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The Pharmacokinetics UK 2011 Meeting Programme and Abstract

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The Pharmacokinetics UK 2011 Meeting Programme and Abstract Welcome to the Pharmacokinetics UK 2011 Meeting Wednesday 9th November – Friday 11th November Radisson Blu Hotel Frankland Lane Durham DH1 5TA Programme and Abstract Book Wednesday 9th November 12:00 Arrival & lunch Welcome and session 1: Pharmacokinetic issues in the field of Oncology 14:00 Welcome: Steve Toon 14:05 Introduction to the First Session: Peter Milligan and Alan Boddy 14:10 Alan Boddy, Newcastle University Pharmacokinetics and metabolism in early phase clinical trials 14:45 Andrew Stone, AstraZeneca Statistical modelling of clinical data before investing in pivotal trials 15.20 Emma Hansson, Uppsala University PKPD Modeling of VEGF, sVEGFR-2, sVEGFR-3 and sKIT as Biomarkers of Tumor Response, Adverse Events and Survival Following Sunitinib Treatment in GIST 15:55 Coffee break 16.10 Clinton Stewart, St. Jude Children‟s Research Hospital Developmental pharmacology of anticancer drugs in infants and young children with brain tumors: it’s not easy being little 16:45 Gareth Veal, Newcastle University Pharmacokinetic studies in children with cancer – a UK perspective 17:20 Session close 18:30 Poster session & free bar (Sponsored by Pharsight) 20:00 Dinner Thursday 10th November Session 2: Clinical Pharmacokinetics and the Paediatric Population 09:00 Introduction to the Second Session: Alison Thomson and Geoff Tucker 09:05 Hussain Mulla, University Hospitals of Leicester Facing the challenges of better medicines for children: A new use for Dried Blood Spots 09:35 Joseph Standing, University College London Inferences from Small First-in-Child Studies 10:05 Leon Aarons, University of Manchester Population Pharmacokinetic Analysis of Ropivacaine and its Metabolite PPX from Pooled Data in Neonates, Infants and Children 10:35 Coffee break 10.55 Lutz Harnisch, Pfizer Model based assessment of Revatio in pediatric pulmonary arterial hypertension (PAH): a viable route to dose recommendation through an integration of PK, biomarker, and clinical endpoints 11.25 Catherijne Knibbe, LACDR, Leiden University Dosage individualisation in children based on predictive population PK-PD models 11:55 Open discussion 12:10 Session close 12:10 Lunch Session 3: Systems Biology-a new world? 13:30 Introduction to the Third Session: Terry Shepard and Steve Toon 13:35 Piet van der Graaf, Pfizer (How) Can Systems Pharmacology help to improve Phase 2 success? 14:20 David Gavaghan, University of Oxford Developing and applying safety-critical software for systems-level modelling 15.05 Coffee break 15.25 Darrell Abernethy, US Food and Drug Administration Pharmacological Mechanism Based Drug Safety Prediction 16.10 Open discussion 16.25 Session close The Peter Coates Lecture, with an introduction by Steve Toon 16.45 Lawrence Lesko, US Food and Drug Administration Pharmacometric Solutions: A Question-Based Review 20:00 PKUK Banquet Friday 11th November Session 4: Open Session 09:00 Introduction to the Open Session: Leon Aarons and Amin Rostami-Hodjegan 09:05 Marc Lavielle, INRIA Saclay A first prototype of the new Clinical Trial Simulator developed within the DDMoRe project 09.25 Zinnia Parra Guillén, University of Navarra Target Mediated Drug Disposition Model to Describe the Expression and Kinetics of IL12 and IFN in Gene Therapy 09.45 Thomas Grandjean, University of Warwick Experimental and Mathematical Analysis of Pitavastatin Hepatic Uptake Across Species 10.05 Kayode Ogungbenro, University of Manchester Semi-mechanistic Modelling of Double Peaks in Pharmacokinetics: LDOPA case study 10:25 Coffee break 11:00 Marco Siccardi, University of Liverpool Pharmacokinetic and Pharmacodynamic Analysis of Efavirenz Dose Reduction Using a Physiologically-Based Dynamic Model 11:20 Ivelina Gueorguieva, Eli Lilly Defining a therapeutic window for the novel TGF-β inhibitor LY2157299 based on a pharmacokinetic/pharmacodynamic (PK/PD) model 11.40 Ashley Strougo, Astellas Pharma “First dose in children”: evaluation of clearance scaling approaches in CYP3A4-metabolized drugs 12:00 Final conclusions, closing remarks and lunch Speaker Abstracts Session 1: Pharmacokinetic issues in the field of Oncology 1. Pharmacokinetics and metabolism in early phase clinical trials Alan Boddy NICR, Newcastle University Phase I studies in cancer are performed in patients rather than normal volunteers. Given the narrow therapeutic index for most chemotherapeutic agents, pharmacokinetic investigations are usually performed in “real-time” in such Phase I studies, and may be used to guide dose- escalation, relative to preclinical PK data. Depending on the relative pharmacology of parent drug and metabolites, the early identification and quantitation of metabolites may also form an important part of pharmacological investigations in Phase I studies. 2. Statistical modelling of clinical data before investing in pivotal trials Andrew Stone Oncology Therapeutic Area Statistical Expert, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK The decision to enter into a pivotal trial represents a major milestone in drug development and involves a substantial increase in investment; this decision is also based on many levels of uncertainty. In order to try and quantify the probability that the pivotal trial will be successful, outcomes are modelled carefully. This presentation will describe approaches used in oncology, many of which are applicable to other therapeutic areas. The concept of assurance or unconditional power will be described which has its basis grounded in a bayesian approach together with how an extension when an intermediate endpoint is used to predict a longer term outcome. Finally, the expected shrinkage of treatment effect between phase II and III will be described; an expected phenomenon even if the phase II trial is perfectly conducted. 3. PKPD Modeling of VEGF, sVEGFR-2, sVEGFR-3 and sKIT as Biomarkers of Tumor Response, Adverse Events and Survival Following Sunitinib Treatment in GIST Emma K. Hansson1, Guangli Ma1,2, Michael Amantea2, Jonathan French2, Peter A. Milligan2, Mats O. Karlsson1, Lena E. Friberg1 1Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, 2Pfizer Global Research and Development Background: A need for new ways of identifying an optimal dose and evaluating response has evolved with the introduction of the targeted therapies in the area of oncology. Identification of predictive biomarkers would improve measures of treatment activity and enable dose optimization. Biomarkers could also serve as an indicator of safety issues and to minimize the occurrence of adverse events by improving clinical interventions. Aim: To characterize biomarker, tumor size, adverse events and survival relationships following sunitinib treatment in imatinib resistant gastro-intestinal stromal tumors (GIST) with focus on the potential biomarkers VEGF, sVEGFR-2, sVEGFR-3, and sKIT. Methods: Data on the four biomarkers, tumor size, adverse events (fatigue, hand-foot syndrome (HFS)) and survival were available from 303 patients across four clinical trials following up to 85 weeks of treatment with sunitinib and/or placebo. PK/PD models were developed to characterize the change in biomarkers, tumor size and for the probability of HFS and fatigue following treatment. The overall survival data was described by a parametric time-to event model. Model predicted time-courses of the variables were evaluated as predictors of tumor size, adverse events and overall survival. Results: The biomarker modulations following sunitinib treatment were described by indirect response models and the longitudinal tumor size data by a previously developed tumor growth inhibition model [1]. The predicted time-courses of the relative changes from baseline for sKIT (most significant) and sVEGFR-3, as well as AUCss, were included as significant descriptors of the change in tumor size. Proportional odds models with a first order Markov element taking into account the previous grade in the probability of a transition between different severity grades were used to describe the probability and severity of HFS and fatigue. The time course of VEGFR-3 described the probability and severity of experiencing HFS and fatigue better than exposure. A parametric time-to-event model with a Weibull distribution described the underlying hazard. The predicted relative change in sVEGFR-3 over time, and tumor size at start of treatment best described survival time and when included in the model, none of the other variables, including tumor response, were of significance. Conclusion: A modeling framework was proposed linking longitudinal biomarker data with overall survival using PKPD models. sVEGFR-3 was found to be the most promising variable for predicting overall survival and adverse events following sunitinib treatment in GIST. References: [1] Claret L. et al. JCO. 2010:27, 4103-4108 4. Developmental pharmacology of anticancer drugs in infants and young children with brain tumors: it‟s not easy being little Clinton F. Stewart, John C. Panetta, Amar Gajjar St. Jude Children’s Research Hospital, Memphis, TN Background: Although anti-cancer drugs are widely used in infants and young children with malignant brain tumors, the dosing of these toxic drugs is often scaled based on body size (e.g., BSA or body weight) or arbitrary age cut-offs. This dosing approach does not take into account the many developmental changes that occur in infants and young children. These changes, which include hepatic and renal maturation, may affect the disposition of anticancer drugs, leading to more severe
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