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Clinical Pharmacokinetics
239
2. Blood Flow: Likewise, lesser is the blood fl ow in the body, lesser shall be the observed dialyzability
of the drug substance administered.
3. Dialyzate Flow: The lesser is the dialyzate fl ow rate, lesser will be the dializability of a drug
administered in the body.
4. Molecular Dimension: The greater the molecular dimension, lesser would be the haemodiaza-
bility of a drug administered.
5. Volume of Distribution (V
d
) or Protein Binding: The greater the volume of distribution (V
d
)
or more the drug undergoes protein-binding, lesser shall be the observed dializability profi le of a
drug substance.
Calculation for Fractionally Removed Drug by Haemodialysis: The fraction ( f ) of the drug
being removed by dialysis (or haemodialysis) may be calculated as follows:
()
0.693
1/2 1/2
1/2
1/2
t(t)
= 1 e /(t )
t
T
d
fd
−
⎡⎤
−
−
⎢⎥
⎣⎦
(y)
where,
f is the fraction of ‘drug’ being removed by dialysis,
t
1/2
is the plasma half-life of ‘drug’ without dialysis,
(t
1/2
)d is the plasma half-life of ‘drug’ while dialysis is on and
T is the duration of dialysis.
Obviously, to maintain (and also sustain) the therapeutic concentration with regard to the quantum
of drug removed from the body by dialysis, it must be replaced by the same amount at the ‘end of the
dialysis’, and this can be calculated as follows:
X
d
= f ⋅ C ⋅ V
d
(z)
where,
X
d
is the amount of drug being removed from the body by haemodialysis,
f is the fraction of ‘drug’ removed by dialysis,
C is the pre-dialysis of plasma–drug concentration and
V
d
is the apparent volume of distribution.
Note
1. Peritoneal Dialysis: It refers to the dialysis pertaining to the per itoneum (i.e., the serous mem-
brane lining the walls of the abdominal and pelvic cavities), and resembles closely to ‘haemodi-
alysis’. In this instance, the peritoneal membrane is being employed; whereas in haemodialysis,
the synthetic membrane is used. Irrespective of the underlying fact that the peritoneal
membrane happens to be much more permeable, the ‘peritoneal dialysis’ appears to be criti-
cally less effective in comparison to ‘haemodialysis’. Perhaps the most plausible explanation
for this anomaly being that ‘lipophilicity’ is essentially required to a certain extent for ena-
bling the process of dialysis by the peritoneal membrane.
2. Haemoperfusion Method: An almost identical methodology, the ‘haemoperfusion
method’ is invariably carried out in the critical removal of a drug substance in a specifi c
instance of ‘drug overdose’.
Essentials of Biopharmaceutics and Pharmacokinetics
240
The phenomenon of haemoperfusion refers to the passing of large volumes of blood over an extra-
corporeal adsorbent substance (i.e., a substance occurring outside the human body) so as to remove the
toxic products.
Drug Dosing in Elderly Patients In usual practice, the drug dosing level must be reduced appreciably
in the elderly patients due to the signifi cant overall decline in
∑ body metabolism and
∑ general functionality.
It has been duly established that the following two aspects, such as:
∑ decrease in ‘lean body mass’ and
∑ increase in ‘body fat’,
invariably come into play even up to 100% in elderly patients vis-à-vis young adults. Following is a com-
parison between the drug dosing profi le in elderly and young adults:
S. No. Elderly patients Young patients
1 Higher-peak alcohol levels are observed due to
smaller volume of total body water.
Normal peak alcohol levels are observed.
2 Apparent volume of distribution (V
d
) for a
water-soluble drug (viz. paracetamol) may get
reduced, and that of a lipid-soluble drug (viz.
diazepam) may get increased.
V
d
has practically no effect either for water-soluble
or lipid-soluble drug.
3 Age-related alterations in both hepatic and renal
functionalities signifi cantly change the overall
clearance of drugs [CL
R
and CL
H
].
No such changes are usually observed.
4 Since there is a progressive decline in the renal
function, the actual dosage regimen of drug
substance which are excreted unchanged in
urine largely must be minimized signifi cantly.
Not applicable at all.
Patient’s Maintenance Dose with Same C
ss.av
: The evolution of a generalized equation which
allows proper calculation of the maintenance dose for a patient of any age (with neonates and infants as
exceptions) with a view to obtain same ‘C
ss.av
’ is given by the following expression:
(wt. in kg) 0.7 (140 age in years)
Patient’s maintenance dose adult dose
1660
−
=×
(aa)
Drug Dosing in Hepatic Disease In a broader perspective, disease states do give rise to major varia-
tions in the observed ‘drug response’. Amazingly, the two well-known bioactive processes,
∑ pharmacokinetics and
∑ pharmacodynamics,
pertaining to several drug substances are critically changed due to various disease conditions, except than
the one that is under treatment.
Clinical Pharmacokinetics
241
It has been amply substantiated that the observed infl uence of the prevailing hepatic disorder upon
∑ drug availability and
∑ drug disposition
appears to be absolutely unpredictable perhaps by virtue of an array of such ‘effects’ which is produced
by an impaired liver (or liver ailments) as follows:
∑ reduced drug-metabolizing enzymes,
∑ drug-protein binding and
∑ ultimate hepatic blood fl ow.
Therefore, it becomes quite necessary to establish a correlation between the following two critical
aspects, such as:
∑ changed drug pharmacokinetics and
∑ observed hepatic function,
and this turns out to become a rather diffi cult task.
In reality, there are a good number of different pathways which a ‘drug’ may follow for its ultimate
ensuing metabolism, and, obviously, each of them gets affected to an altogether different level in
the particular instance of a hepatic disease. In usual practice, the physician normally should mini-
mize the drug-dosage level in such patients having an observed ‘hepatic dysfunction’ record, based
upon the following two criteria:
∑ reduced hepatic clearance and
∑ increased drug availability.
Example
Drug Dosing in Renal Disease The following two important aspects may be observed in patients
having a history of ‘renal failure’, namely:
∑ increased plasma half-life (>>1 t
1/2
) of a drug and
∑ decreased renal clearance [CL
R
],
i.e., the ‘drug’ gets excreted mostly via excretion. Evidently, in such a situation, the drug-dosing adjust-
ment must take care of the following two critical requirements of a patient with ‘renal failure’ or ‘renal
impairment’ profi les:
∑ renal functional ability and
∑ fraction of unchanged drug excreted via wine.
However, one such method termed as ‘active tubular secretion (ATS)’ has been discussed under A.4
in Part IV.
Based on both intensive and extensive ‘clinical pharmacokinetics’ studies have actually put forward
two additional techniques:
∑ Dose adjustment upon total body clearance (TBC) and
∑ Dose adjustment upon elimination rate constant and/or plasma half-life,
Essentials of Biopharmaceutics and Pharmacokinetics
242
which are discussed separately in the following sections.
1. Dose Adjustment upon Total Body Clearance (TBC):
Let us write Equation (f ) as follows:
0
ss.av
R
CL
FX
C
⋅
=
⋅τ
Now, the above equation may be re-written as follows:
C
ss.av
=
F
•
R
1
CL
•
0
X
⎡⎤
⎢⎥
τ
⎣⎦
↑ ↑ ↑ ↑
Maintained Presumed Reduced due to ‘Adjustment’
as ‘Normal’ to be ‘Constant’ ‘Disease State’ Required Urgently
Now, in a particular renal-failure patient, if one considers the above values as CL
R1
, X
o1
and τ
1
,
respectively,
14
one may write the above equation for the dose-adjustment upon total body clear-
ance (TBC) designated as follows
01
ss.av
R1 1
CL
X
C =
⋅τ
(ab)
Rearranging Equation (ab) with respect to drug-dose and drug-dose interval after due adjustment,
we may have the following equation:
01
R1 ss av
1
CL C
X
⋅
=⋅
τ
(ac)
It is, however, appropriate to state that Equation (ac) helps a lot in the critical adjustment of the
dosage regimen by affecting
∑ reduction in drug-dosage amount,
∑ enhancement in drug-dosing interval and
∑ a thoughtful combination of both.
2. Dose Adjustment upon Elimination Rate Constant and/or Plasma Half-Life:
Let us write Equation (g) as follows:
01/2
ss.av
d
1.44 tFX
C
V
⋅⋅
=
τ
The above equation may be rewritten as follows:
ss.av
C
d
1.44F
V
•
1/2
t⋅
•
0
X
⎡⎤
⎢⎥
τ
⎣⎦
↑↑ ↑ ↑
Maintained Presumed Increased due to ‘Adjustment’
as ‘Normal’ to be ‘Constant’ ‘Disease State’ Required Urgently
14
F is presumed to be constant.
=
Clinical Pharmacokinetics
243
In case, one may assign the values t
1/2
′, X
0
′ and τ′ representing the specifi c instance for a typical
renal-failure patient, we may have the following modifi ed version of the above equation as:
1/2 0
ss.av
t
X
C
′′
⋅
=
′
τ
(ad)
Rearranging Equation(ad) with regard to drug-dose and drug-dose interval after due adjustment,
one may arrive at the following equation:
0ss.av
1/2
t
XC
′
=
′′
τ
(ae)
Conclusive Remarks: These essentially include:
(a) The causation of a prolonged plasma half-life (t
1/2
) of a drug substance is mainly due to the signifi -
cant lowering of the renal-function activity, and the actual time taken to obtain the desired plateau:
∑ usually takes longer time and
∑ relates to extent of renal dysfunction.
(b) Interestingly, these patients are invariably recommended with an appropriate ‘loading dose’.
2.3.3. Individualization: Clinical Experience and Optimization Based upon
Plasma–Drug Concentration (C)
Preamble A critical survey of literature has revealed that there are quite a few glaring examples of
well-controlled prospective studies in order to illustrate that the individualization of
∑ initial drug-dosing regimens and
∑ monitoring of plasma–drug concentrations (C ),
so as to optimize the drug-dosage levels do result in a much better and improved drug therapy.
Nevertheless, if this type of evidences were a mandatory requirement, the following surgical procedures
might not be even available as to date:
∑ cardiac bypass surgery (CBS),
∑ liver transplants (LTs) and
∑ several other clinical procedures.
Obviously, in the specifi c absence of the so-called controlled prospective studies, the most values of:
∑ individualization and
∑ optimization
concerned with certain drug therapies should be based absolutely on ‘clinical experience’.
Anti-Arrhythmic Drugs: A majority of anti-arrhythmic drugs exhibit a narrow therapeutic win-
dow, thereby making room for an extremely careful titration of dosage regimen.
Woosley (1988)
15
critically observed that the plasma concentration monitoring with respect to the
anti-arrhythmic agents is quite valuable. However, it is either overemphasized or misused in the process of
15
Woosley RL: Am. J. Cardiol., 62: 9H, 1988.
Essentials of Biopharmaceutics and Pharmacokinetics
244
decision making. He also pointed out categorically that there should be a sound, accurate and dependable
relationship occurring between
∑ plasma–drug concentration and
∑ drug action,
i.e., a relationship regarded to be much more closer than the one existing between drug dosage and
drug action.
1. Quinidine: It is found to be useful for prophylaxis and critical treatment of atrial as well as ven-
tricular arrhythmias.
Important Points These essentially comprise
∑ Nearly 80% of an IV dose of quinidine gets metabolized in the liver; and it shows a plasma half-life
(t
1/2
) ranging between 6 and 7 hrs.
∑ Maintenance doses of quinidine may essentially be minimized by one-third to one-half in patients
having a history of cardiac heart failure (CHF)
16
(Ueda and Dzindzio, 1981).
∑ Usual/normal dosages of quinidine when administered to patients on such enzyme-inducing drugs
as phenobarbital, phenytoin and rifampin, one may observe low- and sub-therapeutic blood levels. It
necessitates, therefore, a higher than the usual dosages of quinidine in a patient.
Note
Quinidine being basic in nature and mostly bound to α-1-acid glycoprotein (AAG), its concen-
tration could vary largely. In this manner, the ‘free-drug concentration’ rather than the ‘total-drug
concentration’ may be found to be more intimately related to the ultimate pharmacologic effect.
2. Lidocaine: It is considered to be the drug of choice as an anti-arrhythmic agent for
∑ short-term management of ventricular arrhythmias—when administered via IV route,
∑ acute myocardial infarction (MI)—given IV and
∑ used prophylactically soon after myocardial infarction either to minimize or prevent the chances
of primary fi brillation or tachycardia.
Individualized Lidocaine Infusion Rates: The lidocaine infusion rates may also be individualized
which is solely based upon the population data duly obtained from the patients with different extent of
heart failure. Lopez et al. (1982)
17
successfully compared the plasma-lidocaine levels in
∑ a ‘control group’ and
∑ an ‘experimental group’,
who eventually received an ‘adjusted lidocaine regimen’ entirely based upon whether the patient had a
heart failure or no heart failure.
Control Group Patients: They were administered with a dose profi le having a usual conventional
approach, i.e., being administered with an infusion at the rate of 1–4 mg min
−1
entirely based on a
clinical judgment.
16
Ueda CT and Dzindzio BS: J. Clin. Pharmacol., 11: 571, 1981.
17
Lopez LM et al.: Ther. Drug Monit., 4: 271, 1982.
Clinical Pharmacokinetics
245
Experimental Group Patients: These patients having ‘no heart failure’ [i.e., Class I] duly received
lidocaine 12–35 mcg min
−1
kg
−1
body weight.
The results obtained from control group and experimental group patients are depicted in Figure 4.8.
Vertical Bars: Represents mean ± 1 ‘Standard Deviation’ for Control & Experimental Groups.
Interestingly, the above cited individualized lidocaine infusion rates approach has certain meritorious
advantage for
∑ certain particular patients remarkable and
∑ even extendable to some patients having Class III or IV heart failures.
2.4. Drug Monitoring and Drug Therapy
2.4.1. Preamble
Ideally, the rationale concept in ‘drug therapy’ essentially needs the individualization of the drug-dosage
regimen based on an individual patient. Therefore, ‘monitoring of drug therapy’ predominantly involves
the critical evaluation of drug response in a specifi c individual at the drug-dosage regimen recommended.
2.4.2. Therapeutic Endpoint
In reality, the most articulated management of the drug-dosage regimen essentially involves an explicit
clinical response invariably termed as the therapeutic endpoint. Nevertheless, the close and effective
monitoring of the ensuing therapeutic endpoint appears to be very simple and easy for several drug
substances, such as:
∑ Anti-hypertensives, viz. Atenolol, Propranolol,
∑ Oral Hypoglycaemics, viz. Tolbutamide, Glyburide, Glipizide.
&RQWURO
*URXS
([SHULPHQWDO
*URXS
7KHUDSHXWLF5DQJH
/LGRFDLQH&RQFÂ >PJ/
±
@
Figure 4.8 Plasma lidocaine concentrations: in control group-dosing based on clinical judgement; and experimental
group-received an adjusted lidocaine dosage regimen: based on the presence/absence of heart failure.
(Adapted from: Lopez LM et al. Themp. Drug Monit., 4, 27, 1982.)
Essentials of Biopharmaceutics and Pharmacokinetics
246
∑ Anti-anginal Drugs, viz. Nifedipine, Verapamil, Dilitazepam.
∑ Analgesics, viz. Aspirin, Sulindac, Ketoprofen, Piroxicam.
∑ Anti-coagulants, viz. Heparin, Lepirudin, Danaparoid.
∑ Anti-hyperlipedemics, viz. Lovastatin, Gemfi broal, Colestipol, Ezetimibe.
2.4.3. Toxic Endpoint
There are a host of drugs for which the observed ‘therapeutic endpoint’ never remains explicitly clear;
and, therefore, the respective toxic concentrations are usually found to be just a little more than the cor-
responding therapeutic concentrations. Thus, for such specifi c drugs, the ‘toxic endpoint’ is duly consid-
ered for the intended therapeutic regimens, for instance, the dryness of mouth in response to treatment
with ‘atropine’ (used as an anti-spasmodic agent).
2.4.4. Importance of Monitoring Drug Therapy
These essentially include:
1. It can be accomplished by closely monitoring the plasma–drug concentrations (i.e., pharmacoki-
netic monitoring). However, this particular approach is extremely benefi cial when
∑ ‘therapeutic point’ is either absent or possesses no defi nite value and
∑ probabilities pertaining to ‘clinical failures’ are signifi cantly high due to either pharmacokinetic
variabilities or unpredictable absorption.
2. It is absolutely useful in deciding the ‘drug-dosage regimen’ in the critical presence of either renal
or hepatic insuffi ciency.
3. It may be understood clearly that the phenomenon of monitoring drug therapy must be regarded
just as an ‘aid’, and not as an ‘alternative substitute’ for the careful clinical observations in the man-
agement of drug therapy.
2.4.5. Variants in Drug Monitoring and Drug Therapy
There are three well-known variants in drug-monitoring and drug-therapy, namely:
∑ therapeutic monitoring,
∑ pharmacodynamic monitoring and
∑ pharmacokinetic monitoring,
which will be discussed briefl y in the following sections.
Therapeutic Monitoring Therapeutic monitoring approach refers to the management plan that
involves rigorous monitoring of the intensity as well as incidence of the two most important effects:
∑ therapeutic effects and
∑ undesired adverse effects.
Sublingual Glyceryl Trinitrate Patches relates to the critical prevention of a pre-empted attacks of
angina or shortening of duration of pain when attack occurs actually.
Example
Clinical Pharmacokinetics
247
Pharmacodynamic Monitoring There are some typical instances wherein the ensuing pharmacologic
activity profi les of a particular drug substance may be measured with a reasonable precision, and subse-
quently, employed as a good guide to the prevailing therapeutic phenomenon. Nevertheless, the ultimate
observed response could possibly correlate or may not do so with respect to the therapeutic effect.
∑ Insulin—its ability to lower the blood-glucose level;
∑ Propranolol, Atenolol—their ability to reduce blood-pressures;
∑ Ferrous Sulphate, Ferrous Glucoate (Hematinics)—their ability to cause enhancement of hae-
moglobin levels in the circulating blood.
Examples
Pharmacokinetic Monitoring The typical approach that essentially engages in monitoring the plasma–
drug concentration very much within a targeted drug concentration range is invariably termed as the
target concentration strategy. A further extension based upon the underlying principle that the ‘free drug’ is
strategically located at the site of action remains in perfect equilibrium with the quantum of drug substance
duly present in plasma. However, the above strategy is specifi cally useful in the following three instances:
∑ First, when the ‘therapeutic endpoints’ are rather diffi cult to expatiate or afford to lack signifi cantly:
Phenytoin—its ability to control and management of epileptic seizures.
Example
∑ Second, when the major aim and objective remains to maintain the overall therapeutic effect so as
to accomplish the ‘optimized usage of the drug’ and
∑ Third, when the chances of the therapeutic failure appears to be pretty high vis-à-vis with drugs with
markedly predominant characteristics, such as:
_ low therapeutic indices,
_ erratic absorption patter and
_ appreciable pharmacokinetic variance.
18
In short, it may be summed up that the successful applicability of the pharmacokinetic monitoring
requires prominently a complete knowledge related to the pharmacokinetic conditions of the drug
entity, namely:
∑ Circumstances under which these conditionalities are prone to be changed, and to the extent these
may be altered,
∑ Usage of a sensitive, accurate and specifi c analytic procedure to be adopted for the estimation of the
drug concentration.
Typical examples of drug substances being monitored pharmacokinetically are
∑ Digoxin
∑ Gentamycin
∑ Phenytoin
∑ Theophylline
Examples
18
That is, when the drug is employed in multiple-drug therapy mode.
Essentials of Biopharmaceutics and Pharmacokinetics
248
3. Single Dose Bioequivalence Study: Design and Relevant Statistics
3.1. Preamble
Bioequivalence refers to the specifi c property of having the same biological effects of that to which a
drug product was compared.
Bioavailability is defi ned as ‘the rate and degree of absorption of a drug from a drug product (dosage
form) into the inner compartments of the body.’
In true sense, an elaborate study of biopharmaceutics provides substantial evidential proof that the
following two vital aspects, namely:
∑ method of manufacture and
∑ ultimate formulation of a drug product,
are solely responsible for the marked bioavailability of the drug.
1. Variants in Bioavailability Studies: The bioavailability studies are of two types:
Type-1—It essentially involves a logical and precise assessment related to the bioavailability of a
new drug product (dosage form). In other words, the respective pharmacokinetic parameters fol-
lowing various routes of administration of the new drug entity are duly achieved, and employed
subsequently in the meticulous development of an optimized dosage regimen. It ultimately enables
the appropriate formulation of a ‘new drug’ meant for a pre-determined intended route of admin-
istration, and assessment of its bioavailability.
Type-2—This particular type of bioavailability study critically causes to participate the eventual
comparison of
∑ a ‘test formulation’ and
∑ a ‘reference standard drug product’,
which enjoys the reputation of a proven safety and effi cacy. Interestingly, this highly specifi c inves-
tigative studies are usually termed as the ‘bioequivalence studies’.
2. Switchability: When two drug products are regarded to be absolutely bioequivalent to each
other, it obviously suggests that the delicate relationship occurring between ‘drug-concentra-
tion’ and ‘time-profi les’ happen to be so close and similar that they fail to exhibit any sort of
differences in their
∑ therapeutic effects and
∑ adverse effects.
Therefore, ‘switchability’ prevailing among the various marketed dosage forms is indeed a matter
of great concern, i.e., a patient must enjoy the liberty and freedom to exchange the drug product
with another only if they are bioequivalent to one another.
Note
Importantly, the above strategy appears to be very useful in proceeding with an individualized
therapy in such patients having either a hepatic or renal impairment which critically necessitates
the initiation of the dose adjustments.