M&S in early development (to support FTiM) M&S to support - PDF document

Modelling and simulation support for design of First-in- Man studies: the MABEL approach Hélène Karcher, Stacey Tannenbaum, Philip Lowe Modelling & Simulation, Novartis Pharma AG EMA-EFPIA Workshop on the role and scope of modelling and simulation in drug development 30 th November – 1 st December, 2011 2 M&S in early development (to support FTiM) � M&S to support design of First-in-Man studies – the MABEL approach � Utilising prior information ( in-vitro , pre-clinical and literature) � Biomarker role in chain of causal evidence � Animal ( in-vitro & in-vivo ) studies � Defining PK-PD strategy M&S should � design safe studies to achieve, efficiently, desired goal, whether it be • healthy volunteer safety and tolerability • PK and PD • safety assessment plus clinical benefit � highlight uncertainties in whatever model(s) is (are) chosen • may not always be popular with our project teams, but a key point in design-test cycle 2 | EMA-EFPIA London | Karcher & Lowe | 30 th Nov- 1 st Dec 2011 1

3 Abstract for examples � As with clinical drug development, preclinical development also has phases: • “I” initial in vivo pharmacology • “II” non-GLP dose range finding • “III” GLP toxicology � Together with an array of in vitro experiments comparing species, these enable an integrated safety assessment prior to entry into man, documenting to investigators and authorities the minimum acceptable biological effect level (MABEL) for a first dose in man � A pharmacokinetic-pharmacodynamically drug-target binding guided process to ascertain the MABEL will be exemplified. 3 | EMA-EFPIA London | Karcher & Lowe | 30 th Nov- 1 st Dec 2011 4 effective 01-Sep-07 4 | COST B-25 | Philip Lowe | 27-May-09 | Business Use Only 2

5 Beyond the “safety factor approach” From NOAEL to MABEL, minimal ACCEPTABLE biological effect level for a first dose in a human Toxicological effect Target-related PD effect 100% 100% Toxicology Anticipated Most-sensitive Human animal species What level Toxicology of effect is Non- Anticipated acceptable human Human PD PD with a first No observable dose in adverse effects human? Human Animal MABEL Dose or Exposure NOAEL First dose in human NOAEL MABEL: Minimal ACCEPTABLE Biological Effect Level NOAEL: No Observable Adverse Effect Level 5 | EMA-EFPIA London | Karcher & Lowe | 30 th Nov- 1 st Dec 2011 6 How? A process for scaling drug effects from non-human species to man 1 2 3 Anticipated Non-human Human dose-response dose-response Measure exposure in Predict exposure same experiments Link with effects Adjust Anticipated Non-human Human for interspecies exposure exposure- differences -response response or assume same ... rather than assuming that a mg/kg bodyweight dose in pharmacology or toxicology species will give equivalent effects in man 6 | EMA-EFPIA London | Karcher & Lowe | 30 th Nov- 1 st Dec 2011 3

7 How? A concept – document causal chain from drug exposure to clinically measureable effects binds Drug changing absorbed Drug in Target(s) Biomarkers body cleared causing Adverse Beneficial effects clinical effects Investigate, for each step in the causal chain • interspecies differences • (and, note, different departments often provide the data!) 7 | EMA-EFPIA London | Karcher & Lowe | 30 th Nov- 1 st Dec 2011 8 Example of correlative review of non-human and human (predicted) exposure and toxicity 300 • Extended pharmacology Dog 100 4160 studies provide initial NOAEL Dog exploration of NOAEL AUC (µg.h/mL) 10 416 • Correlate exposure C ave (ng/mL) Rat NOAEL ( AUC, C ave ) with Rodent NOAEL or LOAEL 1 42 HED through simple Human exposure-response hPAD(s) graphics or function 0.1 4.2 MRSD • Account and correct for 0.1 1 10 100 1000 Dose (mg/kg) interspecies differences such as unbound fraction, receptor potency, etc. Novartis, ancient data on file 8 | EMA-EFPIA London | Karcher & Lowe | 30 th Nov- 1 st Dec 2011 4

9 Exposure safety envelope over time and start to consider occupancy or free target suppression in safety assessment Pharmacokinetics – generate large Pharmacodynamics – target ligand exposure safety margin for potential suppression “on target” “off target” effects • Cell surface target: Biological Limit exposure through study design response, receptor occupancy and/or PK nonlinearity cynomolgus (observed) 3, 30, 100 mg/kg • Soluble target: measure total ligand or mAb-ligand complex } 10 fold Serum concentration • mAb-ligand binding model used to predict suppression of free ligand man (first predicted, then actual) 0.1, 0.3, 1 mg/kg Time (days) 9 | EMA-EFPIA London | Karcher & Lowe | 30 th Nov- 1 st Dec 2011 10 Binding characteristics. Biotherapeutic and target related by simple equilibrium reaction Drug + Target � Drug-Target Complex Add drug, mass balance “pushes” reaction to the right Phil’s 3 rd year notes, 1977 10 | EMA-EFPIA London | Karcher & Lowe | 30 th Nov- 1 st Dec 2011 5

11 Dose for first clinical study? MABEL? What is occupancy at early times, before significant distribution and clearance? Quick method • If [ mAb ] >> [ target ] , 1:1 binding, use [ ] Microsoft Excel mAb = Worksheet Occupancy [ ] D + K mAb mAb + Target � Target-mAb Complex • Binding affinity 1.88 nM (TGN1412) [ ][ ] mAb Target = K [ ] D • 0.1 mg/kg (7 mg) in 2.5 L plasma Complex = + ∴ = − TD mAb Complex m Ab TD Complex • Peak Occupancy 90.9% = + ∴ = − TT Target Complex Target TT Complex ( ) ( ) + + − + + 2 − K TD TT K TD TT 4 . TD . TT With Expression = d d Complex 2 Complex • 150000 CD28 receptors per T cell = Occupancy TT • 1.3 × 10 9 T lymphocytes/litre blood • Assume 1:1 binding & fast equilibrium • Peak Occupancy 90.6% @ 0.1 mg/kg • or 10% @ 1.5 µg/kg (1.1µg/kg quick method) 11 | EMA-EFPIA London | Karcher & Lowe | 30 th Nov- 1 st Dec 2011 12 Incorporating dynamics of drug distribution and elimination plus target turnover – a PKPD binding model target production or expression iv dose + mAb – target target mAb complex elimination elimination elimination mAb target mAb – target complex slow clearance general rule: general rule: V ~ 3 L central, for 70 kg faster than a mAb soluble target – slow t ½ ~ 3-4 w for most (not all) cell surface target – faster proteins Ng CM, Stefanich E, Anand BS, Mager DR, Jusko WJ. General Pharmacokinetic Model for Drugs Fielder PJ, Vaickus L. Pharmacokinetics/pharmacodyn- Exhibiting Target-Mediated Drug amics of nondepleting anti-CD4 Disposition. J PKPD 2001; 28: 507-532 monoclonal antibody (TRX1) in healthy human volunteers. Pharm 12 | EMA-EFPIA London | Karcher & Lowe | 30 th Nov- 1 st Dec 2011 Res 2006; 23:95-103 6

13 Three components of the PKPD model � Pharmacokinetics of the monoclonal antibody: • species differences often well understood and easily characterised • good prediction to man, either by scaling &/or by reference to prior similar antibodies � Binding affinity to the target ligand: • species differences understood during in vitro characterisation of the drug � Localisation, expression and turnover of target, clearance of drug-target complex • species differences sometimes not well understood 13 | EMA-EFPIA London | Karcher & Lowe | 30 th Nov- 1 st Dec 2011 14 Monoclonal antibody binds and occupies cell surface target Nonlinear PK correlates with target saturation; need to assess target expression and replenishment; level of receptor or target can vary between species and between diseases Cynomolgus monkey Human, chronic lymphoid leukaemia & multiple myeloma patients PK PD � Target expression consistent between cynomolgus monkeys � Humans vary by more than order of magnitude � More target → higher dose to achieve saturation � Model used to advise on dose and regimen for next cancer indication 14 | EMA-EFPIA London | Karcher & Lowe | 30 th Nov- 1 st Dec 2011 7