Tracer studies in GSK for Discovery and Development

Transcription

1 Tracer studies in GSK for Discovery and Development 3 rd June a ripple or a wavefront? Graeme Young, DMPK, GlaxoSmithKline R&D, Ware, UK

2 Outline Historical use of AMS at GSK variety of ADME studies; no microdose/microtracer adoption Emerging clinical study designs microdoses (PK & DDI assessments) What has changed in recent months? Microdosing more predictive than we thought? µtracer dosing as predictive as we expect! State of play of microdose and 14 C-tracer studies at GSK

3 Historical use of AMS at GSK

4 Historical use of AMS at GSK All (pre-2006) GSK AMS studies supported by Xceleron Ltd. Some initial sample prep. carried out by GSK including fractionation by HPLC for metabolite profiling Dedicated laboratories for AMS work used throughout temporary laboratory used for pilot and early studies part of conventional ADME lab converted into AMS prep lab AMS sample prep. suite now established at GSK AMS used for atypical projects : more recently..starting to see use for more mainstream assessments

5 History of AMS use at GSK a variety of ADME studies 1998 ; 1999 ; 2001 ; 2003 ; Pilot low dose rat excretion balance study (Garner et al., JPBA, 2000, 24, p ) Pilot low radioactive dose Clinical excretion balance study (Young G et al., Xenobiotica, 2001, 31 (8/9), p619-32) Serum metabolite profiling for Clinical study & In vitro blood cell association study Dog low dose excretion balance study 2003/4 ; Dog plasma and rat tissue metabolite profiling studies 2004/5 ; Low radioactive dose Clinical study [aka Nanotracer or light label ] 2005/6 ; 2 Conventional dose Clinical studies In-house capability: 2006 ; Low dose animal studies (potent respiratory molecules) 2007; Conventional dose Clinical study 3 dose arms incl. repeat cold dose then 14 C dose 2008/9; Low dose animal studies 2009; Clinical IV tracer study PK plus metabolite profiling (MS, NMR & AMS) The pre-2006 studies have been outlined in: Young G.C. & Ellis.W.J., AMS in drug development at GSK, Nucl. Inst. and Methods in Phys. Res. B, 2007, 259:752.

6 Emerging Clinical study designs

7 Emerging Clinical study designs µdose designs ( 1/100 th of clinically active dose and 100µg) to investigate early PK (IV route) to investigate DDI liability (PO route) - NCE administered as µdose; Cyp450 inhibitor at therapeutic dose!! analytical method may not be AMS; LCMS may suffice Early 14 C study by therapeutic route and at therapeutic dose (aka; an early HRS) to investigate systemic exposure to RDM - assist in design of QT liability study IV 14 C µtracer + concomitant Oral therapeutic doses more on this later..

8 So what has changed..?

9 1. CREAM Trial : Use of microdosing to predict pharmacokinetics at the therapeutic dose: experience with 5 drugs, Clin. Pharmacol. Ther., 2006, 80(3), EUMAPP Trial : 3. Does human pharmacokinetic prediction add significant value to compound selection in drug discovery research? ; Beaumont K and Smith D (Pfizer), Current opinion in Drug Discovery & Dev., 2009, 12(1):61-71 What has changed in recent months/years Regulations MIST (Feb 2008) emphasis on understanding human metabolism Data from CREAM 1, EUMAPP 2 + other published data 3 >80% predictability for microdose to therapeutic dose (Oral and IV) 100% (?) predictive for IV route Availability of clinics that conduct IV admin. of 14 C (to Regulatory req.) conventional studies (<1µCi) UK, Europe and US (Aug 09); no dosimetry emergent µtracer study design and adoption by several Pharma in GSK; progression decision made based on this data increased benefit of 14 C presence on the cold metabolism approach repeat dose 14 C study designs are now feasible

10 State of play of microdose and tracer studies in GSK

11 Clinical study type, primary output, decisions and customer(s) Completed Jan 2010 Study Type DDI study Impact Primary - validated output Phase 0 screen Decisions for Main Customer(s) interaction liability of pre-candidates Planned start: July 2010 PK, Metabolite profiling & ID Completed April 2010 Microdose Pharmacokinetics Candidate selection/ 1 0 Endpoint - Absolute F% (Phase 0 approach) progression/termination 2 0 Endpoint (stand - metabolism alone) (incl. bile) Enhanced [Cold Phase or 14 I C design study]; (Human Regional Gut Absorption study) dose of 100µg via IV and/or PO route IV 14 C tracer + Oral therapeutic (concomitantly) Program team 1 0 Endpoint - PK Impact - CS decision/planning for Oral FTIH study [Rapid compared to previous experience in GSK] Planned start:september 2010 Early stages of discussion/planning 1 Absolute 0 Endpoint - Absolute F% F% Direct formulation Project Team Enhanced Phase I design (Human RGA study) Metabolism info. effort? Clinical PK/DMPK Completed July Endpoint Formulation - Absolute scientists F% Project progression? 2 0 Endpoint Regulators - Metabolite profiling and ID Planned 14 start: June 2010 C Nanotracer Dosing June 2010 ADME info. Assessment of Impact acceptable F% ; PK, Metabolite profiling & ID Low dose potent compound DMPK (aka light label ) (incl. mass balance & metabolic liabilities compound progressed 1 0 Endpoint - IV PK to predict for low 14 C human ADME Safety Assessment change extractability) & conventional in therapeutic Human route Endpoints - Mass balance, 14 C Regulators 2ADME 0 Endpoint study - Extractability (HRS); and exposure, metabolite Aid design profiling QTc study metabolism (including bile) and ID Dosed via therapeutic route

12 Example 1..

13 Clinical microdose DDI study Aim - to confirm effect of CYP3A4 inhibition on PK of GSK Drug-Y at a microdose clinical evidence at therapeutic dose of GSK Drug-Y [DDI with Kaletra] use approach for decision on back-up compounds Period 1: 12 human volunteers administered 50µg GSK Drug-Y (250nCi) PO Period 2: Repeat doses of bid (Q12) for 5 days on day 3, administered 50µg GSK Drug-Y (250nCi) PO

14 Clinical microdose DDI study Comparison of therapeutic dose and microdose admin. of Drug-Y with/without co-admin of CYP450 inhibitor Concentration in plasma [ng or pg/ml] same magnitude of DDI for both micro and therapeutic dose of Drug-Y Drug Y (50mg) [ng/ml] Drug Y (50mg) + Kaletra [ng/ml] Drug Y (50µg) [pg/ml] Drug Y (50µg) + ketconazole [pg/ml] Time (Hours) Notes: 1. Sensitive LC/MS method would have provided the answer. 2. Exposure did not scale very well when normalised for dose but DDI risk highlighted.

15 Example 2..

16 Clinical microdose Phase 0 IV PK study Aim - to establish the clinical IV PK of GSK Drug-Z (novel target) with clear GO/No Go decision on IV Clearance; use the IV clearance data to model for Oral dosing in FTIH dose escalation study very different clearance in rat and dog need to define which equates with human PK 6 human volunteers administered 100µg GSK Drug-Z (250nCi) IV infusion Blood for plasma at multiple timepoints to 48 hours Parent drug PK; Go/No Go: Clearance >1/3 LBF (Cl >30L/h) Total drug-related material PK Urine collection for 0-24 hours Definition of renal excretion of total drug-related material

17 Clinical microdose Phase 0 IV PK study Individual profiles for total radioactivity and GSK Drug-Z in plasma to 24 hours after IV infusion (pg equiv. & pg/ml) LLOQ ~900fg/mL Notes: 1. Parent drug accounts for ~50% of total radioactivity in systemic 2. Similar data for all 6 volunteers (CV of 20% for parent PK)

18 Clinical microdose Phase 0 IV PK study Plasma clearance of ~20L/h GO/No Go decision for progression! IV data used to model likely oral exposures Use to plan for starting dose and dose escalation in FTIH Additionally. % drug in urine estimated as 20% Metabolite profiling not conducted due to non-therapeutic route and inability to conduct structural ID of metabolites

19 Example 3..

20 IV Tracer + Therapeutic Oral The Purpose Aim - to understand reason(s) for variable systemic exposure in humans following oral dosing poor/variable absorption? first pass metabolism? terminate project or re-direct effort eg. drug formulation Attraction of the approach rapid evaluation study (relatively low effort) possibility of piggy-backing to another Phase 1 study.enhanced study - Age versus gender - Formulation assessment - Food effect

21 IV Tracer + Therapeutic Oral Dose The Design Study design IV 14 C-tracer dose administered concomittantly at T max of Oral therapeutic dose in a single dosing period Design established in 1970 s; 13 C-drug by IV route, non-labelled by oral route, both at therapeutic levels IV 14 C-dose at 1/500 th of oral <270nCi 14 C

22 IV Tracer + Therapeutic Oral Dose Conventional IV clinical dose approach: Dosing GMP Manufacture IV tolerance Intravenous tox. Animal dosimetry

23 IV Tracer + Therapeutic Oral Dose Microdose general guidance applies but as tracer administered with oral dose (safety package in place). X Intravenous tox. X IV tolerance Adapted GMP Manufacture* Dosing X Animal dosimetry *Traditional GMP manufacture still required for oral dose

24 IV µtracer + Therapeutic Oral dose Example study design: IV tracer ( µg + oral therap. dose ( mg; 8 humans IV dose given at T max of oral dose (2.75-3h), as 15 minute infusion Blood collections for plasma, to 72 hours; urine collection, 0-24 hours IV followed by AMS (total RDM, parent PK [UPLC], metabolism) PO dose followed by LC/MS/MS (parent PK) Concomitant use of IV & oral negates most worries over linearity better design than separate microdose absolute F% study better design than conventional cross-over absolute F% study(?)

25 Data from MS analysis of plasma Plasma concentrations of Drug X (ng/ml) Individual plasma concentrations (ng/ml) of Drug X following a single oral dose of 250mg Drug X to 8 healthy volunteers CV for Drug X AUC of ~90% [reflects data seen in FTIH] Time (hours)

26 Data from UPLC-AMS (Parent drug isolation and analysis) Individual plasma concentrations (ng/ml) of Drug X following a single IV infusion of 100µg [ 14 C]-Drug X Plasma concentrations (ng/ml) CV for Drug X; AUC <25% [<10% for Total 14 C] Time (hours) after start of 15-minute infusion

27 Comparison of Intravenous v. Oral Provided confidence for progression of molecule.. Comparison of plasma concentrations of Drug X following IV (100µg) and Oral doses (250mg); IV data normalised to equivalent dose Concentration of Drug X in Plasma (ng/ml) Time (hours) Oral (dose of 250mg) IV data from 14C tracer of 100ug (Normalised to 250mg) F =~25%

28 Metabolite profile data Reconstructed radiochromatogram (HPLC followed by AMS) of pooled human urine (n=8), 0-24h after oral dose M16 M dpm/200ul HPLC Fraction M13 M11, M8 M15 Parent drug 0.10 M6, M Time (min.) Note : profile reflects excreted radioactive drug-related components from IV dose NB: Peak assignments are based upon co-chromatography to spiked standards of Parent drug + 2 authentic metabolites, in the HPLC separation during isolation of fractions for analysis by AMS, and/or on assessments by MS and NMR

29 IV Tracer + Therapeutic Oral - Metabolism Data from metabolic profiling informs for further development strategies provide useful data for safety assessment and clinical study designs assessment of total observed drug related material in urine (NMR) metabolite profiling of urine & plasma pool; by AMS, MS & NMR each technology provides different insights eg. 14 C use allows assessment of extraction recoveries enables comparison of 14 C profile in animals and human to assess MIST issues IV/PO comparison - assessment of first pass metabolism influence Future studies - Addition of bile sampling provides another insight to elimination pathways

30 Summary Many recent changes all of which are contributing to a greater flexibility in study design easier application of innovative designs decision making studies at CS and later stages of development IV µtracer design may be the most important/influential of the new designs (?) Go/ No Go decisions on molecules in Phase 1 based on F% Design allows further assessments for metabolism investigations (including bile collection) GSK establishing an early clinical trials advisory board to help educate and facilitate for microdosing and tracer studies It seems like a wavefront..rather than just a ripple

31 ACKNOWLEDGEMENTS Many GSK colleagues; particularly Steve Corless and Clive Felgate Xceleron Ltd., particularly for their assistance in the early AMS studies Xceleron (AMS CRO) and Covance for support of the DDI study VITALEA (AMS CRO), SIMBEC and Quotient (fpharmaceutical Profiles) for support of the IV tracer study PRA for support of the IV PK Phase 0 study

32 Back-ups

33 Regulations.. Advent of biomedical AMS (Accelerator Mass Spec.) lead to. microdosing for PK/metabolism EMEA Position paper (2004) 1 ; principle of 1/100th of proposed pharmacological dose - never to exceed 100µg US FDA Exploratory IND (Jan 2006) 2 ; same definition, slightly different (reduced) toxicology package required FDA Critical path initiative 3 encourages alternative approaches to Drug Discovery and Development, to promote innovation ICH M3 R2 guidance (June 2009); section 7.1 clearly outlines support for such approaches 1. EMEA position paper on non-clinical safety studies to support clinical trials with a single microdose: 2. FDA Guidance for industry Investigators and Reviewers. Exploratory IND Studies FDA critical path initiative: