Modelling and Simulation in the Development and use of Anti-Cancer Agents: An Underused Tool?

To help identify the role of modelling and simulation in the development of anti-cancer agents, their main advantages and the obstacles to their rational use, an expert meeting was organized by COST B15. This manuscript presents a synthesis of views expressed at that meeting and indicates future directions. The manuscript also shows some examples where modelling and simulation have proven to be of relevant value in the drug development process for anti-cancer agents.

[1]  H. Harashima,et al.  Development of a pharmacokinetic/pharmacodynamic (PK/PD)-simulation system for doxorubicin in long circulating liposomes in mice using peritoneal P388. , 1999, Journal of controlled release : official journal of the Controlled Release Society.

[2]  P Bauer,et al.  Interim Analysis and Sample Size Reassessment , 2000, Biometrics.

[3]  H. H. Lloyd,et al.  Adequacies and inadequacies in assessing murine toxicity data with antineoplastic agents. , 1979, Cancer research.

[4]  R. Simon,et al.  Optimal two-stage designs for phase II clinical trials. , 1989, Controlled clinical trials.

[5]  J. Wingard,et al.  Association of busulfan area under the curve with veno-occlusive disease following BMT. , 1996, Bone marrow transplantation.

[6]  R Simon,et al.  Accelerated titration designs for phase I clinical trials in oncology. , 1997, Journal of the National Cancer Institute.

[7]  J O'Quigley,et al.  Continual reassessment method: a likelihood approach. , 1996, Biometrics.

[8]  M R Conaway,et al.  Designs for phase II trials allowing for a trade-off between response and toxicity. , 1996, Biometrics.

[9]  M. Relling,et al.  Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. , 1999, Journal of the National Cancer Institute.

[10]  D. Newell,et al.  Revisions of general guidelines for the preclinical toxicology of new cytotoxic anticancer agents in Europe. The Cancer Research Campaign (CRC) Phase I/II Clinical Trials Committee and the European Organization for Research and Treatment of Cancer (EORTC) New Drug Development Office. , 1995, European journal of cancer.

[11]  R. Jain,et al.  Delivery of molecular and cellular medicine to solid tumors. , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[12]  M Buyse,et al.  On the relationship between response to treatment and survival time. , 1996, Statistics in medicine.

[13]  Mats O Karlsson,et al.  Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  R. Gelber,et al.  A quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis of adjuvant radiation therapy and chemotherapy for resectable rectal cancer. , 1996, Journal of the National Cancer Institute.

[15]  L. Weisenthal Antineoplastic drug screening belongs in the laboratory, not in the clinic. , 1992, Journal of the National Cancer Institute.

[16]  S. Nandi,et al.  Beware of contaminating mouse cells in human xenografts from nude mice. , 2000, Anticancer research.

[17]  N Stallard,et al.  Sample size determination for phase II clinical trials based on Bayesian decision theory. , 1998, Biometrics.

[18]  N H Holford,et al.  Simulation of clinical trials. , 2000, Annual review of pharmacology and toxicology.

[19]  B. Druker,et al.  STI571: a paradigm of new agents for cancer therapeutics. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  L B Sheiner,et al.  Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  S Chevret,et al.  The continual reassessment method in cancer phase I clinical trials: a simulation study. , 1993, Statistics in medicine.

[22]  T. Fleming,et al.  Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. , 2001, The New England journal of medicine.

[23]  Roy S Herbst,et al.  Mode of action of docetaxel - a basis for combination with novel anticancer agents. , 2003, Cancer treatment reviews.

[24]  J. Herndon,et al.  A design alternative for two-stage, phase II, multicenter cancer clinical trials. , 1998, Controlled clinical trials.

[25]  R. Kerbel What is the Optimal Rodent Model for Anti-tumor Drug Testing? , 1998, Cancer and Metastasis Reviews.

[26]  I. Fidler,et al.  Critical determinants of cancer metastasis: rationale for therapy , 1999, Cancer Chemotherapy and Pharmacology.

[27]  R. Gelber,et al.  Quality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: an Eastern Cooperative Oncology Group study. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  B. Fingleton,et al.  Matrix metalloproteinases: biologic activity and clinical implications. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  M. Buyse,et al.  What can we learn from a meta-analysis of trials testing the modulation of 5-FU by leucovorin? , 1993 .

[30]  John O'Quigley,et al.  Continual reassessment designs with early termination. , 2002, Biostatistics.

[31]  G Molenberghs,et al.  Sensitivity Analysis for Nonrandom Dropout: A Local Influence Approach , 2001, Biometrics.

[32]  Kyle T. Bradley Prognostic and Predictive Factors in Breast Cancer , 2007 .

[33]  A. Giaccia,et al.  The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. , 1998, Cancer research.

[34]  R. Porcher,et al.  Evaluating treatment strategies in chronic lymphocytic leukemia: use of quality-adjusted survival analysis. , 2001, Journal of clinical epidemiology.

[35]  S. Piantadosi,et al.  Improved designs for dose escalation studies using pharmacokinetic measurements. , 1996, Statistics in medicine.

[36]  D. Budman,et al.  In vitro evaluation of synergism or antagonism with combinations of new cytotoxic agents. , 1998, Anti-cancer drugs.

[37]  E. Raymond,et al.  Phase I and pharmacokinetic study of the new vinca alkaloid vinflunine administered as a 10-min infusion every 3 weeks in patients with advanced solid tumours. , 2003, Annals of oncology : official journal of the European Society for Medical Oncology.

[38]  Peter Nygren, Bengt Glimelius The Swedish Council on Technology Assessment in Health Care (SBU) Report on Cancer Chemotherapy - Project Objectives, the Working Process, Key Definitions and General Aspects on Cancer Trial Methodology and Interpretation , 2001, Acta oncologica.

[39]  S. Goodman,et al.  Some practical improvements in the continual reassessment method for phase I studies. , 1995, Statistics in medicine.

[40]  S. Venkatesh,et al.  Role of the development scientist in compound lead selection and optimization. , 2000, Journal of pharmaceutical sciences.

[41]  E J Freireich,et al.  Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. , 1966, Cancer chemotherapy reports.

[42]  G Molenberghs,et al.  Evaluation of surrogate endpoints in randomized experiments with mixed discrete and continuous outcomes , 2001, Statistics in medicine.

[43]  M. Wientjes,et al.  Computational model of intracellular pharmacokinetics of paclitaxel. , 2000, The Journal of pharmacology and experimental therapeutics.

[44]  A. Ahmed,et al.  Cyclophosphamide (Cytoxan). A review on relevant pharmacology and clinical uses. , 1984, Journal of the American Academy of Dermatology.

[45]  Animal models amd the molecular pathology of Cancer , 1997, The Journal of pathology.

[46]  D. Toppmeyer Phase I Trial Design and Methodology , 1997 .

[47]  PETER ALEXANDER,et al.  Cancer Chemotherapy , 1968, Nature.

[48]  E. Gehan,et al.  The determinatio of the number of patients required in a preliminary and a follow-up trial of a new chemotherapeutic agent. , 1961, Journal of chronic diseases.

[49]  P Nygren,et al.  Assessment of quality of life during chemotherapy. , 2001, Acta oncologica.

[50]  F. Mandelli,et al.  Acute promyelocytic leukemia: clinical and morphologic features and prognostic factors. , 2001, Seminars in hematology.

[51]  E K Rowinsky,et al.  Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[52]  E Wiltshaw,et al.  Carboplatin dosage: prospective evaluation of a simple formula based on renal function. , 1989, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[53]  Chang-Ho Ahn,et al.  Regulatory considerations for preclinical development of anticancer drugs , 1997, Cancer Chemotherapy and Pharmacology.

[54]  P. LoRusso,et al.  In Vivo Methods for Screening and Preclinical Testing , 1997 .

[55]  P F Thall,et al.  A strategy for dose-finding and safety monitoring based on efficacy and adverse outcomes in phase I/II clinical trials. , 1998, Biometrics.

[56]  Yuichi Sugiyama,et al.  A Physiologically Based Pharmacokinetic Analysis of Capecitabine, a Triple Prodrug of 5-FU, in Humans: The Mechanism for Tumor-Selective Accumulation of 5-FU , 2001, Pharmaceutical Research.

[57]  C. Veyrat‐Follet,et al.  Clinical trial simulation of docetaxel in patients with cancer as a tool for dosage optimization , 2000, Clinical pharmacology and therapeutics.

[58]  Explore Configuring,et al.  A Simulation Study to , 2004 .

[59]  R. Erb,et al.  Introduction to Backpropagation Neural Network Computation , 1993, Pharmaceutical Research.

[60]  M. Buyse,et al.  What can we learn from a meta-analysis of trials testing the modulation of 5-FU by leucovorin? Advanced Colorectal Meta-analysis Project. , 1993, Annals of oncology : official journal of the European Society for Medical Oncology.

[61]  Geert Molenberghs,et al.  Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis , 2000, The Lancet.

[62]  M. Ratain Body-surface area as a basis for dosing of anticancer agents: science, myth, or habit? , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[63]  H. Heimpel,et al.  Interferon alfa versus chemotherapy for chronic myeloid leukemia: a meta-analysis of seven randomized trials: Chronic Myeloid Leukemia Trialists' Collaborative Group. , 1997, Journal of the National Cancer Institute.

[64]  Geert Verbeke,et al.  The Effect of Drop‐Out on the Efficiency of Longitudinal Experiments , 1999 .

[65]  H. Ishitsuka,et al.  Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. , 1998, European journal of cancer.

[66]  J. Mazoit,et al.  Streptococcus pneumoniae pneumonia in mice: optimal amoxicillin dosing predicted from a pharmacokinetic-pharmacodynamic model. , 1999, The Journal of pharmacology and experimental therapeutics.

[67]  J O'Quigley,et al.  Continual reassessment method: a practical design for phase 1 clinical trials in cancer. , 1990, Biometrics.

[68]  G. Rosen,et al.  High-dose methotrexate with citrovorum factor rescue: predictive value of serum methotrexate concentrations and corrective measures to avert toxicity. , 1977, Cancer treatment reports.

[69]  Daniel,et al.  There are no bad anticancer agents, only bad clinical trial designs--twenty-first Richard and Hinda Rosenthal Foundation Award Lecture. , 1998 .

[70]  G. Sledge,et al.  Redefining the target: chemotherapeutics as antiangiogenics. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[71]  R. Simon,et al.  A model to select chemotherapy regimens for phase III trials for extensive-stage small-cell lung cancer. , 2000, Journal of the National Cancer Institute.

[72]  Shawn C. D. Johnson,et al.  The Role of Simulation in the Management of Research: What Can the Pharmaceutical Industry Learn from the Aerospace Industry? , 1998 .

[73]  K. Goa,et al.  Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer. , 2003, Drugs.

[74]  H. Gurney,et al.  Dose calculation of anticancer drugs: a review of the current practice and introduction of an alternative. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[75]  R Simon,et al.  Clinical trial designs for cytostatic agents: are new approaches needed? , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[76]  HansâHelge Müller,et al.  Adaptive Group Sequential Designs for Clinical Trials: Combining the Advantages of Adaptive and of Classical Group Sequential Approaches , 2001 .

[77]  B. Druker,et al.  Bcr-Abl inhibition as a modality of CML therapeutics. , 2001, Biochimica et biophysica acta.

[78]  G. Hortobagyi Overview of treatment results with trastuzumab (Herceptin) in metastatic breast cancer. , 2001, Seminars in oncology.

[79]  James A. Powell,et al.  Pharmacokinetics and Tolerability of an Antiangiogenic Ribozyme (ANGIOZYME™) in Healthy Volunteers , 2000, Journal of clinical pharmacology.

[80]  G. Molenberghs,et al.  The validation of surrogate endpoints in meta-analyses of randomized experiments. , 2000, Biostatistics.

[81]  H. Schäfer,et al.  Adaptive Group Sequential Designs for Clinical Trials: Combining the Advantages of Adaptive and of Classical Group Sequential Approaches , 2001, Biometrics.

[82]  K. Blesch,et al.  Population pharmacokinetics and concentration-effect relationships of capecitabine metabolites in colorectal cancer patients. , 2003, British journal of clinical pharmacology.

[83]  R Henderson,et al.  Joint modelling of longitudinal measurements and event time data. , 2000, Biostatistics.

[84]  Y. Nakamura,et al.  Genetic alterations during colorectal-tumor development. , 1988, The New England journal of medicine.

[85]  L Aarons,et al.  Role of modelling and simulation in Phase I drug development. , 2001, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[86]  J L Steimer,et al.  Exploring clinical study design by computer simulation based on pharmacokinetic/pharmacodynamic modelling. , 1997, International journal of clinical pharmacology and therapeutics.

[87]  J. Bergh,et al.  Lack of relationship between systemic exposure for the component drug of the fluorouracil, epirubicin, and 4-hydroxycyclophosphamide regimen in breast cancer patients. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[88]  E Marubini,et al.  Content and quality of currently published phase II cancer trials. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[89]  R. Bruno,et al.  Pharmacokinetic and pharmacodynamic properties of docetaxel: results of phase I and phase II trials. , 1997, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[90]  K. Blesch,et al.  Population Pharmacokinetic Analysis of the Major Metabolites of Capecitabine , 2002, Journal of Pharmacokinetics and Pharmacodynamics.

[91]  Jeffrey R. Eisele,et al.  A Curve‐Free Method for Phase I Clinical Trials , 2000, Biometrics.

[92]  M Danhof,et al.  Mechanism-based pharmacokinetic-pharmacodynamic modeling of the effects of N6-cyclopentyladenosine analogs on heart rate in rat: estimation of in vivo operational affinity and efficacy at adenosine A1 receptors. , 1997, The Journal of pharmacology and experimental therapeutics.