GSK experience of application of AMS to clinical studies the last 5 years & GBC (LC+AMS) Team update

Transcription

1 GSK experience of application of AMS to clinical studies the last 5 years & GBC (LC+AMS) Team update Graeme Young, GSK (& the GBC AMS harmonisation team) 26 th March 2015

2 GSK Clinical study support by AMS the last 5 years And into the future... FTIH IV PK Phase 0 IV µdose Dermal PK IV µtracer + IV µtracer Entero-test TM for bile collection Total DRM and parent in plasma 100 µg Phase 0 IV µdose IV µtracer + IV µtracer & IV µtracer

3 Innovative approaches to Clinical PK & metabolism data; GSK examples iv & po, 14 C & cold, small & large [MWt.], early & late... Validated the platform FTIH mab-dab F = ~ 25% F = ~ 13% Highly Information rich; definitive PK & routes of metabolism at early stage; limited cost/effort FTIH IV PK Acceptable for progression Entero-Test To model therapeutic IV doses and investigate human metabolism DDI study DDI confirmed at µdose ; No Go To provide input to formulation dev. & establish metabolism in humans incl. biliary Acceptable for progression FTIH IV/PO Abs. bio. for Reg submissions; reduced variability, study size (only n= 4 patients) & study duration Trametinib Concentration in human plasma following IV (5µg) and oral (2mg) doses Dabrafenib Discovery Phase Phase 0 Phase I Phase II Phase III Phase IV/ Launch 3 Graeme Young, PTS DMPK

4 Phase 0 (PK) 2010* Background IV clearance data sought to model oral FIH Scaling from rat/dog PK (very different clearance) Phase 0 approach proposed Individual profiles for total radioactivity and GSK in plasma after IV infusion of [ 14 C]GSK (pg equiv. & pg/ml) Key Question Does the molecule have acceptable clinical PK? Results & Impact Acceptable plasma clearance in humans ~20% drug in urine similar PK data [parent and metabolite(s)] for all subjects Lessons learned/value added Optimize FIH design/doses/regimen Allow early planning of PoM via FIH extension * Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK , a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study. Cahn A. et al., BMC Pharmacol Toxicol Feb 28;14 (1):14.

5 Early Phase 2: IV microtracer (2010) Background Entero-Test Switch from oral to IV administration as therapeutic route Better info. for IV starting dose/escalation for next study Collect info. on route & rates of elimination Normalised mean concentrations of Drug X in human plasma following concomitant IV (100µg) and Oral (50mg) doses Key Questions Absolute bioavailability and characterising IV PK? What IV doses are needed for progression? F = 65% Lessons learned/value added Data used to model therapeutic IV doses Data used to build picture of human metabolism particularly biliary elimination Entero-Test

6 * Early Clinical Evaluation of a Novel 5-Lipoxygenase Activating Protein (FLAP) Inhibitor (GSK A). Pharmacokinetics, Bioavailability and Dose Form Selection: Influence of Age, Food, Drug Interactions and Regional Absorption (LPA112071, LPA112362, LPA114604); Daley-Yates P et al., Proceedings of the British Pharmacological Society, BPS Winter Meeting Late Phase 2: IV microtracer (2011)* Background Drug Y has variable PK following oral dosing to humans Selection of appropriate formulation for Phase 3 will be assisted by understanding of absolute bioavailability & optimal regional absorption in humans IV admin. piggy backs regional gut absorption Enterion TM Normalised mean concentrations of Drug Y in human plasma following concomitant IV (100µg) and Oral (100mg) doses Key Questions Window of absorption; guide phase 3 formulation development Test promising formulations for optimal delivery Maximise info. on bioavailability & metabolism for phase 3 F <30% Lessons learned/value added F was low at <30% (all formulations) Data used to provide input to formulation development effort Data used to further establish picture of human metabolism particularly biliary elimination Entero-Test

7 Phase 3: IV microtracer (2011) Trametinib (Oncology)* Background Regulatory requirement for definition of absolute bioavailability Key Questions Define absolute bioavailability in target population; cancer patients Normalised mean concentrations of Trametinib in human plasma following concomitant IV (5µg) and Oral (2mg) doses F =72% Lessons learned/value added Absolute bioavailability measured in only 4 patients (F=72%); precedent set by study on dabrafenib Value of microtracer approach to reduce variability and hence study size and clinical study duration allowing release of patients to rollover therapy study * Concomitant oral and microdose intravenous pharmacokinetics of trametinib, a MEK inhibitor, in subjects with solid tumours, Leonowens C et al., 2014 Sep, 78(3),

8 Global Bioanalysis Consortium: New Frontiers - AMS harmonisation team Representatives from the pharmaceutical industry and biomedical AMS CROs ; Graeme Young (GSK) chair; Mark Seymour & Paul Steinberg (Vitalea Science), Julie Zalikowski (Accium BioSciences ), Mike Butler (Xceleron), Philip Timmerman (Janssen), Kohei Nozawa (Sekisui Medical), Wouter Vaes (TNO), Steve Dueker (Sivvon) Output to date ; focussed on LC+AMS assays for isolated individual analytes (rather than total radioactivity) Publication New Frontiers Accelerator Mass Spectrometry (AMS): Recommendation for Best Practices and Harmonization from Global Bioanalysis Consortium Harmonization Team, Young GC et al., AAPS Journal, 2014, DOI: /s Included aspects related to - Instrument performance: linearity, accuracy and precision Assay qualification/validation: Accuracy and precision details of the procedures yet to be harmonised Analyte recovery Use of QC samples; Preparation of standards and QCs Analyte stability; including reliance on existing data from eg. LC/MS assay support Assay robustness Further harmonisation is underway including ; adoption of the acceptance criteria routinely applied to LC/MS assays generation of calibrants & confirmation by LSC 8

9 Future of AMS development Gas analysis Increased throughput from days to minutes! Improved sensitivity (carry over may be the main challenge) Simpler instruments?? ETH Zurich smaller footprint; BIOMICADAS and pre-prototype µcadas

10 Additional GSK AMS study related references Metabolism and Disposition of Fluticasone Furoate, an Enhanced-Affinity Glucocorticoid, in s. Hughes S.C. et al., Drug Metabolism and Disposition 2008; 36: Metabolism and disposition of vilanterol, a long-acting β2-adrenoreceptor agonist for inhalation use in humans. Harrell A.W. et al., Drug Metab Dispos. 2013; 41: Disposition and metabolism of GSK in humans: a novel boron-containing antibiotic, Bowers GD et al., Drug Metab Dispos., 2013, 41: Absorption, distribution, metabolism, and elimination () of umeclidinium (UMEC) in healthy adults, Kelleher D. Poster at European Respiratory Society (ERS), Vienna, Austria Sep 2012 Comparison of a GSK Microdose CYP3A4 Drug-Drug Interaction Study With a Previous Pharmacological Dose Study, Mahar K.M. et al., 2012 American College of Clinical Pharmacology, Annual Meeting September 23rd-25th, San Diego, California, abstract # Pharmacokinetics and tolerability of SRT2104, a first-in-class small molecule activator of SIRT1, after single and repeated oral administration in man, Hoffman E. et al., Br J Clin Pharmacol Jan;75(1): doi: /j x. AMS in drug development at GSK. Young G.C., Nuclear Instruments and Methods in Physics Research B, 259 (2007), Properties of Drug Molecules: a Plethora of Approaches, Beaumont C., Young GC, Cavalier T. and Young M, Br. J.Clin. Pharmacol., 78:6 (2014), The human biological samples were sourced ethically and their research use was in accord with the terms of the informed consents