The phase I trial unit has acquired a strong experience in application of modeling at different steps of drug development, as showed in some typical examples
Modeling of preclinical genomic data
Algorithms were developed to analyse toxico-genomic data from whole DNA assays, to determine reference doses (BMD, Benchmark dose) along with the lower limit of confidence interval of BMD. This strategy was applied for analysis of germ cell toxicity in rat models.
- Colomban O, Naudet B, Maucort-Boulch, Roy, Girard P. Toxicogenomic dose-response models for DNA chips data from rats treated by flutamide. PAGE 19 (2010) Poster 1854
Animal to human scaling
Physiology-based pharmacokinetic models enable to predict kinetic parameters expected in humans based on those observed in animals. This approach was used to predict receptor linkage as well as effect score in paediatric cancer patients treated with bone marrow transplant and with cyclosporin.
- Gérard C, Bleyzac N, Girard P, Freyer G, Bertrand Y, Tod M. Influence of cyclosporin dosing schedule on receptor occupancy in bone marrow transplantation: analysis with a PBPK-PD model. PAGE 19 (2010) Poster 1924
- Gérard C, Bleyzac N, Girard P, Freyer G, Bertrand Y, Tod M. Influence of Dosing Schedule on Organ Exposure to Cyclosporin in Pediatric Hematopoietic Stem Cell Transplantation: Analysis with a PBPK Model. Pharm Res. 2010 Sep 2 In Press. Abstract HERE
- Gérard C, Bleyzac N, Girard P, Freyer G, Bertrand Y, Tod M. Links Between Cyclosporin Exposure in Tissues and Graft-Versus-Host Disease in Pediatric Bone Marrow Transplantation: Analysis by a PBPK Model. Pharm Res. 2010 In Press. Abstract HERE
Mathematical model to describe in-vivo tumor growth
A tumor growth mathematical model was developed to describe the anti-angiogenic effects induced by sunitinib in mice models (including necrotic and hypoxic tissue percentage changes) in collaboration with B. Ribba, an academic INRIA searcher.
- Ribba B,, Watkin E, Tod M, Girard P, Grenier E, You B, Wei M, Giraudo E, Freyer G. Combined analysis of tumor size data and histological biomarkers drives the development of a semi-mechanistic model of the effect of the antiangiogenic drug Sunitinib in mice. PAGE 19 (2010) Poster 1801
- Ribba B, Watkin E, Tod M, Girard P, Grenier E, You B, Giraudo E, Freyer G. A model of vascular tumour growth in mice combining longitudinal tumor size with histological biomarkers. Eur J Cancer In Press. Abstract HERE
Tumor growth model coupled with interaction model
Our team participates in development of a novel BCRP inhibitor able to reverse irinotecan-resistance. In collaboration with L. Payen (Lyon I), A. Di Pietro (IBCP) et A. Boumendjel (Université de Grenoble), we coupled a tumor growth model with a K-PD model describing irinotecan-MBLI87 interaction to characterize MBLI87 properties and plan its development.
- Sostelly A, Payen L, Ribba B, Di Pietro A, Falson P, Girard P, Tod M. Modelling the interaction between Irinotecan and efflux transporters inhibitors: A KPD tumour growth inhibition model including interaction components. PAGE 19 (2010) Poster 1706
Biomarker analyses to characterize treatment efficacy
In COLOMET study, we developed a model able to describe blood flow in liver metastases measured with contrast enhanced ultra-sound in colon cancer patients treated with bevacizumab.
- Fontanilles M, Pilleul F, Colomban O, Tranchand B, Schott AM, Chayvialle JA, Tod M. Modelization of bevacizumab effect on tumour perfusion assessed by Dynamic Contrast Enhanced Ultrasonography. PAGE 18 (2009) Poster 1546
Moreover, population kinetic approach was used for characterizing dynamically the declines of several serum tumor markers (PSA, hCG, AFP, CA 125) in cancer patients treated with surgery or chemotherapy. A mechanistic model describing PSA production rates by the different prostate compartments was developed using serum PSA concentrations measured in patients with prostate adenoma or cancer treated with surgery.
- You B, Perrin P, Paparel P, Freyer G, Colomban O, Tranchand B, Girard P. Kinetic models of PSA decrease after surgery in prostate tumor diseases as a help for clinician interpretation. PAGE 16 (2007) Communication orale 1119
- You B, Pollet-Villard M, Fronton L, Labrousse C, Schott AM, Hajri T, Girard P, Freyer G, Tod M, Tranchand B, Colomban O, Ribba B, Raudrant D, Massardier J, Chabaud S, Golfier F. Predictive values of hCG clearance for risk of methotrexate resistance in low-risk gestational trophoblastic neoplasias. Ann Oncol. 2010 Aug;21(8):1643-1650. Abstract HERE
- You B, Fronton L, Boyle H, Droz JP, Girard P, Tranchand B, Ribba B, Tod M, Chabaud S, Coquelin H, Fléchon A. Predictive value of modeled AUC(AFP-hCG), a dynamic kinetic parameter characterizing serum tumor marker decline in patients with nonseminomatous germ cell tumor. Urology. 2010 Aug;76(2):423-429. Abstract HERE
- You B, Perrin P, Freyer G, Ruffion A, Tranchand B, Hénin E, Paparel P, Ribba B, Devonec M, Falandry C, Fournel C, Tod M, Girard P. Advantages of prostate-specific antigen (PSA) clearance model over simple PSA half-life computation to describe PSA decrease after prostate adenomectomy. Clin Biochem 2008;41(10-11):785-795. Abstract HERE
- You B, Girard P, Paparel P, Freyer G, Ruffion A, Charrié A, Hénin E, Tod M, Perrin P. Prognostic value of modeled PSA clearance on biochemical relapse free survival after radical prostatectomy. Prostate. 2009 Sep 1;69(12):1325-1333. Abstract HERE
- Sostelly A, Hénin E, You B, Girard P, Karlsson MO. Simultaneous modelling of PSA production in Prostatic Benign Hyperplasia (PBH) and prostatic adenocarcinoma patients treated by prostate surgery. PAGE 18 (2009) Poster 1497
Phase I studies
Our team is involved in new phase I trial designs. In particular model-based escalation methods such as continual reassessment method (CRM) can be used to reduce the number of required patients. We assessed several dose-toxicity models.
- Colomban O, Vassal G, Hénin E, Girard P, Tranchand B. Modèles de toxicité de l’irinotécan (CPT-11) et recherche de la dose maximale tolérée par la méthode de réévaluation en continu. 11ème Journées du GPCO, 2006 Poster
In a phase Ib trial developed in collaboration with Department of Pharmacokinetics, Faculty of Pharmacy Marseille (Prs A Illiadis and D Barbolosi), an adjustment of EPIRUBICIN-DOCETAXEL regimen dose and dosing schedule based on a PK-PD model guidance was feasible and allowed chemotherapy dose dense administration without exacerbated toxicity. More HERE
Modeling of categorial data in phase II and III trials
Safety and efficacy of anti-cancer drugs are frequently assessed using scores or grades. We participated in application of PK-PD models to categorical data. For instance, the relationships between drug concentration and effect was established using PK-PD models in patients with acute GVH disease treated with the new monoclonal antibody inolimomab. Moreover the relationships between capecitabine dose and hand-foot syndrom grade was characterized using a categorical K-PD model.
- Dartois C, Freyer G, Lemenuel A, Darlavoix I, Vermot Desroches C, Michallet M, Tranchand B, Girard P. Exposure-efficacy model of a monoclonal antibody administered in acute graft versus host disease.Leiden 2006 Poster
- Dartois C, Freyer G, Michallet M, Hénin E, You B, Darlavoix I, Vermot-Desroches C, Tranchand B, Girard P. Exposure-effect population model of inolimomab, a monoclonal antibody administered in first-line treatment for acute graft-versus-host disease. Clin Pharmacokinet 2007; 46(5):417-432. Abstract HERE
- Hénin E, Trillet-Lenoir V, Tranchand B, Tod M, Girard P. Patient compliance estimated from pharmacokinetic sample: application to Imatinib. AAPS (2008) Poster # W4310
- Hénin E, You B, Vancutsem E, Hoff P, Cassidy J, Twelves C, Zuideveld K, Sirzen F, Dartois C, Freyer G, Tod M, Girard P. A Dynamic Model of Hand-and-Foot Syndrome in Patients Receiving Capecitabine. Clin Pharmacol Ther 2009;85:418-425. Abstract HERE
Patient adherence modeling to oral chemotherapy prescription
Efficacy and safety are dependent on patient adherence to prescriptions. Adherence can be characterized numerically and integrated in dose-effect models. In the prospective study OCTO, we have developed strategies to assess patient adherence using measured serum drug concentrations and microelectronic monitoring system caps on participants’ drug bottles.
- Hénin E, Trillet-Lenoir V, Tranchand B, Tod M, Girard P. Patient compliance estimated from pharmacokinetic sample: application to Imatinib. AAPS (2008) Poster # W4310
- Hénin E, Tod M, Trillet-Lenoir V, Rioufol C, Tranchand B, Girard P. Pharmacokinetically Based Estimation of Patient Compliance with Oral Anticancer Chemotherapies: In Silico Evaluation. Clin Pharmacokinet 2009 Jun 6;48(6):359-369. Abstract HERE
- Girard P, Blaschke TF, Kastrissios H, Sheiner LB. A Markov mixed effect regression model for drug compliance. Stat Med. 1998 Oct 30;17(20):2313-2333. Abstract HERE
