Biosimilar PK Guidance andNovel 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

EffectsDosing

Regimen‘Plasma’ Concentration

Site ofAction

Pharmacokinetics Pharmacodynamics

What constitutes a dosageregime?

Dosage Regimen

Activity – Toxicity

Therapeutic windowConc- response relationship

Pharmacokinetics

AbsorptionDistributionMetabolismExcretion

Other Factors

Route of adminDosage formTolerance-dependencePharmacogenetics-idiosyncrasyDrug interactionsCost

Clinical Factors

Management of therapy

Therapeutic windowConc- response relationship

State of patient

Age – weightCondition beingTreatedExistence of other disease states

Pharmacokinetics

Absorption

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

DistributionMetabolism

Excretion

AbsorptionPropertiesCytochrome P450

Plasma Protein

Simple Model of DrugAbsorption and elimination

Drug at Absorption

siteDrug 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 plotSD plot

SD 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

CROSSOVERAdvantages

• 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

PARALLELAdvantages

• Long half lives• Beneficial for disorder /

disease progression• Elicit immunogenic response

Disadvantages• Inter and Intra subject

variabilitySuitable 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 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• 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 & ExternalPredictability 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

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 RatioRD070215 External AUClast 404.7 388.1 4.3 1.0RD070215 External Cmax 27.4 27.5 -0.4 1.0RD100803 Internal AUClast 767.5 832.3 -7.8 0.9RD100803 Internal Cmax 43.7 45.7 -4.3 1.0

we have made it!!Thank you for listening!

any questions?