Absolute bioavailability and pharmacokinetic studies in early clinical development using microdose and microtracer approaches.

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1 Absolute bioavailability and pharmacokinetic studies in early clinical development using microdose and microtracer approaches. Dr Lloyd Stevens Senior Research Fellow Pharmaceutical Profiles Nottingham, UK

2 Clinical studies to define key p kinetic characteristics Elimination Metabolism Excretion Formulation Absorption Active Transport Gut Metabolism Intravenous PK 30 July

3 AMS Detects Molecules at Very High Levels of Sensitivity Requires 14 C API Assume labelled drug behaves exactly like nonlabelled drug AMS provides a unique sensitivity LC provides specificity Liquid Scintillation Counting Competitor Immunoassay Mass Spectrometry Accelerator Mass Spectrometry 10-9 g (nanograms) g (picograms) g (femtograms) g (attograms) g (zeptograms)

4 Applications of AMS Candidate selection Human PK profile(s) Metabolite profile SAD design Bioavailability investigation Metabolite profiles/id Elimination (routes, rates) PK modelling Preclinical Phase 0 Further Profiling SAD MAD PoX microdose<100µg API 14 C-dose<270nCi (1µSv) Therapeutic dose light label dosing

5 Microdose PK approach to drug selection Many drug candidates Limited toxicology Screening in vitro in silico etc Promising candidates Animal models Human Microdose Predict behaviour in humans from mathematical models and microdose human in vivo data Wilding and Bell DDT 10 (July 2005) : Select candidate(s) for Phase I

6 Dose extrapolation and pharmacokinetic linearity? Validation for micro to macro dose extrapolation is currently seen as compound specific and is retrospective. Insufficient published industry experience to establish Rules of thumb Time will tell!!. P kinetic micro to macro extrapolation in animals may indicate predictability in man no hard evidence yet.

7 The basic question What are we trying to achieve? Is prediction from micro to macro p kinetics the primary objective in using microdosing? Differentiate between candidate molecules albeit at a microdose level Characterise lead compound Assess other routes Assess metabolism What are the differentiating criteria?

8 PK characteristics relevant to candidate selection/de-selection: Shape EC 50% IC 50% MIC Blood Level of Drug Rapid onset Short duration Migraine Slower onset Long duration Chronic pain 0 24 Time (Hours) Criteria for selection : Dose prediction to achieve??? Onset and duration of action EC 50% & IC 50% or MIC Market driven target product characteristics Dosage regimen Route of administration Drug interaction profile ADME characteristics

9 PK relevant to candidate selection/deselection: Amount & Variability Blood Level of Drug Poor and Variable Bioavailability Subject Time (Hours) Subject 3 Subject 2 Low Bioavailability Blood Level of Drug Short Half Life How much? Low often means.. How Variable? Low may imply extensive metabolism How many & are they active? Measurement of bioavailability relies 0 on IV and Time (Hours) PO crossover 24 study design Good absorption Rapid elimination Short t 1/2 prevents 1x daily dosing

10 Blood Level of Drug PK characteristics relevant to candidate selection/de-selection: Half-life Poor and Variable What s all Bioavailability the fuss about Half-life? Half-life is associated with: 1. Duration of action 2. Time taken to reach steady state In dose extrapolation a doubling Subject of 3 the dose increases the duration Subject 2 of action by only one half-life Subject There is often more Time (Hours) than one halflife. but which is the important one? Potential reasons: Poor permeability? First pass metabolism? Blood Level of Drug Short Half Life 0 24 Time (Hours) Duration of action Good absorption Rapid elimination Short t 1/2 prevents 1x daily dosing

11 Two drugs with the same half-life Ln plasma conc of Drug 0 24 Time (Hours)

12 Two drugs with the same half-life Ln plasma conc of Drug AUC for terminal phase >90% of total AUC Plays a major role in the pharmacodynamic response 0 24 Time (Hours)

13 Two drugs with the same half-life Pharmacodynamic effect is driven by this section of the P kinetic profile Ln plasma conc of Drug AUC for terminal phase <15% of total AUC Plays a minor role in the pharmacodynamic response 0 24 Time (Hours)

14 PK characteristics relevant to candidate selection/de-selection: Metabolism Potential metabolic burden as a differentiating factor! M8 Parent dpm/ml plasma M5-M7 M3 M2 M Retention time (h) Xceleron Ltd all rights reserved 2008

15 Candidate selection: Phase 0 Study designs & logistics Design determined by both scientific and commercial objectives IV-oral crossover Absolute absorption and bioavailability Total and renal clearance plus volumes of distribution Oral crossover Concentration vs time profiles (half-life) Limited information on exposure Ideal if target EC 50% is known AMS measurements Blood/plasma/urine total radioactivity. Decision to fractionate parent drug and describe full specific analyte profile or profiles Subject numbers. Minimum of 4

16 Example: Developability issues arising from a microdose study Concentration (pg/ml) Parent drug IV and oral Total radioactivity IV and oral doses Metabolite burden Time (hours post-dose) Developability issues Rapid absorption High clearance total 14C LowONO-8539 oral(oral) F total 14C (IV) ONO-8539 (IV) Short half-life (<2h) High metabolic burden Q Metabolism p kinetics/activity

17 Example: Developability issues arising from a microdose study Data suggests systemic metabolism At early time points, total 14 C-to-parent differential was more marked after oral dosing.. indicative of first pass effects ng/ml ng/ml Period 1 Mean 14C Period 1 Mean Parent Hours post-dose Period 2 Mean 14C Period 2 Mean Parent PO IV Hours post-dose ng/ml ng/ml Hours post-dose Hours post-dose

18 AMS applications in early clinical development: Absolute bioavailability Mass balance Metabolite profiling Metabolite identification

19 Applications of AMS Candidate selection Human PK profile(s) Metabolite profile SAD design Bioavailability investigation Metabolite profiles/id Elimination (routes, rates) PK modelling Preclinical Phase 0 Further Profiling SAD MAD PoX microdose<100µg API 14 C-dose<270nCi (1µSv) Therapeutic dose light label dosing

20 Clinical studies to determine the drivers of bioavailability Elimination Metabolism Excretion Formulation Absorption Active Transport Gut Metabolism Intravenous PK Enterion TM

21 Why would you want to give an oral NCE by the intravenous route? There is no regulatory requirement to describe the i.v PK for any non-parenteral drug Unless, there is low and variable bioavailability But, there is the potential to gather PK information to enable decision making, such as Total clearance, distribution volumes, absolute bioavailability, potential for biliary excretion, systemic metabolism Assess systemic exposure and absolute bioavailability following vaginal, dermal, ocular, topical, rectal, pulmonary, nasal administration Absolute bioavailability of prodrugs 30 July

22 The Microtracer approach: 14 C-API, AMS + MS IV 14 C-tracer dose given simultaneously at t max with an oral therapeutic/mtd dose in a single period study 1/100 to 1/1000 of oral dose & <270nCi 14 C IV PK for parent drug and metabolites measured using fractionation and AMS Therapeutic oral dose PK measured using LC-MS/MS Piggy-back IV dosing Requires: No supporting animal dosimetry data No in vivo preclinical/clinical tox Possibly IV tolerance test 0 Time (Hours) 24

23 Identify the causes of variable PK Example: t 1/2 increases with dose Is this due to capacity-limited elimination or poor solubility (flip-flop kinetics)? Blood Level of Drug IV Increasing dose IV/PO crossover will differentiate between non-linear clearance and absorption rate-limited elimination 0 24 Time (Hours)

24 Identify the causes of variable PK Example: wide inter-subject variability Is this due to formulation/dissolution/solubility/permeability or elimination? Blood Level of Drug IV Variability due to output of drug will disappear upon IV dosing 0 24 Time (Hours)

25 IV PK data is essential for predicting in vivo formulation performance 1.6 Simulation 300 Deconvolution Plasma Concentration of RSD1235 (ug/ml) IR Hydrophilic Wax 150 Hydrophilic Actual Wax Actual IR Actual 100 Uptake (mg) Predicted Hydr Actual Hydroph Time (hr) Time (hr) 16 October 2007

26 Human, IV PK data - earlier than ever before: Why the need for IV PK data? What are the challenges? Experience to date 30 July

27 Rapid manufacture of iv doses Changing the Landscape Formulation & Process Development Transfer to GMP Process Development & Verification Stability Study IMPD Submission CT Manufacture & Release Shipping to Clinical Site Off the critical path Dosing Industry standard typically 9-12 months 30 July

28 Human, IV PK data - earlier than ever before: Why the need for IV PK data? What are the challenges? Experience to date 30 July

29 Experience with IV microtracer studies 8 studies to date 2 top 5 pharma 10 biotech/med pharma EU, US, and Jp sponsors IV microtracer Increasing utility and demand Early and late stage development projects Data for inclusion in IND and NDA filing Drug conc n cold drug administered at therapeutic dose 14 C intravenous microdose administered at t max 0 24 Time (hrs) Delivers iv PK profile and absolute bioavailability 30 July

30 Pharmacokinetic profiles for therapeutic oral dose & tracer(1/1000 th ) IV dose Oral dose Coefficient of variation = 48% Concentrationsofradioactivity(ngequivalents/mL) Intravenous dose Coefficient of variation = 21% Time (hours post-dose) t 1/2 F(%) Parameter Sub 1 Sub 2 Sub 3 Sub 4 Sub 5 Sub 6 Sub 7 Sub 8 i.v Oral

31 Flexible and integrated protocols: Cost effective generation of critical data Single ascending dose protocol +/- Food Age/gender Dose1 Dose2 Dose3 Dose..n Metabolite ID AbsBio/IV PK Formulation/BA Single Ascending Dose Optional Leg Protocol is specific to the study and tailored to the scientific questions of the project

32 Changing Early Development model Flexible/ integrated SAD/MAD protocols Absolute Bioavailability (oral MTD+ 14 C i.v tracerdose) Single Ascending Dose Traditional Development Multiple Ascending Dose Metabolite Identification (oral light label 14 C MTD)

33 Conclusions AMS: Key role in compound characterisation and early clinical development Microdosing/Phase 0 has proven utility to select compounds based on their human p kinetic characteristics IV-PK data adds value to understanding drivers of poor and variable bioavailability, plus IV PK modelling (IVIVC) IV-Microtracer TM underpinned by rapid GMP manufacture Regulatory acceptance for methods employed and validity in the derived results is established

34 Thank you