Biosimilars PK Considerations PDF/PPT

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PK Considerations

M- Pharma
Department of Pharmaceutics 1


▪ Introduction

▪ Difference Between small mol. Drugs and Biologics

▪ Challenges in PK study of Biologics

▪ Study Designs For the Study

▪ Acceptable limit for Biosimilarity

▪ Immunogenicity Study during the study period

▪ Need for elimination characteristics

▪ Relative purity/Protein Content

▪ Region Specific Reference Drug

▪ Differences – BE and Biosimilarity Study 2



What are Biologics?

✓ Includes such as vaccines, blood and blood components,

allergenics, somatic cells, gene therapy, tissues, and

recombinant therapeutic proteins

✓ Composed of sugars, proteins, or nucleic acids or

complex combinations of these substances, or may be

living entities such as cells and tissues 3


✓ Biologics are isolated from a variety of natural sources – human,

animal, or microorganism

✓ Produced by biotechnology methods and other cutting-edge


✓ Treat variety of medical conditions for which no other treatments are

available 4


Simple Drugs V/s Biologics
Simple Drugs Biologics
Chemical structures are known Chemical structures and
and are same in patent and composition is most likely to be
generic as well different

Side effects are also same for both Side effects may be different for
Generic version and innovators originator and biosimilar

Follow up drugs are usually Follow up drugs are not generic in
generic nature

Chemical integrity is not affected Chemical integrity is affected by
by manufacturing process manufacturing process

Need not to be sterile Aseptic principles initial
manufacturing steps

Usually taken orally Usually injected 5


What is Biosimilarity?

A biosimilar product is defined as a product that
is –
✓Highly similar to the reference product
✓No clinically meaningful differences in terms of

safety, purity, and potency 6


Challenges Involved in PK study of Biologics

✓ Large molecular size and complicated tertiary structure

✓ Lack of effective and validated in vitro systems

✓ No reliable in vitro systems that can predict bioavailability

✓ Limited distribution in tissues

✓ The rate of metabolism for biologics is compound- or modality-

dependent 7


✓ Species difference and host immune response to a biologic

✓ Analytical assay development – Another hurdle

✓ Structure similarity between endogenous proteins and therapeutic biologics – difficulty in

extraction and purification

✓ Enzymatic digestion prior to the structure identification – quantitation becomes a problem 8


ADME-related considerations for Key contributing factors

Physical/chemical properties Size, shape, charge, stability,
heterogeneity in isoforms (including
post-translational modifications)

Absorption mechanism Route of administration, formulation,
injection site, subject characteristics,
FcRn- and target-dependent
mechanisms, physical/chemical

Distribution patterns Size, shape, charge, target binding,
FcRn- and target-dependent
mechanisms, route of administration,

Elimination pathways Proteolysis, target-mediated
clearance, nonspecific endocytosis
and formation of immune-complexes
followed by complement- or Fc
receptor-mediated clearance,
protection from catabolism via FcRn 9


Nonlinear kinetics Saturable target mediated
clearance, immunogenicity, FcRn
(for very high doses or possibly for
FcRn mutants)

Subject characteristics Body weight, age, sex, disease
status, prior exposure to biologics,
concomitant medications

Species difference in PK profiles Target binding affinity, FcRn/IgG
interactions, immunogenicity,
contribution of lymphatic
absorption, off-target effects 10


Pharmacokinetic Analysis of Biosimilars

• Route to market for classic generics is well defined and has been

successfully negotiated

• Small number of studies in healthy volunteers are sufficient to

prove physiochemical and pharmacokinetic (PK) equivalence

• For biosimilars – new and more complex

Hence, there are some key issues which should be considered when

performing pharmacokinetic analyses to prove biosimilarity 11


Study Design

The most common designs associated with
bioequivalence studies are:

▪ Standard design: randomized, two-period, two-

sequence, single dose cross-over design

▪ Alternative design: parallel design (substances

with very long half-lives) and replicate designs (in

case of highly variable drugs or drug products) 12


Cross- Over Design
• Each drug product is administered to

each subject

• Each patient receives different

treatments during the different time

periods, i.e., the patients cross

over from one treatment to another

during the course of the trial

• Thus, estimate (approximate) within-

subject variance can be used to

address switchability and

interchangeability 13


• For a parallel-group study, each

drug product is administered

to a different group of subjects

• Thus, we can only estimate

total variance (between and

within subject variances) not

individual variance

components 14


Cross- Over v/s Parallel Study Design
Parallel Study Design is always preferred, Why?

• Since, Biologics have longer half-lives , a cross-over approach is

generally not practical

• The wash-out period which would be required is often prohibitively


• The potential for biologics to illicit an immune response also limits

the use of cross-over studies

• For follow-on biologics with long half-lives, crossover study would

be ineffective and unethical 15


To negate these issues, it is common to use a parallel group design when

conducting biosimilar studies , as:

▪ Only one treatment period is required for each subject

▪ Removing the need for a wash-out period

▪ Immune response of the patient is limited

But few issues are associated with parallel design as well:

✓ Large sample sizes are required

✓ Treatment differences are estimated between subjects, it is important to

account for covariates in the statistical assessment 16


Acceptance Limits For Biosimilarity
Pharmacokinetic equivalence is demonstrated using
bioequivalence limits of (0.80, 1.25)

Test 90% confidence interval

e of the ratio of
Bioequivalent geometric least squares

means lies entirely
within (0.80, 1.25)

EMA guidance states that
“The acceptance range to conclude clinical comparability w.r.t.
PK parameter – based on clinical judgement, taking into
consideration all available efficacy and safety information on
the reference and test products, clinical comparability limits
should be defined and justified prior to conducting the study” 17


Immunogenicity Study

Anti-Drug Antibodies (ADA)

✓ Biologics Immune response, due to their

nature and a complex manufacturing process

✓ Induce anti-drug antibodies (ADA)

✓ High levels can interfere with the pharmacokinetic and

pharmacodynamic properties of the drug such as:

• Increasing clearance

• The extent of systemic exposure

• Desired effect of the drug 18


✓Assay has to be done: to detect for presence of

ADA at suitable intervals

✓“Differences that could have an advantage as

regards to safety (for instance lower levels of

impurities or lower immunogenicity) should be

explained, but may not preclude biosimilarity”

✓Equivalence in immune response cannot be

assumed and is an integral part of the PK

assessment 19


Elimination Characteristics

Bioequivalence studies are
concerned with:

✓Area under the concentration-time
curve (AUC)

✓Maximum concentration (C-max)
✓Overall extent of systemic exposure
✓Rate of absorption
✓Elimination characteristics (long

half-lives and immune responses)
• Current EMA guidelines state that “the design of

comparative PK studies should not necessarily mimic that
of the standard “clinical comparability” design 20


Similarity in terms of Differences in elimination
absorption/bioavailabil characteristics

ity (Cl and T1/2)

What has to be done?
✓ To fully characterize elimination kinetics in

biosimilarity studies
✓ Implementation of the sampling schedule guidelines

associated with equivalence studies 21


Sampling Schedule:

• Cover the plasma concentration time

• To provide a reliable estimate of the extent of exposure

• Achieved if AUC(0-t) covers at least 80% of AUC(0-∞)

• Three to four samples are needed during the terminal log-linear

phase in order to reliably estimate the terminal rate constant

• Thus, the last sampling time point may be many weeks or even

months after dosing 22


Relative Purity or Protein Content

Manufacture and production of biologics – more complex , often

results in impurities

In synthetic drugs (chemical drugs)

➢ Assay content should not differ by 5% w.r.t. to reference

➢ It may not be possible to meet this criteria for biologics

Hence, the total protein content of drug (both test and reference)

needs to be considered when assessing biosimilarity 23


Case study
PK Parameters


Retacrit® Eprex®
(Biosimilar (Innovator

) biologic)

This study highlighted differences in:
❑ The amount and type of glycoforms (different production

❑ Eprex® comprised more total protein (µg/mL) – more potency
❑ The EMA accepted the comparability – by introducing a correction

❑ Parameters were well within the defined equivalence margins 24


Region-Specific Reference Drugs
According to US-FDA and EU:
• License the biosimilar in both the EU and the USA,
• Necessary to include two reference drugs in the study and

conduct a 3-way comparison (Test Drug : US-licensed Drug :
EEA licensed Drug).

• Should similarity be proven for all 3 treatments in the
Phase 1 studies, subsequent Phase 2 and 3 studies may
then be limited to just one reference drug

To avoid unnecessary repetition of clinical trials
– Compare the biosimilar (clinical studies and in vivo non-clinical

– With a non-EEA authorized comparator – need to be authorized

by a regulatory authority 25


Differences between bioequivalence and biosimilarity
studies 26


• Zhao, L., Ren, T. H., & Wang, D. D. (2012). Clinical pharmacology

considerations in biologics development. Acta pharmacologica
Sinica, 33(11), 1339-47.

• Anon, (2019). [online] Available at:

• Kamath, A. (2016). Translational pharmacokinetics and
pharmacodynamics of monoclonal antibodies. Drug Discovery Today:
Technologies, 21-22, pp.75-83.

• (2019). [online] Available at:

• Phrma. (2019). Biologics & Biosimilars | PhRMA. [online] Available at:
biosimilars 27