PK and PK/PD Guided Starting Dose Selection for First-In-Human Trials. Sylvia Zhao ( 赵子微 ) Translational Clinical Oncology Novartis

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1 PK and PK/PD Guided Starting Dose Selection for First-In-Human Trials Sylvia Zhao ( 赵子微 ) Translational Clinical Oncology Novartis

2 Disclaimer Contents are the opinion of the author and not that of Novartis Pharmaceuticals Corporation 2 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

3 Objectives of FIH Study To evaluate safety and tolerability of the drug, and to characterize dose limiting adverse effects To determine maximum dose (MTD) associated with an acceptable safety profile (or recommended phase II dose, RP2D) To characterize pharmacokinetic profiles To explore pharmacodynamic effects/efficacy and PK/PD(TD) relationships 3 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

4 What is the Appropriate Starting Dose Avoid toxicity and limit safety risk at the initial clinical testing Enable escalation to therapeutic concentrations in an efficient manner Allow reasonably rapid attainment of the phase I trial objectives (tolerability, pharmacodynamic or pharmacokinetic profile) Must be low enough to ensure safety but high enough to avoid excessive dose escalation (costly and timeconsuming) In cancer therapy, to avoid a large proportion of patients being treated at subtherapeutic doses 4 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

5 General Approaches FDA and EMEA guidance Effect based: toxicology and pharmacology Method based: dose scaling and exposure modeling Gibbs, AAPS J., 2010, 4: Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

6 Methods for FIH Starting Dose Selection All relevant preclinical data, including information on pharmacologically active dose, full toxicological profile, and pharmacokinetics (ADME) should be considered (FDA 2005) Effect based Toxicity - Maximum recommended starting dose (MRSD) approach (non-oncology) - HNSTD/STD10 (oncology) Pharmacodynamics/efficacy - Pharmacology active dose (PAD) - Integrated PK/PD modeling approach Methods Dose scaling Pharmacokinetics and PK/PD guided 6 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

7 PK-Guided Dose Selection Assumptions Systemic drug exposure instead of dose is more relevant to toxicity and pharmacological effects Similar exposure-response (toxicity and efficacy) relationship between preclinical species and human Human PK (dose) are predictable from preclinical data (in vitro and/or animal) 7 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

8 Human PK Prediction Key parameters include clearance (CL), bioavailability (F) and volume of distribution (Vd) Common methods of human PK prediction Inter-species allometric scaling - CL and Vd extrapolated from multiple species based on allometry In vitro-in vivo extrapolation (IVIVE) and physiologically-based pharmacokinetic modeling (PBPK) - CL extrapolated from in vitro metabolism in human liver microsomes, hepatocytes or CYPs using physiological scaling factors - Integrating preclinical in vitro and in vivo drug property with human physiology 8 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

9 Allometric Scaling Assume anatomical, physiological, and biochemical similarities across animal species and humans Utilize PK data collected in one or more preclinical species Underlying principle is that physiological functions can be scaled across a wide range of body sizes Y = ɑ x BW b Adjustment with maximum lifespan potential (MLP) and brain weight (BrW) 9 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

10 Interspecies Scaling for mab Ling et al, J Clin Pharmacol, 2009, 49: Empirical allometric method worked well for mabs targeting soluble antigens or membrane-bound antigens with a known limited distribution. A simplified approach: CL in humans might be accurately predicted from monkey data using allometric scaling with exponent of either 0.85 or 0.90 (based on 14 mabs for soluble target and membrane-bound target) 10 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

11 In vitro-in vivo Extrapolation (IVIVE) Extrapolate enzyme kinetic parameters determined in vitro (using human liver microsomes, hepatocytes or recombinant human enzymes) to estimate in vivo clearance IVIVE was based on the use of recombinantly expressed human CYPs, after accounting for inter-system extrapolation factors (ISEF), and the use of human liver microsomes (HLM) with a knowledge of the proportional contribution of each CYP enzyme to overall clearance (e.g. from inhibition studies). MPPGL: the amount (mg) of microsomal protein per g of liver 11 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

12 PBPK Modeling and Simulation PBPK approach mathematically describes the movement and disposition of a drug in a physiological flow model with multiple compartments representing an actual organ or tissue Distribution Log P pka Protein binding Clearance Intrinsic CL Protein binding Blood/Plasma ratio Absorption Fa x Fg x Fh = F Solubility Effective Permeability (Peff) Caco2, Pampa, MDCK First pass (Liver - gut) Transporter 12 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

13 Example of IVIVE vs. Allometry for CL Prediction Shiran et al, Xenobiotica, 2006, 36: (A) Simple allometry (B) MLP allometry (C) BrW allometry (D) BSA allometry (E) Exponent allometry (F) PBPK 13 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

14 Methods Comparison for Human CL Prediction Absolute average fold errors of human CL predicted 14 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only Peng et al, AAPS J, 2012, 14:

15 Prediction of Vd and F in human Volume of distribution (Vd): Allometric scaling using multiple species data in silico modelling based on physicochemical properties (MW, lipophilicity, ionization constant, PSA, No. of hydrogen bond donors, etc.) Bioavailability (F) In vitro: Caco-2 and PAMPA permeability Average/range of preclinical values - Animal bioavailability is not quantitatively predictive of bioavailability in human (Musther et al, 2014) - Caution for drugs with high interspecies first-pass metabolism 15 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only Musther et al, Eu J Pharmaceut Sci, 2014, 57:

16 PK-Guided Dose Selection From predicted human PK parameters to human dose Data NOAEL and corresponding AUC in several animal species determined in toxicity/toxicokinetic studies Species resulting the lowest NOAEL AUC is used as the index (most sensitive) species for scaling Estimation Starting oral dose is the product of the AUC of the drug in the index species and the predicted human CL, corrected by F - Dose = CL human x AUC index species /F - Apply a safety factor, e.g. factor of 10 Starting dose and human PK profile at the dose simulated with model (e.g., PBPK) Maximum concentration (Cmax) (or steady-state concentration Css) may also be used as the base for dose estimation Similar approach with AUC of PAD PBPK assists dose selection for different populations (age, gender, obesity and various disease states) 16 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

17 Considerations for PK Guided Approach Species difference exists in the pharmacokinetic phase Absorption related physiological factors (ph, gastric and intestinal transit time, blood flow rate) Rate of drug distribution (determined by blood flow and rate of diffusion and/or transport to the target cells) Metabolism (including first pass metabolism) Excretion (e.g., biliary excretion rate) Protein binding Challenges with IVIVE and PBPK Design and execution of in vitro measurements could be a major source of error Better applied to drugs through hepatic metabolic clearance (IVIVE) PBPK requires large amounts of experimental data to develop and refine the models Doss not account for pharmacodynamic effects and differences 17 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

18 PK/PD Guided Dose Selection Assumption Similar PD (pharmacodynamics/toxicology) effect among species Assume similar exposure will have same PD effect among species (pharmacodynamics/toxicology) 18 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

19 PK/PD Relationship Combination of pharmacokinetic and pharmacodynamic models to generate response concentration profiles for proposed dosing regimens Provides information on the degree of receptor occupancy or biomarker change to be achieved by a particular exposure/dose and as a function of time Provides better means for translating in vitro and animal data to human pharmacology 19 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

20 Introduction of MABEL Minimal Anticipated Biological Effect Level In 2006, TGN1412, a monoclonal antibody directed against T lymphocytes, produced multiorgan failure in six healthy volunteers in FIH clinical NOAEL was 50 mg/kg from cynomolgus monkeys an HED of 16 mg/kg apply a very conservative safety factor of 160, an MRSD of 0.1 mg/kg MABEL by European Medicines Agency in 2007 For TGN1412, estimated FIH dose is mg/kg using the MABEL-based approach 0.1 mg/kg FIH dose would leads to a receptor occupancy greater than 90%, which is very likely to cause adverse effects 20 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

21 MABEL EMEA 2007 The anticipated dose level leading to a minimal biological effect level in humans The lowest dose that is associated with any biological effect (toxicity or a desired pharmacological effect) MABEL is calculated utilizing in vitro and in vivo PK/PD data Target binding and receptor occupancy in target human and animal cells Concentration response curves in target human and animal cells Dose/exposure response profiles in relevant animal species Exposures at pharmacological active doses in relevant animal species Safety factor applied in the calculation of the FIH starting dose Novelty of active substance, biological potency, mode of action Degree of species specificity Shape of the dose response curve and degree of uncertainty in MABEL calculation For biotherapeutics with potentially agonistic MoA, no more than 10% occupancy is proposed for the FIH trial 21 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

22 Preclinical PK/PD Biochemical potency (e.g., IC 50 ) obtained in vitro (cellular assays) Efficacy evaluation in vivo Identify key in vivo drug and system properties, including magnitude and time course of drug responses under physiological and pathological conditions in animals, as well as corresponding drug exposures Characterize relationship between drug concentration and effect Provides critical information for compound design, ranking and selection 22 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

23 Direct and Indirect PK/PD Effect Direct PK/PD relationships Concentrations correlated with effects in a reversible manner Peak PD effect observed at Cmax Follow sigmoid Emax model (Hill equation): Indirect PK/PD relationships Used extensively to characterize effects for drugs acting on turnover processes 23 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

24 Considerations for PK/PD Guided Approach Difference in pharmacology Target/endogenous ligand expression and localization Affinity to target/receptor (biotheraprutics) Off-target pharmacology Difference in metabolism Formation of active metabolite Correlation of the extent of receptor occupancy or biomarker change with a therapeutic effect 24 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

25 Case Study: Everolimus Phase I Dose Consideration Tanaka et al, J Clin Oncol, 2008, 26: Everolimus (RAD001) is an orally active inhibitor of the mammalian target of rapamycin (mtor) Peripheral blood mononuclear cells (PBMC)-derived S6K1 activity was chosen as a pharmacodynamic (PD) marker PK obtained in preclinical PK and efficacy studies Distribution to tumor was extensive with a tissue-to-blood concentration ratio of 12:1 Half-life comparable in blood and tumor 25 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

26 In vitro and in vivo PK/PD Potent and prolonged inhibition of S6K1 activity in both PBMC and tumor tissue in rats Imax: 102% in PBMC and 97% in tumor IC50: 0.1 nm in PBMC and 0.05 nm in tumor Direct-link model used to predict effects for different dosage regimes in rat A: PBMC B: Tumor C: Prediction for PBMC effect D: Prediction for tumor effect A/B: yellow: 0.5 mg/kg blue: 5 mg/kg 26 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

27 Human PK and PK/PD Predication PK PBPK model developed to describe everolimus concentrations in the blood and tissues of rats Model then scaled up to humans - Replacing the model parameters (e.g., organ volume, blood flow rate, in vitro blood distribution parameters, plasma unbound fraction) from rat to humans - Assume identical tissue distribution parameters, per unit volume of organs - Intrinsic hepatic clearance calculated assuming a well-stirred model PK/PD Direct-link model selected to explore relationship between drug concentrations and changes in S6K1 activity in PBMCs and tumors from rats treated with everolimus - Unbound concentration allowed correction for interspecies differences in tissue distribution caused by differences in protein binding Same model applied to describe changes in S6K1 activity in PBMCs and tumor of patients using the same model parameters (i.e., Imax and IC50) 27 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

28 Human PK and PD Profile Predicted vs. Observed Prediction of PK profiles in patients agreed well with data from clinical study Direct-link PK/PD model reproduced S6K1 inhibition-time profiles in PBMCs of cancer patients 28 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

29 Human Dose Consideration PK/PD model applied to predict PD effect in PBMC and tumor in patients with different dose levels in a weekly regime 5 mg weekly regime corresponded to mean inhibition observed in rat at 0.5 mg/kg weekly dose higher than 20 mg would result in a marginal increase in inhibition of S6K1 activity A phase I clinical trial included a single-agent dose-escalation study of everolimus given weekly at four dose levels (5, 10, 20, 30mg) 29 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

30 Advantages and Disadvantages of Various Approaches Zou et al, AAPS J., 2012, 14: Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

31 Summary An accurate estimation of human starting doses is critical for phase I trials All toxicological, pharmacological, pharmacokinetic, and biopharmaceutical information should be evaluated to determine the optimal FIH dose NOAEL, MABEL, PK, and PK/PD modeling and similar drug comparison approaches also be considered and utilized to estimated doses For PK and PK/PD guided FIH dose selection, human pharmacokinetic parameters (CL, bioavailability, etc.) need to be reasonably well predicted. Initial dose should be determined by either the MABEL or NOAEL, whichever is lower 31 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

32 Backup 32 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

33 Human PK Prediction Large Molecule - mab Limited extravascular distribution of antibodies, Vd similar to plasma volume (40 ml/kg) High success rate in CL prediction clearance using monkey PK and fixed exponent values Factors influencing disposition target-mediated drug disposition - binding with pharmacological target can modulate Vd - removal of complex can enhance clearance - in a dose- and concentration-dependent manner Immunogenicity - Generally antibody-positive animals are excluded from prediction 33 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

34 Doses in MTA FIH Cancer Clinical Trials Tourneau et al, 2010, 28: different molecularly targeted agents (MTA) with 81 trials from Jan 1, 1998 to Apr 1, 2009 In 57 trials specified animal model used to determine the starting dose, 29 (51%) based on rodent data and 28 (49%) of 57 based on non-rodent data Three (3.7%) of 81 trials had starting dose exceeded human MTD Median number of dose levels to reach MTD or MAD from starting dose was five (range, one to 14 dose levels) Median ratio of MTD or MAD to starting dose was 12 (range, <1 to 300) 34 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

35 MRSD Selection in HV 35 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

36 Starting Dose for antineoplastics STD 10 : the dose resulting in 10% mortality over the duration of the study in rats HNSTD: the highest non-severely toxic dose (does not produce death or moribundity) 36 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

37 Interspecies scaling: Time-Invariant Method Elementary Derick Plot Step 1: equivalent times were transformed from monkey data: b selected from the results of simplified allometry. Step 2: corresponding concentration data from monkeys normalized by dose and BW: Step 3: human-like concentration-time profiles constructed: Step 4: PK parameters estimated by noncompartmental analysis 37 Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only

38 Recommended mab clearance prediction scheme in drug discovery and early development Ling et al, J Clin Pharmacol, 2009, 49: Nanjing International DMPK Meeting S Zhao 27 Jun 2015 First Dose Business Use Only