microm octadecyl stationary phase, using isocratic elution. Detection of docetaxel and polysorbate 80 was performed using tandem MS detection with electrospray ionization. Validation results indicated that the method is accurate and precise and has lower limits of quantitation of 0.500 nM (approximately 0.4 ng/ml) and 1.00 microg/ml for docetaxel and polysorbate 80, respectively. The method was subsequently used to measure concentrations of docetaxel and polysorbate 80 in plasma samples in support of a project to assess the influence of polysorbate 80 concentrations on the disposition and toxicity profile of docetaxel in cancer patients receiving Taxotere.

Chromatography, High Pressure Liquid↗
PubMed2004

Liquid chromatographic assays for DE-310, a novel camptothecin analog, and two major enzymatic products in human matrices.

Assays were developed for determination of DE-310, a carboxymethyldextran polyalcohol conjugate of the topoisomerase I inhibitor DX-8951 (exatecan) and two enzymatic products (i.e. glycyl-DX-8951 and unconjugated DX-8951) in human whole blood, erythrocytes and saliva. Sample pretreatment involved a single protein-precipitation step, followed by a thermolysin-mediated deconjugation for the parent molecule. Separation of the compounds was achieved on an Inertsil ODS-80A column (150 mm x 4.6 mm i.d.; 5 microm PS), using isocratic elution. The column effluent was monitored at excitation and emission wavelengths of 375 and 445 nm, respectively. Validation results indicated that the methods are accurate and precise at lower limits of quantitation of 0.5-6.9 ng/ml. The methods were used to study the blood distribution and salivary concentrations in patients receiving DE-310.

Calibration↗
PubMed2004

Effect of cytochrome P450 3A4 inhibition on the pharmacokinetics of docetaxel.

OBJECTIVE: In vitro studies indicate that the anticancer drug docetaxel is primarily eliminated by cytochrome P450 (CYP) 3A4-mediated metabolism. Coadministration of drugs that modulate the activity of CYP3A4 is, therefore, likely to have undesirable clinical consequences. We investigated the effects of the potent CYP3A4 inhibitor ketoconazole on the pharmacokinetics of docetaxel in patients with cancer. METHODS: Seven patients were treated in a randomized crossover design with docetaxel (100 mg/m(2)), followed 3 weeks later by docetaxel (10 mg/m(2)) given in combination with orally administered ketoconazole (200 mg once daily for 3 days), or the reverse sequence. Plasma concentration-time data were analyzed by noncompartmental analysis. RESULTS: Ketoconazole coadministration resulted in a 49% decrease in clearance of docetaxel (P =.018). The mean (+/-SD) clearance values were 35.0 +/- 11.8 L/h (95% confidence interval, 24.1-45.9 L/h) for docetaxel alone and 18.2 L/h (95% confidence interval, 9.22-27.1 L/h) in the presence of ketoconazole, respectively. The docetaxel clearance ratio in the presence and absence of ketoconazole was weakly related to the area under the curve of ketoconazole (R(2) = 0.529, P =.064). CONCLUSION: Inhibition of CYP3A4 by ketoconazole in vivo results in docetaxel clearance values that have previously been shown to be associated with a several-fold increase in the odds for febrile neutropenia at standard doses. Caution should be taken and substantial dose reductions are required if docetaxel has to be administered together with potent inhibitors of CYP3A4.

Administration, Oral↗
PubMed2004

Diflomotecan pharmacokinetics in relation to ABCG2 421C>A genotype.

OBJECTIVE: The adenosine triphosphate-binding cassette transporter ABCG2 (breast cancer resistance protein [BCRP]) functions as an efflux transporter for many drugs, including the topoisomerase I inhibitor diflomotecan, and is expressed at high levels in the intestine and liver. We performed an exploratory analysis to evaluate the effects of the natural allelic variant ABCG2 421C>A on the pharmacokinetics of diflomotecan. METHODS: The drug was administered to 22 adult white patients with cancer as a 20-minute infusion (dose, 0.10-0.27 mg), followed 2 weeks later by an oral solution (dose, 0.10-0.35 mg). RESULTS: The ABCG2 421C>A genotype significantly affected the pharmacokinetics of diflomotecan; in 5 patients heterozygous for this allele, plasma levels after intravenous drug administration were 299% (P =.015) of those in 15 patients with wild-type alleles, at mean values of 138 ng x h/mL x mg(-1) (95% confidence interval, 11.3-264 ng x h/mL x mg(-1)) versus 46.1 ng x h/mL x mg(-1) (95% confidence interval, 25.6-66.7 ng x h/mL x mg(-1)), respectively. Diflomotecan levels were not significantly influenced by 11 known variants in the ABCB1, ABCC2, cytochrome P450 (CYP) 3A4, and CYP3A5 genes. CONCLUSION: These findings provide the first evidence linking variant ABCG2 alleles to altered drug exposure and suggest that interindividual variability in substrate drug effects might be influenced, in part, by ABCG2 genotype.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2004

Mechanism-based models for topotecan-induced neutropenia.

OBJECTIVE: A semiphysiologic pharmacokinetic-pharmacodynamic model was applied to describe topotecan-induced neutropenia, to quantify interindividual and intraindividual pharmacodynamic variability, and to study the effect of covariates on the model. METHODS: Data were obtained from patients treated with topotecan given either orally (118 patients) or intravenously (71 patients), according to different schedules (5 to 21 consecutive days), with or without cisplatin. The model mimics the maturation chain of neutrophils. Topotecan concentration-time profiles affected the proliferation of neutrophil precursors (sensitive cells) through an inhibitory linear model (topotecan is assumed to induce cell loss by a function, E drug, proportional to the topotecan concentration in the central compartment: E drug = Slope . Concentration). The topotecan plasma concentration versus time profile was generated for each patient by modeling the data according to a 2-compartment pharmacokinetic model and first-order absorption for oral administration by use of NONMEM. RESULTS: The model described the time course of neutrophil values well. Topotecan neutropenic effect exhibited a large interpatient variability (coefficient of variation of 82% for the slope values). The oral route was associated with a 43% lower value for slope, corresponding to a lower toxicity. The combination with cisplatin increased the neutropenic effect compared with topotecan alone by a factor 3.5. The intrapatient variability between cycle 1 and cycle 2 on slope was lower for the intravenous administration than for the oral administration. By application of the model to a new weekly schedule of topotecan, neutrophil values at the nadir were consistent with those observed during a phase I study of this regimen. CONCLUSION: This model can be used to describe both the duration and intensity of neutropenia; the area between the curve of neutrophil count versus time and a critical neutrophil count (such as 0.500 x 10(3) /mm 3 ) would be a better toxic endpoint than the unique observed value of neutrophil at nadir. The model may be used to predict neutropenia corresponding to regimens of topotecan not yet explored.

Administration, Oral↗
PubMed2004

Pharmacogenetics of tipifarnib (R115777) transport and metabolism in cancer patients.

The purpose of this study was to perform exploratory relationships between the pharmacokinetics of the farnesyl transferase inhibitor, tipifarnib (R115777, Zarnestra) and allelic variants of genes coding for ATP binding-cassette transporters and drug-metabolizing enzymes. Twenty-eight patients with advanced solid tumors were treated with tipifarnib administered orally at a dose of 200 or 300 mg. Blood samples were collected for pharmacokinetics and genotyping of 10 variants in genes encoding P-glycoprotein (ABCB1), cytochrome P450 isozymes CYP3A4 and CYP3A5, and UDP glucuronosyltransferase isozyme UGT1A1. The homozygous T -allele of ABCB1*8 (1236C > T ) was associated with a trend for a higher area under the curve of tipifarnib as compared to patients with only one or no variant alleles [mean (+/-SD), 5,303 +/- 1,620 ng.h/mL vs. 3,619 +/- 1,275 ng.h/mL; P = 0.047). No statistically significant differences were observed with any other genetic variant ( P > 0.15). Overall, this study indicates that ABCB1 genotype might be correlated with tipifarnib pharmacokinetics, although considerable overlap in exposure measures between genotype groups was observed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Limited cerebrospinal fluid penetration of docetaxel.

Our purpose was to investigate the cerebrospinal fluid (CSF) penetration of docetaxel in cancer patients. Docetaxel was administered as a 1-h infusion at a dose of 75 mg/m2 to two patients with metastatic breast cancer and leptomeningeal carcinomatosis. CSF samples were obtained using a lumbar puncture up to a 72-h time period. Total and unbound docetaxel concentrations in plasma and CSF were determined by liquid chromatography (lower limit of quantitation: 0.5 nM for plasma and 0.050 nM for CSF) and equilibrium dialysis, respectively. The pharmacokinetics of docetaxel in plasma are in line with data of previous studies. The concentrations of docetaxel in CSF did not follow the general pattern in plasma, with relatively stable concentrations over the 72-h time period. The fraction of unbound docetaxel in plasma ranged from 6 to 13%, while that in CSF ranged from 67 to 103%. For total and unbound docetaxel, the CSF to plasma concentration ratio progressively increased in 72 h from 0.01 to 0.6% and from 0.1 to 9%, respectively. These data suggest that measurement of unbound docetaxel is required to accurately assess the extent of drug penetration into CSF and that the drug can produce distribution to CSF at levels associated with significant antitumor activity in experimental models.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Influence of genetic variants in UGT1A1 and UGT1A9 on the in vivo glucuronidation of SN-38.

The uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A9 isoforms are involved in the phase II biotransformation of the irinotecan metabolite, SN-38. Recently, several variants in the UGT1A1 and UGT1A9 genes have been described with altered functionality in vitro. The aim of this study was to evaluate the functional consequence of the UGT1A1(TA)(7)TAA (UGT1A1(*)28), UGT1A9 766G>A (D256N; UGT1A9(*)5), and UGT1A9 98T>C (M33T; UGT1A9(*)3) variants in Caucasian patients treated with irinotecan. Pharmacokinetic studies were performed after the first course of irinotecan in 47 males and 47 females. The mean (SD) area under the curves (AUCs) of irinotecan and SN-38 were 20,348 +/- 6466 ng x h/mL and 629 +/- 370 ng x h/mL, respectively, which is in line with earlier findings. For UGT1A9(*)5,novariant alleles were observed, whereas for UGT1A9(*)3, 1 patient with the variant allele was found (allele frequency, 0.633%). The distribution of the UGT1A1(*)28 variant showed 44 wild-type patients (Wt), 37 heterozygotes (Het), and 5 homozygotes (Var). The median AUC ratio of SN-38G to SN-38 was significantly reduced in carriers of the variant UGT1A1(*)28 allele (7.00 [Wt] vs. 6.26 [Het] vs. 2.51 [Var]; p =.022). It is concluded that UGT1A9 functional variants are rare in Caucasians and likely to be clinically insignificant in irinotecan regimens. Screening for the UGT1A1(*)28 polymorphism may identify patients with altered SN-38 pharmacokinetics.

Adult↗
PubMed2003

Determination of irinotecan (CPT-11) and SN-38 in human whole blood and red blood cells by liquid chromatography with fluorescence detection.

An analytical method was developed for the anticancer agent irinotecan (CPT-11) and its main metabolite SN-38 in human whole blood and in red blood cells (RBCs). Sample pretreatment involved deproteinization of whole blood or plasma-diluted RBCs isolated by MESED instruments, with a mixture of aqueous perchloric acid and methanol (1:1, v/v). Separation was carried out using isocratic elution on a Hypersil ODS stationary phase, with detection at excitation and emission wavelengths of 355 and 515 nm, respectively. The lower limit of quantitation (LLQ) in blood was established at 5.00 ng/ml for both compounds, with values for within-run precision (WRP) and between-run precision (BRP) of less than 10%. The method is currently being applied to investigate the blood distribution of CPT-11 and SN-38 in cancer patients.

Antineoplastic Agents↗