H.J.G.D. van den Bongard

Publications (9)11.16 Total impact

• Article: Determinants of the elimination of methotrexate and 7-hydroxy-methotrexate following high-dose infusional therapy to cancer patients.

  M Joerger, A D R Huitema, H J G D van den Bongard, P Baas, J H Schornagel, J H M Schellens, J H Beijnen
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  ABSTRACT: To characterize determinants of the elimination of methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX) in patients receiving high-dose MTX therapy (HDMTX). 24 and 48-h blood samples from 76 patients receiving HDMTX (dose range 300 mg m-2 to 12 g m-2) were analysed, and concentration-time data were subjected to population pharmacokinetic and covariate analysis using nonlinear mixed-effect modelling (NONMEM). Treatment-related mortality was 1.3% (one patient with renal failure). Values for MTX clearance (CLMTX) and 7-OH-MTX clearance (CL7-OH-MTX) were estimated at 8.85 and 2 L-1, respectively. Baseline creatinine clearance correlated with CLMTX and CL7-OH-MTX. Concurrent administration of benzimidazoles led to a 27% decrease in CLMTX and a 39% decrease in CL7-OH-MTX. Prior administration of nonsteroidal anti-inflammatory drugs (NSAIDs) resulted in a 16% decrease in CLMTX and a 38% decrease in CL7-OH-MTX. Plasma MTX concentrations were significantly higher in patients also receiving benzimidazoles at 24 h (2.01 micromol L-1vs. 0.66 micromol L-1, P<10(-4)) and at 48 h (0.25 micromol L-1vs. 0.12 micromol L-1, P<10(-4)). 7-OH-MTX plasma concentrations were also significantly higher in patients with concurrent benzimidazoles as compared with patients without benzimidazoles at 24 h (4.47 micromol L-1vs. 2.52 micromol L-1, P=0.0009) and at 48 h (1.11 micromol L-1vs. 0.72 micromol L-1, P=0.031). In patients receiving HDMTX, concurrent administration of benzimidazoles was associated with a significant decrease of CLMTX and CL7-OH-MTX, resulting in significantly higher plasma concentrations of MTX and 7-OH-MTX. The data suggest that benzimidazole treatment should be seen as a relative contraindication for HDMTX.
  British Journal of Clinical Pharmacology 07/2006; 62(1):71-80. · 2.96 Impact Factor
• Source

  Available from: uu.nl

  Article: In vitro pharmacokinetic study of the novel anticancer agent E7070: red blood cell and plasma protein binding in human blood.

  H J G D van den Bongard, D Pluim, R C A M van Waardenburg, M Ravic, J H Beijnen, J H M Schellens
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  ABSTRACT: E7070 is a novel sulfonamide anticancer agent that arrests the G(1)/S phase of the cell cycle. Preclinical and phase I studies have demonstrated non-linear pharmacokinetics (PK) of the drug. A population PK analysis revealed that the human plasma concentration-time data were best described by a three-compartment model with non-linear distribution. We have studied the in vitro interaction of 14C-radiolabeled E7070 with red blood cells (RBC) and its binding to plasma proteins in the concentration range where non-linearity in disposition was observed in humans to get more insight into the behavior of the drug. After the addition of E7070 to whole blood at 37 degrees C, the drug is taken up or binds to RBC in a concentration-dependent manner. The addition of sodium azide, however, did not result in a decrease of drug uptake by RBC, indicating passive diffusion processes. A non-linear increase in drug uptake was observed at incubation concentrations above 4 microg/ml E7070 in whole blood. This non-linearity was confirmed by lower partition coefficients between RBC and plasma at higher incubation concentrations (from 2.37 at 4 microg/ml to 0.31 at 200 microg/ml). The plasma protein binding of E7070 was high (98-99%) and linear in the concentration range studied (20-200 microg/ml). In conclusion, E7070 in whole blood is preferentially bound to RBC and exhibits high plasma protein binding. The non-linear distribution of E7070 in humans can be caused, in part at least, by saturable binding of E7070 to RBC.
  Anti-Cancer Drugs 08/2003; 14(6):405-10. · 2.41 Impact Factor
• Source

  Available from: Olaf van Tellingen

  Article: A population analysis of the pharmacokinetics of Cremophor EL using nonlinear mixed-effect modelling.

  H J G D van den Bongard, R A A Mathôt, O van Tellingen, J H M Schellens, J H Beijnen
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  ABSTRACT: The purpose of this study was to develop a population pharmacokinetic model for Cremophor EL used as a formulation vehicle for paclitaxel. Plasma concentration-time data from 70 patients (85 courses) treated with paclitaxel dissolved in Cremophor EL were used. The nonlinear mixed-effect modelling (NONMEM) program was used for the population pharmacokinetic analysis. The influence of patient characteristics on the pharmacokinetics of Cremophor EL was determined. The stability of the final model was evaluated using bootstrapping. The data were optimally fitted to a three-compartment model with Michaelis-Menten elimination from the central compartment. The following pharmacokinetic parameters were estimated: volume of the central compartment (V1=2.59 l), volumes of two peripheral compartments (V2=1.81 l, V3=1.61 l), intercompartmental clearance between central and peripheral compartments (Q12=1.44 l/h, Q13=0.155 l/h), maximal elimination rate (Vmax=0.193 ml/h), and concentration at half Vmax (Km=0.122 ml/l). Interindividual variability of the pharmacokinetic parameters was quantified for V1 (25%), V2 (36%) and Vmax (31%). Residual variability consisted of a combined additional (0.095 ml/l) and proportional error (7%). Gender, body surface area and performance status according to the World Health Organization were significantly correlated with V1, V2 and Vmax, respectively ( P<0.0001). The median parameter estimates of 1000 bootstrap samples were in accordance with those obtained with the original data set, indicating the validity of the population model. The population model was able to adequately describe the pharmacokinetic parameters and influence of covariates on the pharmacokinetics of Cremophor EL. This model can be used when studying the relationship between the pharmacokinetics and toxicity of Cremophor EL, and the drug's influence on the pharmacokinetics of paclitaxel.
  Cancer Chemotherapy and Pharmacology 07/2002; 50(1):16-24. · 2.83 Impact Factor
• Article: A population pharmacokinetic model for Cremophor EL using nonlinear mixed‐effect modeling: model building and validation

  H. J. G. D. Van Den Bongard, R. A. A. Mathôt, O. Van Tellingen, J. H. M. Schellens, J. H. Beijnen
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  ABSTRACT: Cremophor EL is a polyethoxylated castor oil that is used for the formulation of a variety of hydrophobic drugs. Recently, it has been demonstrated that the pharmacokinetic (PK) behaviour of Cremophor EL influences the disposition of paclitaxel [1]. Consequently, assessment of the clinical PK of Cremophor EL during paclitaxel administration is of major importance. The purpose of the present study was to develop a population PK model of Cremophor EL as a solubilizing agent for paclitaxel.Plasma concentration-time data (85 courses) of Cremophor EL concentrations were collected from 71 patients with solid tumours treated with paclitaxel dissolved in Cremophor EL. Cremophor EL was intravenously infused during 3, 24 and 96 h (doses ranging from 8.3–20.8 ml m−2). Population PK analysis of plasma concentration-time data was performed using the nonlinear mixed effect modeling software program NONMEM. Thirteen covariates were investigated for their influence on the PK parameters of Cremophor EL. The stability of the final model was evaluated by bootstrapping. The median parameter estimates obtained from 1000 bootstrap replicates were compared with those obtained from the original data set.The data were fitted to a 3-compartment model with Michaelis-Menten elimination from the central compartment. The following PK parameters were estimated: volume of the central compartment V1=2.59 l), volume of the first peripheral compartment (V2=1.81 l), volume of the second peripheral compartment (V3=1.61 l), intercompartmental clearance between the central compartment and the first peripheral compartment (Q12=1.44 l h−1) and the second peripheral compartment (Q13=0.16 l h−1), maximal elimination rate (Vmax=0.19 ml h−1), and the plasma concentration at half of the Vmax (Km=0.12 ml l−1). Interindividual variability (IIV) was estimated using an exponential error model, and was quantified for V1 (25%), V2 (36%), and Vmax (31%). Residual variability was small with a combined additional and proportional error of 0.095 ml l−1 and 7%, respectively. Significant relationships (P<0.001) between the covariates and the PK parameters were determined between V1 and sex, between V2 and BSA, and between Vmax and performance status. The median PK parameter values from the bootstrap procedure were in accordance with the parameter estimates of the population PK model.The non-linear PK of Cremophor EL could adequately be described by the developed population PK model. Sex, BSA and PS partially explained the IIV in V1, V2 and Vmax, respectively. The PK model may be used when studying the clinical PK of paclitaxel.
  British Journal of Clinical Pharmacology 05/2002; 53(5):552P - 553P. · 2.96 Impact Factor
• Article: A population pharmacokinetic model for Cremophor EL using nonlinear mixed-effect modeling: model building and validation

  H.J.G.D. van den Bongard, R.A. Mathot, O van Tellingen, J.H.M. Schellens, J.H. Beijnen
• Article: Successful rescue with leucovorin and thymidine in a patient with high-dose methotrexate induced acute renal failure

  H.J.G.D. van den Bongard, R.A.A. Mathot, W Boogerd, J H Schornagel, J.H.M. Schellens, J.H. Beijnen
• Article: Pharmacokinetically guided administration of chemotherapeutic agents

  H.J.G.D. van den Bongard, R.A.A. Mathot, J.H. Beijnen, J.H.M. Schellens
• Source

  Available from: uu.nl

  Article: Pharmacokinetically guided dosing of chemotherapeutic agents

  H.J.G.D. van den Bongard, R.A.A. Mathot, J.H. Beijnen, J.H.M. Schellens
• Article: An excretion balance and pharmacokinetic study of the novel anticancer agent E7070 in cancer patients

  H.J.G.D. van den Bongard, D. Pluim, H. Rosing, L. Nan-Offeringa, M. Schot, M Ravic, J.H.M. Schellens, J.H. Beijnen