Biosimilar PK Guidance and Novel Approaches Dr Alison Wilson, - PowerPoint PPT Presentation

Biosimilar PK Guidance and Novel Approaches Dr Alison Wilson, Senior Pharmacokinetist, BioClin Research Laboratories

Pharmacokinetics?

Pharmacokinetics (from Ancient Greek pharmakon "drug" and kinetikos "moving, putting in motion“ PK is a branch of pharmacology dedicated to determining the fate of substances administered externally to a living organism

Pharmacokinetics Quantitative framework for drug design, evaluation and administration Pharmacokinetics Pharmacodynamics Dosing ‘ Plasma’ Effects Site of Regimen Concentration Action

What constitutes a dosage regime? Pharmacokinetics Activity – Toxicity Absorption Therapeutic window Distribution Conc- response relationship Metabolism Excretion Dosage Regimen Other Factors Clinical Factors Route of admin State of patient Management of therapy Dosage form Tolerance-dependence Age – weight Therapeutic window Pharmacogenetics-idiosyncrasy Condition being Conc- response Drug interactions Treated relationship Cost Existence of other disease states

Pharmacokinetics Pharmacokinetics provides a mathematical basis to assess the time course of drugs and their effects in the body. Absorption Absorption Distribution Metabolism Properties Plasma Protein Cytochrome P450 Excretion

Simple Model of Drug Absorption and elimination Excreted drug Drug at Absorption Drug in body site Metabolites Drug at Absorption site Drug in body Metabolites Excreted drug

Pharmacokinetic Parameters Kel (lambda z) Cmax (tmax) Thalf SD plot AUClast Css trough AUCinf ∞ Tau SD plot SS plot

Guidance for Industry Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) May 2014 Biosimilars

Biosimilar Development Plan Discussion with the FDA (early stage) • Study Design • Reference Product • Study Population • Dose Selection • Route of Administration • PK Measures • PD Measures • Defining the appropriate PD time profile • Statistical Comparison of PK and PD results

Study Design PARALLEL CROSSOVER Advantages Advantages • Long half lives • Confounding covariates (each • Beneficial for disorder / patient serves as own control) disease progression • Statistically efficient (fewer • Elicit immunogenic response subjects) Disadvantages Disadvantages • Inter and Intra subject • Sequence effects variability • Carry over effects Suitable for conditions that exhibit Single dose randomised crossover time related changes associated study is generally preferred design exposure to drug

Reference Product  Ideally US licensed reference product  Non-US licensed comparator product • Scientific justification • Bridging data including data from analytical studies (structural and functional data) directly comparing all three products (PK and if appropriate PD data for all three)

Study Population  Healthy Volunteers vs Patients • Most informative to detect and evaluate differences in PK and PD profiles between test and reference products • Healthy – more sensitive (less variability) • Patients – precluded due to safety / ethical considerations  Demographic Groups • Should be conducted in subject or patient demographic group most likely to provide a sensitive measure of difference between the proposed biosimilar product and the reference

Study Population  Total number of subjects to provide adequate power for similarity assessment  Analysis of the data from all subjects as one group represents the primary study endpoint, and a statistical analysis of the data from the subgroups would be exploratory only

Dose Selection  Dose selected should be the most sensitive to detect and evaluate differences in the PK and PD profiles  Dose should be the one most likely to provide clinically meaningful and interpretable data  Patient study – approved dose for the reference product (best demonstrate pharmacological effect in clinical setting) / lower dose if non-linear PK or if exceeds dose required for max PD effect  Healthy volunteer study – lower dose in the steep part of the exposure – response curve maybe appropriate  Adequate justification required

Route of Administration  Same route of administration in both test and reference products  If there are multiple routes approved for the reference product, route selected for the assessment of PK and PD similarity should be the one most sensitive for detecting clinically meaningful results  Subcutaneous or other extravascular routes preferred (more information on the PK differences during the absorption phase in addition to distribution and elimination phase

Pharmacokinetic Measures  Cmax and AUC in a relevant biological fluid  SINGLE DOSE • AUC (primary endpoint for SC study) • AUCinf (primary endpoint for IV study) • Cmax  MULTIPLE DOSE • AUC tau (primary endpoint) • Ctroughss (secondary endpoint) • Cmax (secondary endpoint)  POPULATION STUDIES  Not suitable for similarity PK assessments

PD Measures  Human PK and PD data that demonstrate similar exposure and response may be sufficient to completely assess clinically meaningful differences between the products.  If PD measure reflects the mechanism of drug action (wide dynamic range over a range of drug concentrations)  Time points and durations very important  If PD response lags after administration, MD study and SS conditions may be important  If only one PD measure , simultaneous drug concentration measurement necessary (broader panel of biomarkers adds value)

Appropriate PD Time Profile  May differ from PK measure  For PK, frequent early sampling and decrease at later time points  For PD, may be a lag after administration  Sampling strategy should be optimised during clinical pharmacological studies

Statistical Comparisons  Clinical pharmacology similarity assessment  Criterion to allow comparison (log transformation)  Confidence interval for the criterion (90% CI for the ratio between the means)  Acceptable limit (80-125%)  PK and or PD results fall outside acceptable limits – all not lost!  Analyse and discuss!

Simulations Tools for study design & analysis  Modelling and simulation tools useful in PK and or PD study design  Useful for dose selection (steep portion of the dose- response curve of reference product)  Need to supply data to support the claim that the selected dose is on the steep part of the dose- response curve  May need to generate exposure – response data (PK- PD study at multiple dose levels to get a dose response and exposure response data) eg MD study measuring EC50, Emax and slope of concentration effect relationship

Study Population  Total number of subjects to provide adequate power for similarity assessment  Analysis of the data from all subjects as one group represents the primary study endpoint, and a statistical analysis of the data from the subgroups would be exploratory only

Novel Approaches

Simulations – Step 1 Objective: To attain target concentrations & duration of time cover  Range of doses  Range of lag times  Range of sustained release properties

Simulations – Step 2  Pharmacokinetic model (goodness of fit estimates)

Simulations – Step 2

In Vitro In Vivo Correlation  IVIVC are the predictive, mathematical models relating an in vitro property (e.g. dissolution) and the in vivo response (e.g. amount of drug absorbed) thus allowing an evaluation of the QC specifications, change in process, site, formulation and application for a biowaivers etc.

Levels of IVIVC  Level A – point-point, first deconvolution to get in vivo % drug absorbed then compared with % dissolved  Level B – statistical moments: MRT or MDT in vivo vs MDT in vitro  Level C – single point, PK parameter vs % dissolved

Developing the correlation  Most commonly seen process for developing a Level A IVIVC is to 1. Develop formulations with different release rates (slow, medium fast, or a single release rate if dissolution is condition independent) 2. Obtain in vitro dissolution profile and in vivo plasma concentration profiles for these formulations 3. Estimate the in vivo absorption or dissolution time course using deconvolution

Developing the correlation  IVIVC relationship should demonstrate consistently release rate(s) corresponding to differences in absorption profiles  Ideally the formulation should be compared in a single crossover study  In vitro dissolution methodology should adequately discriminate among formulations  Initially a 1 to 1 correlation should be attempted  Time scale may be used as long as time scaling factor is the same for all formulations

Internal & External Predictability  Internal Predictability  Average absolute percentage prediction error (%PE) of 10% or less for Cmax and AUC  % PE for each formulation should not exceed 15%  External Predictability • % PE of 10% or less for Cmax and AUC – external predictability • %PE 10-20% - inconclusive predictability (additional data required) • %PE 20% or greater – inadequate predictability