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

Effects Dosing Regimen ‘Plasma’ Concentration

Site of Action Pharmacokinetics Pharmacodynamics

What constitutes a dosage regime?

Dosage Regimen

Activity – Toxicity Therapeutic window Conc- response relationship Pharmacokinetics Absorption Distribution Metabolism Excretion Other Factors Route of admin Dosage form Tolerance-dependence Pharmacogenetics-idiosyncrasy Drug interactions Cost Clinical Factors Management of therapy Therapeutic window Conc- response relationship State of patient Age – weight Condition being Treated Existence of

• ther disease

states

Pharmacokinetics

Absorption

Pharmacokinetics provides a mathematical basis to assess the time course of drugs and their effects in the body.

Distribution Metabolism Excretion Absorption Properties

Cytochrome P450 Plasma Protein

Simple Model

• f

Drug Absorption and elimination

Drug at Absorption site Drug in body Excreted drug Metabolites

Drug at Absorption site Drug in body Excreted drug Metabolites

Pharmacokinetic Parameters

Cmax (tmax) AUClast AUCinf Kel (lambda z) Thalf

∞

Tau Css trough SS plot SD plot SD plot

Guidance for Industry Clinical Pharmacology Data to Support a Demonstration

• f 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

CROSSOVER

Advantages

• Confounding covariates (each

patient serves as own control)

• Statistically efficient (fewer

subjects) Disadvantages

• Sequence effects
• Carry over effects

Single dose randomised crossover study is generally preferred design

PARALLEL

Advantages

• Long half lives
• Beneficial for disorder /

disease progression

• Elicit immunogenic response

Disadvantages

• Inter and Intra subject

variability Suitable for conditions that exhibit time related changes associated 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

• f 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
• AUCtau (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)
• f 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

Application of an IVIVC

• Biowaivers for changes in the manufacturing of a

drug product

• Change in manufacturing site
• Change in non release controlling excipient
• Lower strength
• New strength
• Setting dissolution specifications

In Vitro In Vivo Correlation

Unit Impulse Response

• Vivo UIR observed vs predicted profile

Example of an individual IR profile (BID) Mean modelled profile

Deconvolution

• Fraction absorbed vs Fraction dissolved profile

Convolution

• Observed and Predicted Concentrations vs Time profiles

Validation Errors

• Meets internal and external criteria

Formulation Parameter Predicted Observed %PE Ratio RD070215 External AUClast 404.7 388.1 4.3 1.0 RD070215 External Cmax 27.4 27.5

• 0.4

1.0 RD100803 Internal AUClast 767.5 832.3

• 7.8

0.9 RD100803 Internal Cmax 43.7 45.7

• 4.3

1.0

we have made it!!

Thank you for listening! any questions?