Biosimilars
PK Considerations
M- Pharma
Department of Pharmaceutics
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Contents
▪ 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
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Introduction
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
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✓ Biologics are isolated from a variety of natural sources – human,
animal, or microorganism
✓ Produced by biotechnology methods and other cutting-edge
technologies
✓ Treat variety of medical conditions for which no other treatments are
available
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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
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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
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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
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✓ 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
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ADME-related considerations for Key contributing factors
biologics
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
properties
Distribution patterns Size, shape, charge, target binding,
FcRn- and target-dependent
mechanisms, route of administration,
formulation
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
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mechanism
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
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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
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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)
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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
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• 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
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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
long
• 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
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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
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Acceptance Limits For Biosimilarity
Pharmacokinetic equivalence is demonstrated using
bioequivalence limits of (0.80, 1.25)
Referenc
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”
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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
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✓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
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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
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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
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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
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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
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Case study
PK Parameters
Comparison
Retacrit® Eprex®
(Biosimilar (Innovator
) biologic)
This study highlighted differences in:
❑ The amount and type of glycoforms (different production
processes)
❑ Eprex® comprised more total protein (µg/mL) – more potency
❑ The EMA accepted the comparability – by introducing a correction
factor
❑ Parameters were well within the defined equivalence margins
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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
studies)
– With a non-EEA authorized comparator – need to be authorized
by a regulatory authority
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Differences between bioequivalence and biosimilarity
studies
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References
• 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:
http://www.appliedclinicaltrialsonline.com
• Kamath, A. (2016). Translational pharmacokinetics and
pharmacodynamics of monoclonal antibodies. Drug Discovery Today:
Technologies, 21-22, pp.75-83.
• Ingentaconnect.com. (2019). [online] Available at:
https://www.ingentaconnect.com/content/ben/cdm/2014/00000015/0
0000003/art00003?crawler=true
• Phrma. (2019). Biologics & Biosimilars | PhRMA. [online] Available at:
https://www.phrma.org/advocacy/research-development/biologics-
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THANK YOU
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