BIOPHARMACEUTICS
All pharmaceuticals, from the generic analgesic tablet in the community pharmacy to
the state-of-the-art immunotherapy in specialized hospitals, undergo extensive
research and development prior to approval by the U.S. Food and Drug Administration
(FDA). The physicochemical characteristics of the active pharmaceutical ingredient (API,
or drug substance), the dosage form or the drug, and the route of administration are
critical determinants of the in-vivo performance, safety and efficacy of the drug
product. The properties of the drug and its dosage form are carefully engineered and
tested to produce a stable drug product that upon administration provides the desired
therapeutic response in the patient. Both the pharmacist and the pharmaceutical
scientist must understand these complex relationships to comprehend the proper use
and development of pharmaceuticals.
Biopharmaceutics is the science that examines this interrelationship of the
physicochemical properties of the drug, the dosage form in which the drug is given, and
the route of administration on the rate and extent of systemic drug absorption.
Thus, biopharmaceutics involves factors that influence
(1) the stability of the drug within the drug product,
(2) the release of the drug from the drug product,
(3) the rate of dissolution/release of the drug at the absorption site, and
(4) the systemic absorption of the drug. A general scheme describing this dynamic
relationship is described in
The study of biopharmaceutics is based on fundamental scientific principles and
experimental methodology.
Studies in biopharmaceutics use both in-vitro and in-vivo methods.
In-vitro methods are procedures employing test apparatus and equipment without
involving laboratory animals or humans.
In-vivo methods are more complex studies involving human subjects or laboratory
animals.
PHARMACOKINETICS
After a drug is released from its dosage form, the drug is absorbed into the
surrounding tissue, the body, or both.
The distribution through and elimination of the drug in the body varies for each
patient but can be characterized using mathematical models and statistics.
Pharmacokinetics is the science of the kinetics of drug absorption, distribution, and
elimination (ie, excretion and metabolism).
The description of drug distribution and elimination is often termed drug disposition
The study of pharmacokinetics involves both experimental and theoretical
approaches. The experimental aspect of pharmacokinetics involves the development
of biologic sampling techniques, analytical methods for the measurement of drugs
and metabolites, and procedures that facilitate data collection and manipulation. The
theoretical aspect of pharmacokinetics involves the development of pharmacokinetic
models that predict drug disposition after drug administration. The application of
statistics is an integral part of pharmacokinetic studies.
CLINICAL PHARMACOKINETICS
During the drug development process, large numbers of patients are tested to determine
optimum dosing regimens, which are then recommended by the manufacturer to produce
the desired pharmacologic response in the majority of the anticipated patient population.
However, intra- and interindividual variations will frequently result in either a subtherapeutic
(drug concentration below the MEC) or toxic response (drug concentrations above the
minimum toxic concentration, MTC), which may then require adjustment to the dosing
regimen. Clinical pharmacokinetics is the application of pharmacokinetic methods to drug
therapy. Clinical pharmacokinetics involves a multidisciplinary approach to individually
optimized dosing strategies based on the patient's disease state and patient-specific
considerations.
PHARMACODYNAMICS
Pharmacodynamics refers to the relationship between the drug concentration at the site
of action (receptor) and pharmacologic response, including biochemical and physiologic
effects that influence the interaction of drug with the receptor. The interaction of a drug
molecule with a receptor causes the initiation of a sequence of molecular events
resulting in a pharmacologic or toxic response. Pharmacokinetic-pharmacodynamic
models are constructed to relate plasma drug level to drug concentration in the site of
action and establish the intensity and time course of the drug. Pharmacodynamics and
pharmacokinetic-pharmacodynamic models are discussed more fully in.
TOXICOKINETICS AND CLINICAL TOXICOLOGY
Toxicokinetics is the application of pharmacokinetic principles to the design, conduct,
and interpretation of drug safety evaluation studies and in validating dose-related
exposure in animals. Toxicokinetic data aids in the interpretation of toxicologic findings
in animals and extrapolation of the resulting data to humans. Toxicokinetic
studies are performed in animals during preclinical drug development and may
continue after the drug has been tested in clinical trials.
Clinical toxicology is the study of adverse effects of drugs and toxic substances (poisons) in
the body.
MEASUREMENT OF DRUG CONCENTRATIONS
Because drug concentrations are an important element in determining individual or
population pharmacokinetics, drug concentrations are measured in biologic samples,
such as milk, saliva, plasma, and urine.
Sensitive, accurate, and precise analytical methods are available for the direct
measurement of drugs in biologic matrices.
Such measurements are generally validated so that accurate information is
generated for pharmacokinetic and clinical monitoring. In general, chromatographic
methods are most frequently employed for drug concentration measurement,
because chromatography separates the drug from other related materials that may
cause assay interference.
Sampling of Biologic Specimens
Only a few biologic specimens may be obtained safely from the patient to gain
information as to the drug concentration in the body. Invasive methods include
sampling blood, spinal fluid, synovial fluid, tissue biopsy, or any biologic material that
requires parenteral or surgical intervention in the patient. In contrast, noninvasive
methods include sampling of urine, saliva, feces, expired air, or any biologic material
that can be obtained without parenteral or surgical intervention. The measurement of
drug and metabolite concentration in each of these biologic materials yields important
information, such as the amount of drug retained in, or transported into, that region of
the tissue or fluid, the likely pharmacologic or toxicologic outcome of drug dosing, and
drug metabolite formation or transport.
Plasma Level Time Curve
The plasma level time curve is generated by obtaining the drug concentration in plasma
samples taken at various time intervals after a drug product is administered. The
concentration of drug in each plasma sample is plotted on rectangular-coordinate graph
paper against the corresponding time at which the plasma sample was removed. As the
drug reaches the general (systemic) circulation, plasma drug concentrations will rise up to a
maximum. Usually, absorption of a drug is more rapid than elimination. As the drug is
being absorbed into the systemic circulation, the drug is distributed to all the tissues in the
body and is also simultaneously being eliminated. Elimination of a drug can proceed by
excretion, biotransformation, or a combination of both.
The relationship of the drug level time curve and various pharmacologic parameters for the
drug is shown in .
MEC and MTC represent the minimum effective concentration and minimum toxic
concentration of drug, respectively.
For some drugs, such as those acting on the autonomic nervous system, it is useful to know
the concentration of drug that will just barely produce a pharmacologic effect (ie, MEC).
Assuming the drug concentration in the plasma is in equilibrium with the tissues, the MEC
reflects the minimum concentration of drug needed at the receptors to produce the desired
pharmacologic effect.
Similarly, the MTC represents the drug concentration needed to just barely produce a toxic
effect.
The onset time corresponds to the time required for the drug to reach the MEC.
The intensity of the pharmacologic effect is proportional to the number of drug receptors
occupied, which is reflected in the observation that higher plasma drug concentrations
produce a greater pharmacologic response, up to a maximum.
The duration of drug action is the difference between the onset time and the time for the
drug to decline back to the MEC.
In contrast, the pharmacokineticist can also describe the plasma level time curve in terms
of such pharmacokinetic terms as peak plasma level, time for peak plasma level , and area
under the curve , or AUC.
The time of peak plasma level is the time of maximum drug concentration in the plasma
and is a rough marker of average rate of drug absorption.
The peak plasma level or maximum drug concentration is related to the dose, the rate
constant for absorption, and the elimination constant of the drug. The AUC is related to
the amount of drug absorbed systemically.
Drug Concentrations in Tissues
Tissue biopsies are occasionally removed for diagnostic purposes, such as the verification of
a malignancy. Usually, only a small sample of tissue is removed, making drug concentration
measurement difficult. Drug concentrations in tissue biopsies may not reflect drug
concentration in other tissues nor the drug concentration in all parts of the tissue from
which the biopsy material was removed.
For example, if the tissue biopsy was for the diagnosis of a tumor within the tissue, the
blood flow to the tumor cells may not be the same as the blood flow to other cells in this
tissue.
In fact, for many tissues, blood flow to one part of the tissues need not be the same as
the blood flow to another part of the same tissue. The measurement of the drug
concentration in tissue biopsy material may be used to ascertain if the drug reached the
tissues and reached the proper concentration within the tissue.
Drug Concentrations in Urine and Feces
Measurement of drug in urine is an indirect method to ascertain the bioavailability of a drug.
The rate and extent of drug excreted in the urine reflects the rate and extent of systemic
drug absorption. The use of urinary drug excretion measurements to establish various
pharmacokinetic parameters is discussed in.
Measurement of drug in feces may reflect drug that has not been absorbed after an oral
dose or may reflect drug that has been expelled by biliary secretion after systemic
absorption.
Fecal drug excretion is often performed in mass balance studies, in which the investigator
attempts to account for the entire dose given to the patient.
For a mass balance study, both urine and feces are collected and their drug content
measured. For certain solid oral dosage forms that do not dissolve in the gastrointestinal
tract but slowly leach out drug, fecal collection is performed to recover the dosage form.
The undissolved dosage form is then assayed for residual drug.
Drug Concentrations in Saliva
Saliva drug concentrations have been reviewed for many drugs for therapeutic drug
monitoring . Because only free drug diffuses into the saliva, saliva drug levels tend to
approximate free drug rather than total plasma drug concentration. The saliva/plasma
drug concentration ratio is less than 1 for many drugs. The saliva/plasma drug
concentration ratio is mostly influenced by the pKa of the drug and the pH of the saliva.
Weak acid drugs and weak base drugs with pKa significantly different than pH 7.4
(plasma pH) generally have better correlation to plasma drug levels.
The saliva drug concentrations taken after equilibrium with the plasma drug
concentration generally provide more stable indication of drug levels in the body.
The use of salivary drug concentrations as a therapeutic indicator should be used with
caution and preferably as a secondary indicator.
Significance of Measuring Plasma Drug Concentrations
The intensity of the pharmacologic or toxic effect of a drug is often related to the
concentration of the drug at the receptor site, usually located in the tissue cells.
Because most of the tissue cells are richly perfused with tissue fluids or
plasma, measuring the plasma drug level is a responsive method of
monitoring the course of therapy.
Clinically, individual variations in the pharmacokinetics of drugs are quite common.
1-Monitoring the concentration of drugs in the blood or plasma ascertains that the
calculated dose actually delivers the plasma level required for therapeutic effect. With
some drugs, receptor expression and/or sensitivity in individuals varies, so monitoring
of plasma levels is needed to distinguish the patient who is receiving too much of a drug
from the patient who is supersensitive to the drug.
2-Moreover, the patient's physiologic functions may be affected by disease, nutrition,
environment, concurrent drug therapy, and other factors. Pharmacokinetic models allow
more accurate interpretation of the relationship between plasma drug levels and
pharmacologic response. In the absence of pharmacokinetic information, plasma drug
levels are relatively useless for dosage.
3-Monitoring of plasma drug concentrations allows for the adjustment of the drug
dosage in order to individualize and optimize therapeutic drug regimens. In the
presence of alteration in physiologic functions due to disease, monitoring plasma drug
concentrations may provide a guide to the progress of the disease state and enable the
investigator to modify the drug dosage accordingly. Clinically, sound medical judgment
and observation are most important. Therapeutic decisions should not be based solely
on plasma drug concentrations.
In many cases, the pharmacodynamic response to the drug may be more important
to measure than just the plasma drug concentration. For example, the
electrophysiology of the heart, including an electrocardiogram (ECG), is important to assess in
patients medicated with cardiotonic drugs such as digoxin. For an anticoagulant drug, such as
dicumarol, prothrombin clotting time may indicate whether proper dosage was achieved.
Most diabetic patients taking insulin will monitor their own blood or urine glucose levels
For drugs that act irreversibly at the receptor site, plasma drug concentrations may not
accurately predict pharmacodynamic response. Drugs used in cancer chemotherapy often
interfere with nucleic acid or protein biosynthesis to destroy tumor cells. For these drugs, the
plasma drug concentration does not relate directly to the pharmacodynamic response. In this
case, other pathophysiologic parameters and side effects are monitored in the patient to
prevent adverse toxicity.
