B.
15 Absolute and Relative Bioavailability
Roland Wesch
PURPOSE AND RATIONALE
The assessment of a drug’s bioavailability (BA) is the most
important information on its pharmacokinetics. Conse-
quently, numerous guidelines primarily focus on this issue
as from the exposure efficacy as well as safety for the
patient (Study Design et al. 2003; ICH E4: Dose–Response
Information to Support Drug Registration March 1994;
EU CPMP: Note for Guidance on Modified Release Oral
and Transdermal Dosage Forms: Section II (Pharmacoki-
netic and Clinical Evaluation) July 1999; EU CPMP: Note
for Guidance on the Investigation of Bioavailability and
Bioequivalence July 2001; US FDA Guidance for Industry:
Food-Effect Bioavailability and Fed Bioequivalence Stud-
ies December 2002; US FDA Guidance for Industry:
Bioavailability and Bioequivalence Studies for Orally
Administered Drug Products – General Considerations
March 2003; US FDA Guidance for Industry: Bioavailabil-
ity and Bioequivalence Studies for Nasal Aerosols and
Nasal Sprays for Local Action April 2003; EU CPMP:
Points to Consider on the Clinical Requirements of Mod-
ified Release Products to be Submitted as a Line Extension
of an Existing Marketing Authorization June 2003).
Bioavailability is defined as the rate and extent by
which the active moiety becomes available at the site of
action. Because neither concentrations nor amounts can
generally be determined at the site of action, plasma/
serum concentrations are used as a surrogate to determine
the rate and extent of bioavailability. Provided that the
pharmacokinetics of the drug considered is linear and
time invariant, the area under the curve (AUC) is
a measure for the fraction of the dose available according
to Dost’s law of corresponding areas. Absolute bioavail-
ability is deduced from the comparison of an extravascular
and an intravascular administration, i.e., AUCPO/AUCIV.
Relative bioavailability compares the exposure following
two different extravascular application forms, i.e., AUCIM/
AUCSC or AUCPOtest/AUCPOreference. Extravascular routes
of administration that require documentation of bioavail-
ability and/or bioequivalence include the oral (PO), intra-
muscular (IM), or subcutaneous (SC) routes, and – in
most instances – vaginal, dermal, ocular, topic, rectal,
nasal, or pulmonary administration.
H. G. Vogel, J. Maas, A. Gebauer (eds.), Drug Discovery and Evaluation: Methods in Clinical Pharmacology, DOI 10.1007/978-3-540-89891-7_B.15,
# Springer-Verlag Berlin Heidelberg 2011
For absolute BA studies, the AUC after intravascular
(IV or intra-arterial) administration is the reference and is
set to 100% availability. Factors that reduce the availability
of a drug prior to entering the systemic circulation may
include poor absorption from the gastrointestinal tract
(Zhou 2003), an (entero-)hepatic recirculation (Ezzet
et al. 2001; Bergman et al. 2006), or a fast degradation
prior to reaching the central compartment, the first pass
effect or first pass metabolization (Kharasch et al. 2005;
Zahng and Benet 2001; Chan et al. 2004; Thummel and
Wilkinson 1998).
Bioavailability is defined for a formulation, not for
a drug.
Bioavailability studies quantify rate and extent of
absorption. They compare the efficiency of the disposition
of several drug formulations, for example, immediate-
release vs. modified-release solid formulation or capsule
vs. tablet or tablet A vs. tablet B, etc. or they compare
the disposition of different routes of administration, for
example, PO vs. SC or PO vs. IV. According to the defini-
tion, a comparison to the intravenous bolus injection
yields the ‘‘absolute’’ bioavailability.
Bioavailability figures should always be given for the
active moiety of a drug. If the parent drug is pharmacody-
namically inactive, details on relevant active metabolite(s)
should be given.
The criterion of bioequivalence applies if there is
a similarity in bioavailability (statistically proven) that is
unlikely to result in clinically relevant differences in effi-
cacy and/or safety.
The bioavailability of a drug formulation is best
described by the rate (Cmax/tmax) and the extent (area
under the plasma concentration-time curve AUC).
Details on the design of and the interpretation of data
from bioavailability studies are given in guidelines and
guidances from ICH, FDA, or CPMP.
PROCEDURE
The design for an absolute bioavailability study is presented
in > Example 1. The drug in question undergoes in-
tensive Phase II metabolism, leading to numerous conju-
gates, the cysteine conjugate being predominant. For the
174 B.15 Absolute and Relative Bioavailability
purposes of simplicity, the description is limited to the
collection, handling, and interpretation of pharmacokinetic
data although safety parameters were also in the focus.
The design for a relative bioavailability study is presented
in > Example 2. The drug in question had exhibited a
marked positive food effect when being administered as
film tablet. The purpose of this study was to compare
a newly developed capsule to a pilot capsule formulation
and to include an oral solution as the reference.
B.15.1 Example 1
B.15.1.1 Protocol Outline
A phase I, open-label, randomized, crossover study to
investigate the bioavailability, safety, tolerability, and
pharmacodynamics following single oral administration
of 25 mg XYZ1234 as capsule and single intravenous
administration of 10 mg XYZ1234 in healthy men.
B.15.1.1.1 Primary Objective
To characterize the bioavailability of XYZ1234 drug sub-
stance (25 mg) as a capsule formulation following a single
oral administration in fasting conditions in healthy male
adult volunteers, using 10 mg of intravenously adminis-
tered XYZ1234 as the reference formulation.
B.15.1.1.2 Study Design
This was an open-label, single-dose, randomized, two-
period crossover study with a minimum washout period
of 7 days. Each treatment group received treatment A
(10 mg XYZ1234, intravenously administered) and treat-
ment B (25 mg XYZ1234 as capsule, orally administered),
once each under fasting conditions.
B.15.1.1.3 Inclusion Criteria
Healthy male subjects, aged 18–45 years (inclusive), with
a Body Mass Index between 18 and 27 kg/m2 (inclusive),
normal or clinically irrelevant abnormal findings (in the
opinion of the investigator) in the medical history and
physical examination, laboratory values, ECG, blood pres-
sure and pulse rate, negative serology (HIV antibody,
hepatitis B surface antigen, hepatitis C antibody), and
urine screen for drugs of abuse.
B.15.1.1.4 Treatments
Regimen A (Reference Treatment):
Intravenous (IV) administration of XYZ1234 (10 mg,
administered over 30 min)
Regimen B (Test Treatment):
Oral (PO) administration of XYZ1234 (25 mg, as a
capsule formulation)
B.15.1.1.5 Pharmacokinetic Data
Concentrations of unconjugated XYZ1234 and Cystein
(CYS)-conjugated XYZ1234 in plasma were measured
pre-dose and at predetermined times up to 48 h post-dose.
The primary analysis examined pharmacokinetic
parameters calculated from plasma concentrations of
CYS-conjugated XYZ1234 using non-compartmental
techniques. The secondary analysis examined the pharma-
cokinetic parameters of unconjugated XYZ1234.
EVALUATION
The primary analyses consisted of characterizing the bio-
availability of oral XYZ1234 using intravenous XYZ1234 as
the reference. Determination of bioavailability was based on
the plasma concentrations of CYS-conjugated XYZ1234.
Descriptive statistics and formal statistical analysis were
used to summarize and analyze the pharmacokinetic
parameters of unconjugated XYZ1234 and CYS-conjugated
XYZ1234 in all evaluable subjects.
The secondary analyses consisted of assessing the
safety, tolerability, and pharmacodynamic responses after
administration of XYZ1234 and XYZ1234 in plasma and
urine using descriptive statistics.
CRITICAL ASSESSMENT OF THE METHOD
For the oral route of administration, the dose of 25 mg was
selected according to the experience from the first-in-man
study, where this dose was safe and well tolerated and was
at the higher end of the dose-proportional range. The dose
for the intravenous route of administration was adjusted
according to the results from animal bioavailability studies
where the absolute bioavailability was in the range of 50%.
Bioavailability – or, in a stricter sense, bioequivalence
– studies are usually conducted in healthy subjects.
Although the inclusion of women is now being encour-
aged, we enrolled only men. This study was the second
clinical trial in the project.
As the bioequivalence rules are clearly defined, the
study population must ensure a high level of standardiza-
tion, making it sometimes difficult to extrapolate to
patient settings. It must be ensured that inter-occasion

variability is limited to the formulations used. Typical
enrolment criteria are:
● Non-smoking subjects between 18 and 45 years
● Normal for weight and BMI
● (Clinically) healthy
● Not using any medication
● Massive dietary and general restrictions (‘‘life style’’)
● No hypersensitivities
● No recent history or presence of any condition that
might interfere with the absorption, distribution,
metabolism, or elimination of the drug under
investigation
In the context with the last criterion, it is important to
document any adverse event during the study, especially
close to the PK profiling day(s) that might affect the
disposition of an orally administered drug under investi-
gation, for example, nausea (delaying the gastric emptying
time, increasing the intestinal residence times), vomiting
(erasing drug still being in the stomach, reducing the
absorption from the intestine), or diarrhea (decreasing
absorption from the intestine).
MODIFICATIONS OF THE METHOD
In this example, an oral formulation has been compared to
an intravenous one, aiming at ‘‘absolute’’ bioavailability.
More often, the relative bioavailabilities of different oral
formulations are assessed in BA studies (see > Example 2).
Depending on the primary purpose of these investiga-
tions, the reference formulation can be a marketed
(solid) drug product, an early clinical phase ‘‘pilot’’ drug
product, or an oral solution/suspension.
If the drug under investigation has a toxic potential
(e.g., drugs directed against cancer), BA studies have to be
conducted in the patient setting the drug is intended for use.
Deviations from the high level of standardization
might become necessary depending on the properties of
the compound.
Crossover study designs allowing for intra-individual
comparisons are preferred for the purpose of bioavailability
testing. Exceptions, i.e., parallel group design, might become
necessary, for example, if the terminal half-life of the drug
exceeds 7 days. Such a long half-life would translate into
a washout period of five times the elimination half-life, or
more than 35 days, in order to avoid trough concentrations
for the second trial period of more than 5% the individual
maximum concentration (Cmax) in this trial period.
Almost all clinical study types described in the PK
section of this book deal in any way with bioavailability
and/or bioequivalence questions. Specifics – if there are
any – are mentioned there.
Absolute and Relative Bioavailability B.15 175
B.15.1.2 Example 1
To illustrate the type of data that can be obtained using the
discussed study, a high level summary of the pharmacoki-
netic results obtained from the study described above
under ‘‘PROCEDURE’’ is presented below. Due to the
anticipated mode of action of the drug (blood pressure
lowering) in this example, instead of an intravenous bolus
injection an intravenous infusion over 30 min was chosen.
B.15.1.2.1 Results – Pharmacokinetics
The calculated bioavailability on the basis of the AUClast of
conjugated XYZ1234 was 38%. However, this could be
a slight underestimation of the bioavailability since this
AUClast could only be determined until 6 h post-dose.
A calculation of the bioavailability on the basis of the
AUClast or AUC0–inf of unconjugated XYZ1234 yielded
a slightly higher bioavailability of 45–47%.
A summary of the pharmacokinetic parameters in
plasma is presented in > Table B.15-1.
For unconjugated and conjugated XYZ1234, Cmax was
reached on average 1–1.5 h after oral treatment, after which
a rapid initial elimination phase and a slow terminal elim-
ination phase was observed, with a terminal elimination
half-life of 3.5–4 days (unconjugated XYZ1234). This long
half-life in combination of a washout period of a minimum
of 7 days resulted in a small carry-over effect in Period 2 for
unconjugated XYZ1234. Correction for pre-dose concen-
trations was not needed, as none of the individual values
exceeded a 5% threshold of Cmax. Due to a relatively high
lower limit of quantitation of 10 ng/mL of the assay for
conjugated XYZ1234, the terminal elimination phase for
this analyte could only be reliably determined for one
subject. The concentrations of conjugated XYZ1234 in
plasma were five- to tenfold higher than of unconjugated
XYZ1234. The AUClast (both analytes) and AUC0–inf
(unconjugated XYZ1234 only) were similar after treat-
ment with XYZ1234 25 mg PO and XYZ1234 10 mg IV.
Results of bioavailability analysis
Treatment ratio
Analyte Parameter (PO/IV) 90% CI
XYZ1234 AUClast 0.38 0.33–0.43
(conjugated)
XYZ1234 AUC0–inf 0.47 0.38–0.59
(unconjugated)
XYZ1234 AUClast 0.45 0.43–0.47
(unconjugated)
Note: Data were dose corrected
176 B.15 Absolute and Relative Bioavailability

. Table B.15-1
Summary of the pharmacokinetic parameters in plasma

Treatment Cmax (ng/mL) Tmax a (h) AUClast (ng.h/mL) AUC0–inf (ng.h/mL) t½ (h)
Unconjugated XYZ1234
10 mg IV 49.5 (30.4–96.7) 0.50b (0.50–0.58) 81.8 (42.7–149.2) 207.4 (85.1–602.4) 85 (36–165)
25 mg PO 15.1 (8.8–24.3) 1.00 (0.50–4.00) 85.0 (60.5–136.4) 215.9 (127.8–337.8) 94 (61–192)
Conjugated XYZ1234
10 mg IV 280.8 (198.0–420.6) 0.50b (0.50–0.75) 367.1 (256.5–1344.5) nd nd
25 mg PO 98.1 (45.9–209.9) 1.50 (1.00–4.00) 317.1 (139.0–704.7) nd nd
nd not determined
a
For Tmax, the median (range) is given instead of the geometric mean (range)
b
The time point 0.50 h is identical with the end of infusion of 30 min/0.5 h duration

In summary, the calculated bioavailability on basis of B.15.2.1.3 Inclusion Criteria

the AUClast of conjugated XYZ1234 was 38%. However,
this could be a slight underestimation of the bioavailabil-
ity since this AUClast could only be determined until 6 h
post-dose. A calculation of the bioavailability on basis of
the AUClast or AUC0-inf of unconjugated XYZ1234 yielded
a slightly higher bioavailability of 45–47%.
B.15.2 Example 2
B.15.2.1 Protocol Outline
An open-label, crossover study to compare bioavailability,
pharmacokinetics, safety, and tolerability of three different
oral formulations of 50 mg HMR123 in healthy men.
B.15.2.1.1 Primary Objective
To assess the relative bioavailability and pharmacokinetics
of three oral formulations (one liquid and two capsule
formulations) containing 50 mg HMR123.
Healthy Caucasian males, aged 18–55 years (inclusive),
with a Body Mass Index between 18 and 28 kg/m2 (inclu-
sive), normal or clinically irrelevant abnormal findings
(in the opinion of the investigator) in the medical history
and physical examination, laboratory values, ECG, blood
pressure and pulse rate, negative serology (HIV antibody,
hepatitis B surface antigen, hepatitis C antibody), and
urine screen for drugs of abuse.
B.15.2.1.4 Treatments
Treatment A (reference):
Single oral dose of 50 mg solution PEG400/Water/
HMR123
Treatment B (test 1):
Single oral dose of two 25 mg capsules (filled with
granules) HMR123
Treatment C (test 2):
Single oral dose of two 25 mg capsules (liquid-filled)
HMR123

B.15.2.1.5 Pharmacokinetic Data

B.15.2.1.2 Study Design
This was an open-label, single-dose, randomized, three-
way, three sequences (ABC, BCA, CAB), three treatments,
three periods crossover study with a minimum washout
period between treatments of 7 days. Each subject received
a single dose of each of the three oral formulations, each of
which containing 50 mg HMR123 under fasting condi-
tions. The sequence of administration (treatments A, B,
and C) was determined according to a randomization
schedule.
Concentrations of HMR123 in plasma were measured
pre-dose and at predetermined times up to 96 h post-dose.
The primary analysis examined pharmacokinetic
parameters calculated from plasma concentrations of
HMR123 using non-compartmental techniques.
EVALUATION
The primary analyses consisted of characterizing the
bioavailability of three different oral formulations of
HMR123. Determination of bioavailability was based on

the plasma concentrations. Descriptive statistics and for-
mal statistical analysis were used to summarize and ana-
lyze the pharmacokinetic parameters of HMR123.
Analysis of variance (ANOVA) was performed on the
log-transformed pharmacokinetic parameters Cmax, AUC0–t
and AUC0–inf, with sequence, subject nested within
sequence (subject (sequence), period and treatment effects
as main effects. The sequence effect was tested using the
subject (sequence) mean square from the ANOVA as an
error term. All other main effects were tested against the
residual error (error mean square) from the ANOVA.
The ANOVA was performed on ln-transformed data.
The mean square error was used to construct 90% confi-
dence intervals for treatment ratios. The point estimates
were calculated as ratio of the antilogs of the least square
means and were expressed as percentages.
In order to compare the relative bioavailability of the
three oral formulations, the following ratios (point esti-
mates and corresponding 90% confidence intervals) were
calculated using adequate contrasts: A:B, A:C, and B:C for
both AUC and Cmax.
Bioequivalence was concluded if the 90% confidence
interval for the treatment ratios were fully contained
within the (80–125%)-acceptance range.
The secondary analyses consisted of assessing the safety
and tolerability of single oral 50 mg doses of HMR123.
CRITICAL ASSESSMENT OF THE METHOD
An oral solution consisting of water, PEG400, and
HMR123 was selected as the reference formulation. Oral
solutions are widely accepted as the ‘‘gold standard,’’
because they are devoid of any limitations concerning
dissolution. In order to maintain a high level of standard-
ization single units of solid formulations are preferred, for
example, one tablet or one capsule. We used two units
instead, as at the time of implementation of this study,
the maximal dose strength was 25 mg, and a minimum
effective dose of 50 mg was anticipated. In preceding
studies, single doses of up to 100 mg had proven to be
safe and well tolerated by healthy male subjects.
If a subject prematurely terminates the study – this was
the case in our study – the replacer subject has to be
administered the same treatment sequence as the subject
he or she replaces.
This study was the third clinical trial in the project. In
the First-in-Man study, a film-coated tablet has been used,
which was dropped due to high interindividual variability
in PK parameters. The second one used the test formula-
tion 1, compared to an oral solution. Test formulation 1
was to be dropped also due to a marked negative food
effect. The test formulation 2 was the result of
Absolute and Relative Bioavailability B.15 177
optimization efforts from the Galenics department. In
this context please refer also to > Chap. B.14, Specific
Studies for Formulation Development.
B.15.2.2 Example 2
To illustrate the type of data that can be obtained using the
discussed study, a high-level summary of the pharmacoki-
netic results obtained from the study described above under
‘‘PROCEDURE’’ as > Example 2 is presented below.
B.15.2.2.1 Results – Study Accounting
In total, 13 male subjects were enrolled in the study and
received the investigational product according to the ran-
domization schedule. Twelve subjects completed the trial.
One subject (subject no. 1xxx) was withdrawn due to
adverse events on day 5 of trial period I (treatment A).
He was replaced by subject no. 6xxx with the same treat-
ment sequence, i.e., ABC.
B.15.2.2.2 Results – Pharmacokinetics
All subjects who completed the study and for whom the
concentrations of HMR123 were considered sufficient and
interpretable by the sponsor were included in the phar-
macokinetic analyses. The 12 subjects who met these
criteria were included in the PK analysis according to
the analysis procedures described in the study-specific
Statistical Analysis Plan.
In > Figs. B.15-1 and > B.15-2, the plasma concentra-
tion versus time profiles are given in linear and log-linear
presentation. For all subjects who were included in the PK
analysis, the individually latest time point of quantifiable
concentration Tlast was 72 h post-dose.
Cmax and Tmax were obtained from the highest con-
centration of the measured data. The apparent terminal
elimination rate constants (lz) were determined using
nonlinear regression analysis on those concentration–
time pairs visually assessed to be in the terminal phase.
The terminal phase half-life (t1/2,z) was calculated as the
ratio of ln 2 to lz. Areas under the curve were determined
using the log/linear trapezoidal rule (linear up to the
maximum concentration and log thereafter). The area
up to infinity (AUC0–inf ) was determined by extrapolation
from the last observed data point: the extrapolated area
was calculated as Clast/lz.
Arithmetic and geometric means for the pharmacoki-
netics parameters are displayed in the table below.
178 B.15 Absolute and Relative Bioavailability

µg/mL
1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0
0 6 12 18 24 36 48 72
Relative time (h)
Treatment:
A B C

Treatment A (reference): oral solution

Treatment B (test 1): capsule filled with granules
Treatment C (test 2): capsule (liquid-filled)

. Figure B.15-1
HMR123 plasma concentration, linear scale

Following treatment with the solution formulation, no (Tmax) and for the last quantified plasma concentration
blood samples were available for subject 1zzz for the 15, (Tlast).
24, and 48 h sampling times. Consequently, a number of Tmax was observed most frequently at 4 h after treat-
pharmacokinetic parameters could not be determined and ment A (4 out of 12 subjects), at 6 h after treatment B
this subject had to be excluded from the population used (4 out of 12 subjects) and at 8 h after treatment C (5 out
for the sensitivity analysis. of 12 subjects). Tlast was most frequently observed at 48 h
after dosing for all three treatments (for 5 of 12 subjects
Descriptive statistics for pharmacokinetic parameters each).
Arithmetic mean (geometric mean)
PK Parameter Treatment A Treatment B Treatment C B.15.2.3 Comparison of Treatments
Cmax (mg/mL) 1.37 (1.35) 1.21 (1.15) 1.25 (1.17)
AUC0–t 26.53 (25.65) 23.97 (22.67) 24.80 (23.04)
B.15.2.3.1 Treatment A vs. Treatment B
(mg*h/mL)
The 90% confidence intervals are not completely within
AUC0–inf 30.06 (29.24) 26.28 (25.01) 27.35 (25.87)
(mg*h/mL)
the 0.8–1.25 range of bioequivalence and therefore no
equivalence could be concluded.
t1/2,z (h) 21.39 (20.90) 20.61 (19.99) 20.03 (19.33)
Rate constant 0.034 (0.033) 0.036 (0.035) 0.037 (0.036)
(1/h) B.15.2.3.2 Treatment A vs. Treatment C
Vz (L) 52.16 (51.57) 60.09 (57.75) 59.33 (53.82)
The 90% confidence intervals are not completely within
Frequency tables were prepared for the blood sam- the 0.8–1.25 range of bioequivalence and therefore no
pling times of maximum observed plasma concentration equivalence could be concluded.
 Absolute and Relative Bioavailability B.15 179

µg/mL
10.00

1.00

0.10

0.01
0 6 12 18 24 36 48 72
Relative time (h)

Treatment:
A B C

Treatment A (reference): oral solution

Treatment B (test 1): capsule 1 (filled with granules)
Treatment C (test 2): capsule 2 (liquid-filled)

. Figure B.15-2
HMR123 plasma concentration, log-linear scale

B.15.2.3.3 Treatment B vs. Treatment C
The 90% confidence intervals are completely within the
0.8–1.25 range of bioequivalence and therefore equiva-
lence could be concluded.
only be concluded for the comparison of treatment B vs.
treatment C, i.e., for both capsule formulations. The lack
of equivalence between the capsule formulations and the
reference oral solution probably results from an increased
ratio of the treatments and not from increased variability.

90% CI for treatment effect

Parameter Treatment LS-mean Reference LS-mean Ratio Lower Upper

Cmax (mg/mL) A 1.347 B 1.154 1.168 0.988 1.380

A 1.347 C 1.167 1.154 0.977 1.364
B 1.154 C 1.167 0.988 0.837 1.168
AUC0–t (mg*h/mL) A 25.649 B 22.674 1.131 0.978 1.309
A 25.649 C 23.042 1.113 0.962 1.288
B 22.674 C 23.042 0.984 0.851 1.138
AUC0–inf (mg*h/mL) A 29.967 B 25.948 1.155 1.003 1.330
A 29.967 C 27.048 1.108 0.962 1.276
B 25.948 C 27.048 0.959 0.833 1.105

The results of the sensitivity analysis for all treatment Generally, slightly lower Cmax and later tmax values
comparisons are presented below. Bioequivalence could were observed for HMR123 following administration of
180 B.15 Absolute and Relative Bioavailability
the capsule formulations in comparison to the solution
formulation. This suggests a slightly lower rate of bioavail-
ability for the capsules, which would be anticipated owing
to the time required for breakdown of the capsules to
occur. The extent of absorption was also a little higher
for the solution formulation, as evidenced by the AUC0–t
and AUC0–inf data. After 8 h post-dose, however, the
median plasma concentration versus time curves were
almost identical for all the three formulations investigated
in this study. Statistical comparison of Cmax, AUC0–t and
AUC0–inf between the capsule formulations and the oral
solution indicated that the confidence intervals for the
parameter ratios were not fully contained within the
0.80–1.25 range: a slightly higher bioavailability was thus
confirmed for the solution formulation. A statistical com-
parison of the two-capsule administrations on the other
hand showed the corresponding confidence intervals to be
fully within the 0.80–1.25 range; i.e., the criteria for bio-
equivalence were met for these two capsule formulations.
Coefficients of variation on the primary pharmacoki-
netic parameters (reflecting inter-subject variability) were
generally about 30% for the two-capsule formulations and
about 25% for the oral solution. Slightly lower values were
seen for the capsule filled with wet granules in comparison
to the liquid-filled capsules.
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