Pharmacokinetics/Pharmacodynamics PDF

Effect (PD) Concentration (PK) Pharmacokinetics/Pharmacodynamics with focus on biopharmaceutics Mia Lundblad| Clinical Pharmacology Scientific Director| Novo Nordisk A/S Agenda Definitions and background Pharmacodynamics Pharmacokinetics...

Effect (PD) Concentration (PK) Pharmacokinetics/Pharmacodynamics with focus on biopharmaceutics Mia Lundblad| Clinical Pharmacology Scientific Director| Novo Nordisk A/S Agenda Definitions and background Pharmacodynamics Pharmacokinetics ADME PK with focus on biotherapeutics From research to the clinic Discovery/research Non-clinical development Clinical development incl. NOAEL and MABEL definitions and dose setting Model-building Learnings and take-home message Definitions and background  Definitions and background The dose makes the poison Paracelsus (1493-1541): Dosis sola venenum facit  Definitions and background Distinction between PK and PD Pharmacokinetics (PK) needed to: Pharmacodynamics (PD) needed to: Determine and understand the fate of Determine what the drug does to the a drug in the body, i.e. the relation body between dose and drug concentration in the body Change in drug amount/concentration in How the drug effect/side-effect changes the body over time following a drug dose over time following a drug dose Concentration “what the body does to the drug” “what the drug does to the body” Effect Time Time  Definitions and background PK/PD Concentration (PK) is always underlying the effect (PD): Rarely 1:1 association between effect and concentration: Double concentration could mean more or less Effect (PD) than double effect Time delays between concentration and effect may occur The dose-concentration-time-effect relation may be described in a mathematical PK/PD model Concentration (PK)  Definitions and background Questions to be answered by PK and PD assessments Which dose should be given initially? Which maintenance dose should be given? How often should/could the drug be dosed (dosing frequency)? How high can we dose? Which administration route? Knowledge about PK/PD relationships used to: Evaluate the safety and efficacy of a drug Establish an appropriate dosing interval in the target population Establish the most appropriate dose regimen for the individual patient  Definitions and background Pharmacodynamics How a drug affects the body, focusing on the relationship between concentration and response and response duration Studies to be performed not only at a single dose but preferably at repeated dosing at several dose levels (large dose interval) Can be performed in vitro, ex vivo and in vivo Animal models, mimicking the human disease, often used but the limitations and the potential difficulties with translatability to humans must be acknowledged  Definitions and background PK: Absorption, distribution, metabolism, excretion (ADME) absorption rate=elimination rate Area-Under-Curve (AUC) is a measure of total drug exposure www.eupati.eu  Definitions and background PK parameters summarise the drug exposure Why PK parameters?: Summarises the PK properties of a drug slope = -k = ln(2)/t1/2 = CL/V Summarises the total exposure of a drug to a subject Cmax Used as secondary endpoints in clinical trials May be used for exposure response analysis Most commonly used: Cmax (observed maximum concentration) Cavg Tmax (time for observed Cmax) AUCtau AUC (Area-under-the-curve) Cmin Half-life (t½) Clearance (CL) Volume of distribution (V) AUCiv = dose / CL Others (C=concentration): Cavg(average concentration in steady state ) Time Cmin = Ctrough (minimum concentration in dosing interval) AUCinf single dose = AUCtau in steady state  Definitions and background Comparison of ADME properties * Dedicated studies usually not needed Small molecules Therapeutic proteins Size < 1 kDa > 1 kDA Route of administration Mostly oral (also i.v., s.c., i.m.). I.v., s.c., i.m. Absorption Dissolution followed by intestinal uptake Transport in the subcutis to the absorbing (diffusion, active transport, etc.). blood or lymph capillaries. Distribution Dependent on lipid solubility, water solubility Lymphatic system involved in and binding to plasma proteins (e.g. albumin). distribution/efflux. Tissue distribution is a relatively fast process, Tissue distribution is a more slow process often described by the “well-stirred“ model. and determined by FcRn binding (IgG). Metabolism Metabolism mainly in liver * Elimination largely by catabolism in by e.g. cytochrome P450 enzymes. endosomal space of cells to peptides or aa. Usually a saturable process at high TMDD can occur (dependent on dose and concentrations. target). Relatively fast elimination, dosing ~ once Slow elimination, dosing ~ once weekly- daily-weekly. monthly. Excretion Through the kidneys (intact or as metabolites) Re-entering of amino acids (aa) into or the bile (but bile is far less common). endogenous pool. PK with focus on biotherapeutics  PK with focus on biotherapeutics Delivery of biologic therapies Due to large molecular size, poor permeability and degradation in GI tract, oral delivery is difficult I.v. administrations (infusion or bolus): + 100 % bioavailability (rapid exposure) + No dose/volume restrictions - Invasive process, risk of infections - Administration at hospital S.c. administrations: + Patient convenience: Less pain, lower risk for systemic infection, handled by patient, better complicance - Greater inter-individual variability - Dose/volume restrictions Adapted from McDonald et al: Current Opinion in Molecular Therapeutics 2010 12(4):461-470  PK with focus on biotherapeutics Altering PK of biologics Subcutaneous (s.c.) administration. Increasing molecular weight by binding to carriers such as polyethylene glycol (PEG) and albumin. Fusion to Fc-regions. Modulation of non-specific endocytosis: Altering the isoelectric point/charge changes the clearance. Improving FcRn binding: Increased FcRn binding at acidic pH but weakly at neutral pH (releasing IgG from FcRn at the cell membrane and being rescued from lysosomal degradation). Recycling efficiency can be further improved by engineering the Fc to increase the FcRn binding at acidic pH.  PK with focus on biotherapeutics Elimination of biologics Renal filtration is the major elimination pathway for drugs with a molecular weight < 50 kDa (i.e. small molecules, peptide molecules that are non-mAb domain- based entities and peptidic protein molecules) Non-IgG proteins, e.g. immunoglobulin E (IgE) and thrombomodulin have a relatively fast elimination (t1/2 ~ 3-5 days) even though they have a molecular weight above 50 kDa and negligible renal clearance IgG-based mAbs are usually around 150 kDa and have negligible renal elimination and thus quite a relatively slow elimination, depending on the concentration of the target versus the mAb mAbs are degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG Typically display nonlinear PK, due to target mediated drug disposition (TMDD) Research - clinic  Research - clinic The ultimate goal: To treat patients Once the preclinical program has been completed (and approved by authorities) the first step is to conduct a First-in-Human (FiH) trial with the aim to: Evaluate safety, tolerability, and PK (PD) at increasing dose levels in humans. Compare the preclinical effects and translatability to humans Obtain sufficient data on PK and PD and safety to perform scientifically valid and safe phase II trials and with the goal of selecting the optimal dose for performing pivotal phase III trials.  Research - clinic Discovery/research investigations Data needed before determining dose setting in early clinical development Clinical Registration Discovery Non-clinical Maintenance phase phase Mode of action (pharmacodynamics) Pharmacokinetics Metabolism (NA for biologics) Plasma protein binding (NA for biologics) Concentration-response data in vitro and in vivo, ultimately combining PK and PD data from a relevant animal model Binding affinity to the target (in human target cells and cells from tox. species): Kd, Ki, kon, koff Ligand concentration and ligand turnover (in humans and tox. species) Receptor concentration (in humans and tox. species) Account for potential differences in potency between animals and humans  Research - clinic Non-clinical development Data needed for determining dose setting in early clinical development Registration Discovery Non-clinical Clinical Maintenance phase phase The purpose of non-clinical development Characterisation of toxic effects with respect to: Target organs Dose dependence Relationship to exposure Potential reversibility This information is used to: Estimate an initial safe starting dose for the human trials Set a dose range for the human trials and determine a maximal exposure Identify parameters for clinical monitoring for potential adverse effects  Research - clinic Exposure response for First-Human-Dose (FHD) 100 Desired PD effect Adverse effects PD effect (% of max.) 80 NOAEL 60 Toxicity not related to pharmacology Negligible effect Therapeutic range 40 MABEL Predicted PAD/ATD 20 Toxicity = exaggerated pharmacology 0 0.0001 0.0010 0.0100 0.1000 1.0000 NOAEL: No observed adverse effect level Exposure MABEL: Minimum anticipated biological effect level  Research - clinic Dose setting: NOAEL approach Process for selecting maximum recommended starting dose (MRSD), based on FDA guidance from 2005 (1) Determine the NOAEL in each animal species tested. (2) Convert the NOAEL to an HED (human NOAEL can be used when there is a higher level equivalent dose) using appropriate scaling of confidence associated with the MoA or an factors (dose normalization by body surface area). evident class effect. (3) Apply a safety factor to the HED to define NOAEL approach usually considered for small the human MRSD (maximum molecules, whereas biologics should be recommended starting dose), generally at considered with the MABEL approach. least a factor of 10. (4) Finally, the MRSD may need to be Arbitrary safety factor applied. adjusted based on the pharmacologically active dose.  Research - clinic Dose setting: MABEL approach Based on the EMA guidelines from 2007 and 2017 (1) In vitro target binding and receptor occupancy in target human and animal cells. MABEL approach requires exhaustive data and may require a greater number of dose (2) In vitro concentration–response curves cohorts in the clinic but is the safest in target human and animal cells. approach when there is a high degree of uncertainty associated with the candidate (3) In vivo dose–exposure–response drug. profiles in most appropriate animal species (IC50, EC50, etc.). (4) Exposures at pharmacological active doses in relevant animal species.  Research - clinic Dose setting: Combined approach A combined approach using both NOAEL/HED, and MABEL is recommended, applying the most conservative estimate.  Research - clinic Risk factors for selection of starting dose Mode of Action Higher Concern Lower Concern Primary Pharmacology Stimulatory Inhibitory Agonist stim. pathway Antagonist stim. pathway Antagonist inhib. pathway Agonist inhib. pathway Pleiotropic Effects Target in multiple pathways or ubiquitously expressed Target not in multiple pathways or narrowly expressed Amplification Effect Targets biological amplification cascade Does not involve amplification cascade Dose response curve Steep Not steep Nonclinical Toxicology Higher Concern Lower Concern Animal species No relevant species At least one animal species Translation to human Uncertain human translation Similar or translatable response Animal PD & Tox response Severity of adverse findings Severe findings Non-severe Reversibility of adverse findings Recovery not demonstrated Recovery demonstrated Monitorability of adverse findings Difficult to monitor Can monitor Nature of Target Higher Concern Lower Concern Novelty No prior clinical experience No clinical safety concerns from other molecule(s) with Target/mechanism/pathway Unknown biology same target or MOA Limit subjects dosed short term Extent of clinical experience Many subjects dosed long term (e.g. post P3) (e.g. a single SAD)  Research - clinic Strategy for human PK/PD model building Pharmacokinetic prediction A. 1:1 PK vs known compound in humans B. Allometric scaling (by size) of key PK parameters (clearance, C. Novel volume of distribution) modality/class/bio- Multi-species scaling from 2-5 species to humans - or - B. Mecha- logy; mechanisms and Single species scaling from a species known/believed to A. Closely nisms well- species translation most predictive for human PK for the class related understood uncertain Species bridging as needed: plasma protein binding (PPB), compound receptor affinity (TMDD) C. Case-by-case choice of QSP modelling and mechanistic Prior knowledge modelling: often more in vitro and in vivo data needed. Prediction uncertainty inherently larger Prediction uncertainty + Sensitivity analysis of different approaches, incl. allometric Data requirement scaling as ”gold standard” (Model complexity) TMDD: target mediated drug disposition  Research - clinic The (PK/PD) pathway to First-in-Human trial PK profiles after different dosings Concentration Effect (PD) In vitro PD In vivo PD Predicted human doses EC50 Time Concentration (PK) In humans: In vitro PK In vivo PK Clearance (CL) (PPB) (diff. species) Distribution volume (Vd) Concentration PPB: Plasma protein binding Time  Research - clinic Strategy for human PK/PD model building Pharmacodynamics Select and design the in vitro and in vivo systems most closely resembling human biology/disease Typically EC50, affinity, IC50 etc. used as parameter values in the model Animal PD data not always available or relevant  translation from in vitro data only If human data for similar compound with same target: perform bridging as with animal data Sensitivity analysis of different assays and in vitro to in vivo translation approaches as relevant: scenarios for predicted dose-exposure-response in humans  Research - clinic Translation of PK/PD from animals to humans Allometric scaling Physiological processes often follow power law of allometry: A larger body weight (BW) results in a less than proportional increase in e.g. cardiac output Parameterhuman = parameteranimal *(BWhuman/BWanimal)exponent Routinely applied in pharmacokinetics for clearance (elimination), often with exponent=0.75 Reflected in cardiac output, renal clearance, heat production relationship to BW From Rowland and Tozer. Clinical Pharmacokinetics and Requires that the same physiological mechanisms Pharmacodynamics 4th ed. 2011. p. 664 are governing the elimination and distribution across species  Research - clinic Human PK/PD model building PK model driving LDLc inhibition, as an example Absorption parameters based Potency parameters based on monkey PK model on monkey PKPD model – supported by: monkey vs human in vitro potency 1:1 marketed Drug X antibodies Clearance and volume of Physiological parameters distribution based on cross on LDLc turnover based species scaling on literature  Research - clinic Clinical development Registration Discovery Non-clinical Clinical Maintenance phase phase Target validation Lead candidate Phase 1 clinical Pre-IND Human PKPD model for Phase 2-3 selection design, starting dose setting MoA modelling Dose setting in tox, Phase 1 and 2 clinical dose and dose pharmacology trial design escalation for FHD CMC planning QTc/TQT Bridging to other populations Food effect Hepatic impairment Drug-drug interaction (DDI) Renal impairment PoP/ PoC Bioequivalence MAD SAD Phase 1 Phase 2 Phase 3 Phase 4 SAD: Single ascending dose MAD: Multiple ascending dose Biologics and small molecules PoP: Proof-of-principle PoC: Proof of concept Small molecules QUESTIONS Learnings PK and PD necessary to understand and establish a safe and efficacious dose regimen for the patient population as well as the individual patient Understand the differences in ADME properties between small molecules and biotherapeutics and how this affects the PK and advantages and disadvantages for different dosing strategies Is the molecule suitable for the intended dosing (dose, frequency administration route)? Differentiate between dose setting approaches, advantages and disadvantages In vitro and ex vivo data as well as animal studies needed to predict appropriate doses and concentrations in humans Suggested reading Guohua et al: J Clin Pharmacol. 2020 Feb; 60(2): 149–163 Dudal et al, Drug Discovery Today; 27 (6), 2022, 1604-1621 Mishra et al., European Journal of Clinical Pharmacology (2020) 76:1237–1243 Deng et al: mAbs 3:1, 61-66; January/February 2011 Dong et al: Clin Pharmacokinet 2011; 50 (2): 131-142 Guideline on the clinical investigation of the pharmacokinetics of therapeutic proteins, 2007; CHMP/EWP/89249/2004 Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products, 2017; EMEA/CHMP/SWP/28367/07 Rev. 1 Shen et al., Clin Transl Sci (2019) 12, 6–1 Ferl et al., Biopharm. Drug Dispos. 37: 75–92 (2016) BACK-UP  Definitions and background Mode of action Definition: The biochemical interaction through which a drug substance produces its pharmacological effect, e.g. by binding to an enzyme or a receptor. To understand the MoA is important for: Defining potential pharmacological differences, e.g. determining receptor expression levels and receptor homology and subtypes in different animal species and humans. Understanding potential differences in effect, e.g. performing binding studies in different tissues from different species.  PK with focus on biotherapeutics Elimination of antibodies Conventional antibody Recycling antibody by FcRn Recycling antibody Conventional antibody A conventional antibody binds to A pH-dependent dissociation of the antibody from the e.g. a membrane-bound antigen, antigen in the endosome, the dissociated antibody being the antibody-antigen complex is recycled to plasma by FcRn enabling the antibody to bind to transferred to lysosome and other antigens repeatedly, reducing the antibody clearance, degraded by protease. while the antigen is transferred to lysosome and degraded (effective to minimize the rapid elimination mediated by TMDD) Ref: Adapted from Chugai (https://www.chugai-pharm.co.jp/english/ir/rd/technologies_popup1.html)  Research - clinic Non-clinical development Data needed before clinical investigations and for dose setting in early clinical development Dose-response, determination of NOAEL Single/repeated dose Duration of study determines max. duration of clinical Conducted in trials (up to app. 6 months dosing) toxicity Determination of antibody formation, immunogenicity pharmacologically relevant assessment species (usually rats and To ensure there is no risk for mutations, using e.g. Ames cynomolgus monkeys for Genotoxicity test biologics) Biologics not expected to interact with DNA For long-term treatment, using rodents For biologics where there is no cross-reactivity or *Incl. fertility studies, either Carcinogenicity immunologic response other approaches should be as part of repeat-dose tox or considered (KO-animals, in vitro cell proliferation, etc.) as separate fertility tox in Biologics show less cross-reactivity to species usually Reproductive used for such studies, i.e. rabbits and rats rodents and embryo-fetal, Low likelihood of placental transfer due to molecular size pre-and postnatal toxicity* but transport via FC receptor occurs development as well as To identify potential local adverse events, e.g. at Local tolerance injection site for s.c. injections juvenile tox Identify off-target binding and other potential non- Tissue cross identified targets (for guidance on organ toxicity) reactivity In vivo immunohistochemical (IHC) staining of tissues  Definitions and background Species differences in target expression Quantitative and qualitative differences in target between animals and humans are important to understand in order to make correct dose/concentrations- response predictions.  Definitions and background Important PK parameters (needed for dose setting) Distribution – volume of distribution (V): A proportionality factor that relates the amount of drug in the body to the concentration of drug measured (V=dose/conc) Log-linear Elimination – clearance (CL): A constant determining the body’s ability to clear a specific volume completely of drug, i.e. ‘the volume of plasma cleared of drug per unit slope = -k = ln(2)/t1/2 time’ (e.g. mL/h) = CL/V Half-life (t1/2): Half-life is the time required for the concentration to fall to 50% of the initial value assuming a 1-compartment model and linear elimination AUCiv = dose / CL Bioavailability (F): The fraction of given dose that unchanged reaches the systemic circulation Time Absorption rate (ka) : The rate at which unchanged drug proceeds from site of administration to site of measurement within the body  Research - clinic Scaling of PK from animals to humans Allometric scaling relates primary PK Based on actual concentration data in parameters (CL and V) to body weight animals, a PK model can be established Concentration Allometric scaling for mAbs that exhibit linear PK in non-human primates can predict human PK within a twofold range Time Predicted PK profile in humans after s.c. dosing Subsequent allometric scaling of clearance and distribution volume can be used to simulate the human PK profile