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Clinical Pharmacokinetics
249
3. Elicitation of Therapeutic Effect: In order to accomplish a reasonably good elicitation of the
desired therapeutic effect, the drug substance (i.e., an active entity) must be:
∑ specifi cally delivered at the very site of action,
∑ critically delivered in an effective concentration and
∑ effectively delivered during the desired period.
Importantly, it becomes quite necessary that the overall performance of the drug product co pris-
ing the ‘drug’ remains totally reproducible in the body in order to anticipate the uniform therapeu-
tic effect. Therefore, it is absolutely essential that the actual bioavailability of the ‘drug’ in a dosage
form is well established and also remains perfectly reproducible.
In the recent past, both bioavailability and bioequivalence have mustered an ever-growing atten-
tion, indulgence and involvement because there exists an avalanche of ‘generic drugs’
19
in the
pharmaceutical trade across the globe.
4. Abbreviated New Drug Application (ANDA): In true sense, the ‘bioequivalence study’ rep-
resents an extremely important segment of ANDA that needs to be submitted to the Food and
Drug Administration (FDA) by a perspective ‘pharmaceutical manufacturer’ who intends to launch
a ‘generic drug’ in the market.
5. Intricacies of Bioequivalence: Following are some of the vital intricacies of bioequivalence:
(a) Bioequivalence may not prove to be a simple and straightforward phenomenon for a majority
of drug substances.
(b) A plethora of drugs are usually recognized to be quite notorious for showing the bioequiva-
lence features explicitly.
(c) Satisfactory bioequivalence properties could be seen with a host of dosage forms comprising
aspirin, tolbutamide, tetracycline and vitamins produced by different manufacturers.
(d) Bioequivalence-related problematic issues of ‘digoxin’ are indeed of great importance due to
its inherent narrow therapeutic index. Likewise, a host of other drugs essentially having narrow
therapeutic index also pose similar type of intricate bioequivalence problems.
Note
The above concept and ideology holds good only if various strict and mandatory laws stipulate
that all new drug products must be both safe and effi cacious in nature.
Note
The Ad Hoc Committee on Drug Product Selection of the American Pharmaceutical Association
published a List of Drugs which exhibit bioequivalence exclusively.
Therefore, based upon the above statement of facts, the ‘drugs’ have been judiciously categorized into
three following sections, namely:
∑ high-risk potential,
∑ moderate-risk potential and
∑ low-risk potential.
19
Generic Drugs: They broadly refer to a ‘chemically equivalent copy’ of a branded-drug product whose patent has expired.
Essentials of Biopharmaceutics and Pharmacokinetics
250
6. Important Defi nitions: It would be worthwhile to understand fully a few important terminologies
and defi nitions before proceeding deep into the various glaring aspects of the ‘bioequivalence study’:
∑ Drug Product (or Dosage Form): A drug product refers to a dosage form suitable for market-
ing and dispensing to patients, e.g., tablets, capsules, oral solutions, injectables etc., comprising
the active substance (or drug) either with or without the inactive ingredients (viz. excipients).
∑ Pharmaceutical Equivalents [Syn: Genetic Equivalent]: When a drug product that contains the
same active ingredients (S) and is found to be absolutely identical in
_ dosage form and
_ potency,
to ‘another drug product’, but may not be equal in pharmacological or therapeutic response by
virtue of the dosage-form effects.
Table 4.1 Selected drug substances with three different types of bioequivalence potentials
S. No. Low risk potential S. No. Intermediate risk potential S. No. High risk potential
1 Acetaminophen
(paracetomol)
1 Amphetamine 1. Aminophylline
2 Codeine 2 Ampicillin 2 Aspirin (in high doses)
3 Hydrochlorothiazide 3 Chloramphenicol 3 Bishydroxycoumarin
4 Ephedrine 4 Chlorpromazine 4 Digoxin
5 Isoniazid 5 Digitoxin 5 Phenytoin
6 Meprobamate 6 Erythromycin 6 para-Amino salicylic acid
7 Penicillin V 7 Griscofulvin 7 Prednisolone
8 Sulfi soxazole 8 Oxytetracycline 8 Prednisone
9 Penicillin G 9 Quinidine
10 Pentobarbital 10 Warfarin
Note
It may be understood clearly that the pharmaceutical equivalent does not necessarily mean
bioequivalence.
In reality, the ‘pharmaceutical equivalent’ may essentially consist of altogether different range of the
‘inactive ingredients’, for instance colour, fl avour, excipients and shape. Obviously, the observed
differences in three different drug product variants (see Table 4.1) made of a number of manufac-
turers may also give rise to distinct variance in the absorption pattern in vivo.
∑ Pharmaceutical Alternative: The pharmaceutical alternative refers to a drug product that
contains the same therapeutic moiety/potency, and is administered by the same route, but dif-
fers in the kind of salt, ester or dosage form.
Obviously, two dosage forms are regarded to be pharmaceutical alternatives if they comprise
the same drug molecule but in different chemical form, i.e., present in
Table 4.1 records a few selected ‘drugs’ belonging to each of the aforesaid categories:
Clinical Pharmacokinetics
251
_ different salt (viz. ferrous fumarate—ferrous gluconate; chloramphenicol succinate–
chloramphenicol palmitate) and
_ different dosage form or strength (tablets of 25, 50 and 100 mg).
∑ Bioequivalents: Two drug products are usually regarded to be bioequivalent, only if
_ they happen to be pharmaceutical equivalents or alternatives and
_ they exhibit the same bioavailability after being administered with the same molar dose.
Evidently, their overall effects in terms of their inherent safety and effi cacy shall remain the
same.
∑ Therapeutic Equivalent: The therapeutic equivalent refers to a chemical equivalent which
when administered at the same dosage level will defi nitely provide the same therapeutic
effect—as measured by the control of a specifi c symptom, sign or ailment.
Note
In a broader perspective, ‘bioequivalence’ is a widely accepted evidential concrete proof to ascer-
tain the therapeutic equivalence of two drug products.
∑ Essentially Similar Products: A drug product is regarded to be ‘essentially same’ to the
original product (i.e., the ‘Innovator Product’) provided it possesses the similar ‘qualitative’ and
‘quantitative’ composition in terms of the following aspects:
_ drug substance,
_ formulation type and
_ bioequivalence
7. Aims and Objectives of Bioavailability Studies: Following are the four cardinal aims and
objectives of bioavailability studies:
∑ Preliminary stages of development of an appropriate dosage form (drug product) for a new
drug entity.
∑ Estimation of related infl uence of such aspects as:
_ excipients,
_ patient-associated factors and
_ probable interaction with other drug substances upon the effi ciency of absorption ultimately.
∑ Critical development of ‘Never Formulations’ of the existing drug substances.
∑ Strict control of quality of a ‘dosage form’ specifi cally in the early stages of marketing so as to
establish exactly the infl uence of such factors as
_ processing modalities and
_ storage and stability on drug absorption process.
3.2. Bioequivalence Study Parameters
It has been duly proved that two products are pronounced to be ‘bioequivalent’ only when they explic-
itly demonstrate
∑ similar rate (speed) and
∑ degree of drug release pattern.
Essentials of Biopharmaceutics and Pharmacokinetics
252
Furthermore, the quantum of drug molecules released and also the rate (speed) at which the same are
released must be similar by all means. However, in the in vivo studies of two different drug products with
respect to their characteristic features, the following parameters need to be taken into consideration:
∑ Area Under the Curve (AUC): AUC designates the area under the plasma–drug concentration time
curve, and provides adequate information concerning the quantum of drug present in plasma, i.e., the
degree of release.
∑ C
max
: It represents the maximum plasma–drug concentration. However, C
max
partially depends upon
the rate of drug release from the drug product (i.e., the formulation).
∑ T
max
: It critically involves the actual time required to reach maximum plasma–drug concentration. T
max
necessarily dependent upon the rate of drug release from the dosage from (i.e., from the formulation).
∑ T
1/2
: It designates the plasma half-life of a drug. T
1/2
also provides the required information (S) per-
taining to the drug substance from the body.
Additional Parameters: There are, in fact, three additional parameters that are invariably studied in a
bioequivalence study profi le, namely:
∑ Normalized C
max
,
∑ Mean residence time (MRT),
∑ Plasma peak trough fl uctuation (%),
∑ Area under blood/plasma time–concentration curve (AUC),
∑ Mean absorption time (MAT),
∑ Plateau time (PT),
∑ Half-value duration (HVD),
∑ Time above the average concentration (T
above
C
avg
),
∑ Percentage swing (% S) and
∑ Area under curve fl uctuation (AUCF),
1. Normalized C
max
: C
max
, i.e., the maximum plasma–drug concentration (mcg mL
−1
) and t
max
, i.e.,
the maximum time interval (hrs) are known to exhibit highly signifi cant intra-subject incidence of
variability, and, therefore, it critically necessities the usage of the ‘normalized C
max
’ in certain typical
instances. However, the normalized C
max
may be calculated by means of the following expression:
Normalized
max
max
AUC
C
C =
(af )
where,
AUC is the area under the curve and
C
max
is the maximum plasma–drug concentration.
Several investigative studies have logically established that the ‘normalized C
max
’ invariably exhibits
relatively lesser ‘intra-subject incidence of variability’ vis-à-vis ‘C
max
’.
2. Mean Residence Time (MRT): The MRT gives a reasonably good idea with regard to the
time a drug molecule remains in the body before its elimination from the body. To calculate MRT
precisely, fi rst the critical ‘area under the moment curve (AUM C
0 − ∞
)’ is divided by ‘area under the
curve (AUC
0 − ∞
)’, as given under:
0–
0–
AUM
MRT =
AUC
C
∞
∞
(ag)
Clinical Pharmacokinetics
253
AUM C
0 − t
: It is usually calculated from the product of time and the concentration of drug
against the time and
AUM C
t
− •
: It is normally calculated by dividing the last plasma/blood-time concentration
product by the elimination rate constant (K
E
).
Therefore, we may have
AUM C
0 − ∞
= AUC
0 − t
+ AUM C
t − ∞
(ah)
Table 4.2 records the data of the product of time-concentration at different time intervals (hrs).
Calculate AUC from the values of the product of time concentration against the time (hrs). It
will yield the AUM C
0 − 24
. Now, dividing the last product of time concentration, i.e., 78 at 24th hr
by K
E
shall be given by AUM C
24 − ∞
. Thus, we may have
AUM C
0 − ∞
= AUM C
0 − 24
+ AUM C
24 − ∞
3. Plasma Peak Trough Fluctuation (%): In usual practice, the plasma trough fl uctuation (%)
parameter is largely employed in the study of bioequivalence for the sustained-release drug prod-
ucts exclusively. Importantly, the sustained-release formulations are designed in a manner so as
to maintain a steady-state plasma–drug concentration specifi cally meant for extended time peri-
ods. Evidently, the critical bioequivalence study of the ‘sustained-release drug products’ generally
involves an elaborative comparison with regard to the steady-state plasma–drug concentrations
duly accomplished from two altogether different dosage forms. Hence, in this particular instance,
one may have to take two additional parameters into consideration, namely:
∑ C
min
, i.e., the lowest plasma–drug concentration just prior to the next dose to be administered and
∑ PTF%, i.e., the plasma–drug concentration percentage change observed between the two dose
administered is duly calculated by the following equation:
max min
avg
PTF%
CC
C
−
=
(ai)
where, C
avg
is the average plasma–drug concentration during the closing duration.
Table 4.2 Product of time-concentration and time (hrs)
S. No. Time (hrs)
Product of time concentration (mcg mL
−1
)
10 0
21 2
32 11
43 20
54 31
66 64
79 69
812 45
924 78
Essentials of Biopharmaceutics and Pharmacokinetics
254
4. Area Under Blood/Plasma Time Concentration Curve (AUC): AUC refers to the pharmaco-
kinetic integral expression directly proportional to a specifi c amount of material undergoing a change.
AUC of blood levels vs. time is directly proportional to the actual quantum of drug absorbed from
a ‘single-dose over infi nite time’.
Example
Explicitly, AUC provides a measure of quantity of the drug present in the body at a particular duration.
Determination of AUC: The two most prevalent methods invariably employed to determine the AUC are
∑ Trapezoidal rule and
∑ Estimation of AUC from blood/plasma level equations,
which would be discussed briefl y in the following sections.
1. Trapezoidal Rule: The blood level time curve may be described by the help of a series of trap-
ezoids
20
which are eventually determined by each and every concentration time point. In fact, it is
possible to fi nd out the area of a trapezoid, which is equal to one-half the product of the sum of
the concentrations and the time difference.
Let us assume that the concentrations of a ‘drug’ X duly present in plasma at different time
intervals in a volunteer are as stated under:
S. No. Time (hrs)
Product of time concentration
(mcg mL
−1
)
10 0
21 4
32 7
43 13
54 18
66 14
79 9
812 6
9 24 0.5
(Adapted from: Garg KK, In: Pal TK, Ganesan M, eds. Bioavailability and Bioequivalence in Pharma-
ceutical Tec hnology, New Delhi, India: CBS-Publishers & Distributors Pvt. LTD, 2009.)
Based on the above data, one may calculate AUC by applying the ‘trapezoid rule’ as given below:
AUC
0 − 24
(mcg mL
−1
hr
−1
) = (0 + 4 × 1 – 1) + (4 + 7 × 2 – 1) + (7 + 13 × 3 – 2) + (13 + 18 × 4 – 3) + (13 + 18 × 4 – 3)
+ (18 + 14 × 6 – 4) + (14 + 9 × 9 – 6) + (9 + 6 × 12 – 9) + (6 + 0.5 × 24 – 12)/2
20
Trapezoid: It refers to a four-sided fi gure having two parallel sides and two divergent sides.
Clinical Pharmacokinetics
255
AUC
0 − 24
(mcg mL
−1
hr
−1
) = 4 + 11 + 20 + 31 + 64 + 69 + 45 + 78/2
AUC
0 − 24
(mcg mL
−1
hr
−1
) = 322/2 = 161
Now, AUC
24 − ∞
, i.e., the remaining area under the curve, can be easily calculated by dividing the
‘last plasma-level point’ by using the elimination rate constant (K
E
) under the assumption that the
aforesaid point is beyond the following two phases:
∑ absorptive phase and
∑ distributive phase
on the terminal slope of the plasma level curve.
Therefore, AUC
0 – ∞
= AU C
0 − 24
+ AU C
24 − ∞
2. Estimation of AUC from Blood/Plasma Level Equations: Thus, in a situation when the
blood/plasma level–time curve of a specifi c drug substance in a certain dose-size is obtainable duly,
the AUC may be calculated as per the following two relationships:
∑ Intravascular Route of Administration: we have,
()
11
0
Ed
AUC = mcg × mL × hr
×
D
KV
−−
−⋅∞
or
0
0
tt
AUC
CL
D
−⋅∞
−
=
where
D is the drug dose (mcg),
KE is the elimination rate constant,
V
d
is the apparent volume of distribution and
CL
t
0
− t
is the total clearance.
∑ Extravascular Route of Administration: we have
0
Ed
AUC
Df
KV
−∞
⋅
=
⋅
or
0
0
t-t
AUC
CL
Df
−∞
⋅
=
where f is the fraction of drug absorbed.
Based on AUC, it may be possible to arrive at the following two functionalities, namely:
∑ bioavailability ( f ) of a drug substance and
∑ relative bioavailability (RBA).
Thus, we have:
()
()
-1 -1
0-
-1 -1
0-
AUC ‘Oral’ mg mL hr IV mg
AUC ‘IV’ mg mL hr oral mg
D
f
D
∞
∞
⎡⎤
⋅
⎣⎦
=
⎡⎤
⋅
⎣⎦
()
()
-1 -1
0SD
-1 -1
0TD
AUC ‘Oral’ TD mg mL hr mg
RBA
AUC SD mg mL hr mg
D
D
−∞
−∞
⎡⎤
⋅
⎣⎦
=
⎡⎤
⋅
⎣⎦
Essentials of Biopharmaceutics and Pharmacokinetics
256
where
D is the dose of the ‘drug’,
TD is the test drug and
SD is the standard drug.
3. Mean Absorption Time (MAT): The mean absorption time (MAT) is normally calculated by
using the following formula:
MAT = MRT (Oral) MT (IV)⋅
4. Plateau Time (PT): The plateau time (PT) usually designates the time span of either one dosing
interval or one dosing cycle, e.g., 24 hrs in the course of which the observed serum/plasma–drug
concentration critically deviate from the maximum concentration by an amount less than a clini-
cally stipulated differences or percentage.
Importantly, in a particular instance related to the controlled-release theophylline dosage forms,
the observed PT represents the duration where the concentration exceeds 75% of the maximum
concentration. It may be adequately denoted by ‘T 75% C
max
’, as illustrated in Figure 4.9.
Various important aspects include
1. C
max
is attainable after 5 hrs from the administration of the drug at an observed value of
C
max
= 19.25 mcg mL
−1
.
2. C
min
is accomplished after 12 hrs from the administration of the drug at a recorded value of
C
min
= 5 mcg mL
−1
.
Explanation
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37+U
7LPH7DERYH&DYJ+U
+DOIYDOXH'XUDWLRQ+9'+U
6HUXP3ODVPD±'UXJ&RQFHQWUDWLRQ>PFJP/
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7LPH+U
Figure 4.9 Serum/plasma–drug concentration vs. time curve showing C
max
, C
min
, PT and HVD.
Clinical Pharmacokinetics
257
3. PT—the plateau time comes out to be 5.6 hrs.
4. C
avg
—the average concentration level of the drug in serum/plasma stands at 6.5 hrs.
5. HVD—the estimated half-value duration is found to be 9.3 hrs.
5. Half-Value Duration (HVD): The half-value duration (HVD) duly represents the time span of
one dosing-interval or one dosing-cycle of 24 hrs during which the serum/plasma–drug concentra-
tion level critically deviates by 50% from the maximum concentration (C
max
) as shown in Figure 4.9.
Note
In some specifi c instances, the HVD of certain drugs may almost correspond to the ‘plateau time’ (PT).
6. Time Above the Average Concentration (T
above
C
avg
): The time above the average concen-
tration (T
above
C
avg
) relates to time-span of one dosing cycle or one dosing interval 24 hrs during
which the serum/plasma–drug concentration almost stands above the average concentration (C
avg
)
of one dosing cycle or dosing interval, as depicted in Figure 4.9. In fact, C
avg
is duly calculated by
dividing the AUC of one dosing interval or dosing cycle by the dose time interval.
7. Percentage Swing (% S): In reality, ‘swing’ refers to the peak-trough concentration difference of
the drug substance in the course of one-dosing interval to the average concentration (C
avg
).
Thus, we may have,
()
max min
min
100 –
%S =
CC
C
8. Area Under Curve Fluctuation (AUCF): In true sense, AUCF is based upon the partial AUCs
over one-dosing interval. Therefore, AUCF represents the difference between AUC both
∑ above average range and
∑ below average range,
specifi cally extended up to AUC in the course of one-dosing interval. It may be expressed by the
following expression:
()()
avg avg
100 above – AUC below
AUCF % =
AUC
CC
General Remarks: On the basis of the above-stated ‘additional parameters’ expatiated from (a) through
( j ), we may conclude the following overall general remarks:
1. PT—the plateau time, T
above
C
avg
—the time above average concentration, and the plasma trough
fl uctuation (%) are solemnly regarded to be rate characteristic of the drug.
2. Percentage swing (% S) and the area under curve fl uctuation (AUCF) distinctly measure the degree
of fl uctuation of the ensuing serum/plasma–drug concentration at a predominantly steady state.
3. Bearing in mind the glaring fact that both ‘Fast-Releasing’ and ‘Conventional-Releasing’ drug
products do release drug at a steady state, there exists an appreciable degree of fl uctuations observed
generally in %S and AUCF.
Essentials of Biopharmaceutics and Pharmacokinetics
258
3.3. Bioequivalence Study Protocol
In a broader perspective, any elaborated ‘bioequivalence study’ is invariably geared by a well-planned
study protocol. Importantly, the bioequivalence study protocol must comprise the following essential
aspects, namely:
1. Title—it specifi cally includes
∑ Principal investigator or study director
∑ Nomenclature of project, protocol number and date of commencement.
2. Study Objective—it consists of major aspects pertaining to the engaged study objectives.
3. Study Design—it is the most critical aspect of the entire study undertaken, and consists of
∑ Design
∑ Dosage forms (or Drug Products)
_ Test product
_ Reference product
∑ Dosage regimen
∑ Sample collection schedule
∑ Housing of volunteers
∑ Fasting and meal schedule
∑ Analytical method selected
4. Study Population—it forms an important aspect as well:
∑ Subjects (or volunteers)
∑ Selection of subject:
_ Medical history of subject (S)
_ Physical check-up
_ Clinical laboratory tests
∑ Inclusion and exclusion criteria
∑ Limitations during investigative study
5. Clinical Methodologies—to provide valuable information:
∑ Drug and dosage administration profi le
∑ Biological sampling modes
∑ Handling of biological samples
6. Ethical Considerations—to cater for suffi cient preventive measures
∑ Institutional review board
∑ Informed consent of subject (S)
∑ Critical indications for withdrawal of subjects
Perhaps these critical fi ndings could be better explained due to the fact that these ‘dosage forms’
get absorbed rather rapidly when they are administered orally so as to cause rapid elimination
of drug via the fi rst-order kinetics ultimately leading to reasonably lower trough concentration.
Besides, it causes signifi cant fl uctuations in comparison to the corresponding sustained/control-
led release drug products, in which case the rate of absorption of drug substance may appear to
be much slower and extending over to a longer-duration, ultimately leading to a lower plasma/
serum peak concentration, and higher concentration producing less fl uctuations.
Explanation