Bioavailability & Bioequivalence

Pharmacokinetic Principles

Bioavailability and Its Assessment

Bioavailability:
The rate and extent to which the parent
compound reaches the general circulation.
Absolute Bioavailability
requires I.V. administration
Ratio of the oral: intravenous AUC values normalized for dose
Fabs= (AUC oral / AUC iv)*(Dose iv / Dose oral)
Relative Bioavailability
no I.V. reference
comparison AUC values (ratio) of different dosage forms / formulations
Frel = (AUC a / AUC b) * (Dose b /Dose a)

Area Under the Concentration

Time Curve (AUC)
A quantitative measure
for exposure from
dosing time to time t
An important parameter
in PK
AUC(t) and AUC(inf)
Determined by
trapezoidal method
AUC(inf) = AUC(t) + Ct/k
Units: Conc*t (mg/L * h)
Proportional to Dose
(linear PK)
Accuracy of the
estimate depends on
frequency of sampling

Plasma Concentration-Time Profile for a

Drug Following a Single Oral Dose

Rate of drug accumulation at

any time:
dDBODY/dt= dDABS/dt dDELIM/dt

Absorption Phase:
dDABS/dt > dDELIM/dt

At time of peak drug conc.:

dDABS/dt = dDELIM/dt

Post-absorption Phase:
dDABS/dt < dDELIM/dt

Comparison of the Rates of Drug

Absorption

Effect of a Change in Absorption Rate

Constant (Ka) on Plasma Drug
Concentration Versus Time Curve
0.5/hr

0.2/hr

Pharmacokinetic Assessment of
Absorption Interactions
Clinically significant interactions are typically
assessed in terms of:

Rate of Absorption:
peak plasma drug concentrations (Cmax)
time to Cmax (tmax)

Extent of Absorption:
area under the concentration-time curve (AUC)

Bioequivalence
Definition
It is the absence of significance difference
in the rate and extent to which active
ingredient or active moiety in
pharmaceutical equivalent or
pharmaceutical alternative becomes
available at the site of drug action when
administered at the same molar dose
under similar conditions in an
appropriately designed study

Regulatory Requirements for BE

Evaluation of Quality and

interchangeability of Medicinal
Products

Regulatory Requirements
for BE
FDA - Guidance for Industry: Bioavailability and
Bioequivalence Studies for Orally Administered Drug
Products .
WHO Multisource (generic) pharmaceutical products:
Guidelines on registration requirements to establish
interchangeability
CN Guidance for Industry; Conduct and analysis of
bioavailability and bioequivalence studies Part A: Oral
dosage formulations used for systemic effects

 ICH Guidelines
Development Safety Update Report;

Structure and Content of Clinical Study Reports;

Good Clinical Practice;

General Considerations for Clinical Trials;

Clinical Safety Data Management: Definitions and

Standards for Expedited Reporting;

Statistical Principles for Clinical Trials;

Validation of Analytical Procedures Text and

Methodology;

Test Procedures and Acceptance Criteria for New

Drug Substances and New Drug Products Chemical
Substances;

India (CDSCO):
Central Drugs Standard Control Organization
Bioavailability / Bioequivalence:
Requirements and Guidelines for Permission to Import and / or
Manufacture of New Drugs for Sale or
to Undertake Clinical Trials:
Submission of Clinical Trial Application for Evaluating Safety and Efficacy:
Ethical Guidelines for Biomedical Research on Human Participants

Regulatory Requirements for BE

Bioequivalence Studies

in vivo comparison of products by means of

volunteers serving as in-vivo dissolution model
biological quality control

comparison of product characteristics in order to

ensure therapeutic equivalence

Immediate and Modified Release

Dosage Forms
BE is generally required and can be
investigated by means of
pharmacokinetic (BE) studies (preferred as
most sensitive)
comparative pharmacodynamic studies
comparative clinical trials
comparative in vitro trials

Immediate Release (IR) Dosage Forms

possible BE exemptions
aqueous solution (incl. syrups, elixirs, but no
suspensions)
gases
aqueous optic or ophthalmic products (contg. the same
actives and excipients)
nebulizer inhalation products or nasal sprays (contg.
the same actives and excipients)

Bioequivalence for Immediate Release

Dosage Forms
the parent drug substance within a single
dose 2-period crossover design is usually
appropriate

dose- or time-dependent kinetics

specific food recommendations in the SPC
active metabolites
pro-drugs
enantiomers

Modified Release (MR) Dosage

Forms
controlled (extended, sustained) release
delayed release
single unit formulations
multiple unit formulations

single dose study (fasting)

multiple dose study (steady state conditions)
food-effect study (dose-dumping under
high-fat conditions;)

Product strengths
bioequivalence proven for one strength
same manufacturer and manufacturing

process
linear drug input
same qualitative composition of different
strengths (WHO)
same ratio between active substance and
excipients, or same excipients in case of low
concentration (less than 5 % API)
similar in vitro dissolution (WHO)

Bioequivalence for transdermal

therapeutic systems (TTS)

BE by means of single and multiple dose

studies
performing a replicate design study is
advisable (investigation of subject by formulation interaction)
BE regarding local tolerability
dose proportionality issue: thorough in vitro
release testing and exact proportionality (partial
effective surface area!)

Bioequivalence for topical dosage forms

without systemic action

usually therapeutic studies necessary

(therapeutic equivalence, safety and tolerability usually
not possible by means of blood sampling and PK data)

usually therapeutic studies necessary

(specific FDA guidance for corticosteroids..)

possibilities are e.g. skin stripping, micro dialysis

inhalatives metered dose

inhalers(locally acting)
usually therapeutic studies necessary
in some cases PK studies for safety reasons
in some cases PK studies in addition to in-

vitro (quality - deposition characteristics e.g.

FPD)
usually in patients