Pharmacokinetics v Pharmacodynamics

INTRODUCTION:
The scope of this article is to introduce the concepts of pharmacokinetics (PK) and
pharmacodynamics (PD), give a brief overview of how they are used in early drug
development and potential uses in the clinical setting. Both are very complex areas
of research and are scientific specialisms in there own right. Regulatory bodies, e.g.
EMEA or FDA, issue guidelines relating to PK and PD studies that need taken into
account when designing a clinical study program.
PHARMACOKINETICS:

What is it?

The human body is an incredibly complex organism, in which biological,

physiological and biochemical processes have influence in the movement and
action of drugs around the body. For the purposes of research, the specifics of
these bodily processes are grouped together and commonly referred to as:

! Absorption: the processes of getting drug into the body (NOTE not necessarily
the systemic circulation. For intravenous dosing there is no absorption process and
direct delivery in the systemic circulation means that 100% of the drug is available)
! Distribution: the processes of distribution of the drug into the tissues
! Metabolism: the processes of changing the drug into other molecules i.e.
breakdown of the parent drug into metabolites
! Excretion: the processes that remove drug and associated metabolites from the
body

Together these are referred to as “ADME” and in humans will be dependent on

! the genetic make-up, age and gender of the human body
! influences of the disease state e.g. liver or kidney disease reduces metabolism
and excretion therefore increasing drug availability
! the different biological, physiological and biochemical impacts of the drug
molecule

The action of a drug is dependent on getting enough active drug product

(concentration) to the receptor sites in an timely manner (rate) to influence
biochemical functioning of the body system in question.
Pharmacokinetics (PK) is the application of mathematical calculation and
modelling techniques to the time course of Absorption, Distribution, Metabolism,
and Excretion of drugs in the body. PK is primarily concerned with the analysis of
concentration and rate of drug availability to the required receptor site.

It is important to note that pharmacokinetic analysis is not usually limited to the

parent drug molecule itself, but also identified metabolites, whether active or
inactive.

How is it measured?
The volume of information gathered about drug concentrations in various body
tissues, especially at the receptor sites, is extremely important in the safe and
appropriate development of the drug molecule candidate. It is not usually possible
to measure specific drug concentration at receptor sites and so measuring the
concentration of drug in plasma and assuming that the site of action is in rapid
equilibrium with the plasma is a more accepted method for monitoring
pharmacokinetics. There is therefore a direct link between PK and PD because of
this mechanism.
The determination of an appropriate blood-sampling schedule and assay method is
critical to the success of any PK program. Many factors will determine suitability of
sampling times and procedures; however, there are some common issues:

! Drug type: in vitro and animal studies will indicate potential sampling profile
and metabolites but are by no means definitive. Different classes of drug may
display different characteristics in different body systems etc.
! Drug formulation: different manufacturing techniques, active ingredients,
excipients or storage conditions could affect the physical or chemical structure of
the drug which in turn can have knock-on effects on ADME e.g. oral liquids and
suspensions give more rapid absorption and thus a quicker onset of action or
sustained/modified release preparations provide a sustained action form once
daily dosing.
! Route of administration: oral, intravenous, sublingual etc will effect how you
set up a profiling blood draw schedule as first pass metabolism, speed of
absorption etc will be altered.
! Single dose or steady state dosing: what is the primary objective? Are you
looking at a single ADME cycle or peak concentrations, clearance rates, potential
accumulation etc.
! What biological matrix the drug is in: plasma, serum, whole blood etc.
! Plasma processing and storage post sampling: the drug under investigation
and stability in blood/plasma/serum will determine processing of the
plasma/serum. Proper storage vials should be selected as drug may adhere to
some plastics, react with rubber seals etc, giving inaccurate results after analysis.
! Validated assay method: the procedures used to analyze the plasma
samples

NOTE that that not all drugs can have their PK measured directly e.g. biologics or
vaccines may be measured indirectly by e.g. assessing specific antibody responses.

What does it mean?

Pharmacokinetic parameters can be descriptive or conceptual. Descriptive results

are simple in nature and used for any concentration-time profile when no
understanding of what the body is doing to the drug is required. In its simplest
form, sample analysis will target concentration of drug as time progresses,
resulting in the production of a ‘plasma concentration-time curve’. Various indices
are calculated from this graph, most commonly;
! maximum plasma concentration (Cmax)
! time to maximum plasma concentration (Tmax)
! area under the plasma concentration curve (AUC): a calculation to assess the
bodies total exposure to a drug over a given time
! half life (t1/2): the time taken for the plasma concentration to fall by 50%

NOTE: Cmax and Tmax are indicators of absorption for a non intravenous route as
direct delivery into the systemic circulation means both of these measurements are
instantaneous.

The figure below demonstrates these concepts:

Conceptual parameters are used to investigate what actually happens to the drug
in the body. Three primary conceptual PK parameters are used to describe the
outcomes of ADME processes in a quantitative manner:

! Clearance: the rate of drug elimination divided by the plasma concentration,

having units of flow (ml/min) which can be corrected for bodyweight
(ml/min/kg). It provides a measure of the body’s ability to eliminate the drug
substance from the plasma, by either metabolism or excretion, thus mainly
involving the liver and kidneys. Clearance is important measurable as it
determines the dosing rate necessary to maintain the desired plasma
concentration.
! Bioavailability: the proportion of an administered dose that reaches the
systemic circulation, usually expressed as a percentage. Intravenous drugs score
100%, however other routes of administration are affected by incomplete
absorption or metabolism (e.g. first pass metabolism in the liver for orally
administered drugs) and thus should always be less than 100%. It is calculated as
AUCoral/AUCiv.
! Volume of Distribution: the amount of drug in the body divided by the plasma
concentration, having units of volume (L) which can be corrected for bodyweight
(l/kg). Volume of distribution is a very complex concept as it rarely relates to an
actual volume, having no upper limit and can be very much larger than actual
body volume.

How is it used?
Sponsor drug companies: single ascending and multiple ascending studies are
conducted in Phase 1 study to determine initial dose escalation and when drug
reached steady state. As understanding increases the sponsor will use the data to
refine the dose regimens for later phase studies to ensure they are safe and
potentially efficacious. The half life is especially important here and is used to
working out the dose regime e.g. once daily, twice daily etc.

Regulatory bodies: assessment of safety monitoring and confirmation that

appropriate calculations have been done. Clarification that proper study design
has been followed and that there are no obvious areas for concern for subject or
patient safety. PK data is Page: 4 [0]used to back up the labelling claims made by
sponsors e.g when to take the drug, what not to take with it (drug- drug and drug-
food interactions), dose amendments in special populations e.g. elderly, renal
impaired or hepatic impaired. 80% of a drug label comes form Phase1 PK studies.

Molecule development: Pharmacokinetics in animal modelling are essential in the

initial selection of a dose range for first in man studies, safety analysis, formulation
development, drug candidate screening.

Clinical Practice: therapeutic dose monitoring for patients to ensure adequate drug
cover or assessment of the potential for drug-drug interaction when patients ore
using more than one treatment concomitantly. Although an important aspect, it is
generally only done for drugs with a narrow therapeutic window e.g anti-
epileptics, warfarin, digoxin.

PHARMACODYNAMICS:

What is it?

The pharmacodynamic process describes all those issues concerned with the
pharmacological actions of a drug, whether they are intended aspects of the
therapeutic effect (efficacy). Although not instantly obvious, the majority of early
phase studies have a pharmacodynamic element, as assessment of the safety and
tolerability of the drug is often stated as a primary or secondary objective of the
study. Originally, pharmacodynamics was the primary interest of patient studies,
although efficacy assessment has become increasingly important in phase 1
studies. As regulatory requirements increase, trials take longer to conduct and thus
costs invariably rise, there is therefore increasing pressure to assess the therapeutic
potential of drugs and remove non-viable drug candidates at the earliest stage.
Therefore, efficacy components are being built into phase 1 studies on a more
regular basis when possible.
As with PK analysis, it is important to note that pharmacodynamics are not limited
to the parent drug molecule itself, but will also assess identified metabolites,
whether considered active or inactive.

How is it measured?

Once at the activity site, there are several ways in which drugs may produce
pharmacological effects:
! Through receptors, either targeted or not
! Indirect alteration of endogenous agonist or antagonist activity
! Inhibition of transport processes
! Alteration of enzyme activity i.e. inhibition, activation or modification
! Analogue of natural ligand e.g. replacement therapy

Any method used to measure the pharmacodynamic response to drug

administration must assess an actual, identifiable physiological parameter in a
quantifiable way. Special care must be taken to ensure you are not measuring
artefacts or responses to other, non-drug stimuli. This can be quite difficult in
certain cases, for example in assessment of the ability of a drug to control pain, as
pain is an emotional response to a physiological event and therefore can be
perceived in different ways by different people at different times. Drug effect can
be assessed on body systems as a whole or at the biochemical level. Accurate
pharmacodynamic analysis in early phase studies is often quite difficult, especially
when conducted in normal healthy subjects with no disease process. In these cases
the method of choice is usually to identify, and then monitor, biomarkers. A
biomarker is defined as a characteristic that is objectively measured and evaluated
as an indicator of a normal physiological process, pathogenic process or
pharmacological response to a therapeutic intervention e.g. blood glucose for anti-
diabetic drugs, coagulation for new anticoagulants.

What does it mean?

As discussed above, the pharmacological effect of a drug is related to the

concentration of the drug at the site of action. This should be seen as only a general
rule however as certain drugs may be susceptible to saturation or desensitizing
effects. The “dose-response curve” is used to describe the relationship between the
concentration of drug at the site of action and the intensity of pharmacological
effect caused. Graphs can then be used to analyse individual drug activity, or be
compared with other graphs to assess, for example, potency (the amount of drug
needed to produce similar effects) or maximal efficacy (concentration of drug
required to produce maximum effect). The figure below outlines these concepts.

How is it used?
Sponsor drug company: PD data will be assessed and used to guide the decision
process on whether to proceed or not to proceed with full clinical development
(go/no go) or to amend the development programme.

Regulatory bodies: assessment of safety and adverse reactions. Clarification that

proper study design has been followed and confirmation that the drug is targeting
appropriate biological processes.
Molecule development: essential in the estimation of therapeutic and toxic dose
levels, safety analysis, formulation development, drug candidate screening.

Clinical Practice: biomarkers can be used in the clinical setting to monitor and
assess of the effectiveness of drug activity.

CONCLUSION:

Pharmacokinetics is:
! the study of the action the body has on the drug
! concerned with measuring drug movement around the body
! provides an analysis of rate and concentration
! examines how and why does the drug get to the site of action
! assessed in the early stages of drug development to identify potential dosing
ranges or physiological safety issues
Pharmacodynamics is:
! the study of the action the drug has on the body

! concerned with measuring the efficacy of drug activity

! provides an analysis of benefit : risk
! examines the questions of how and why the drug works
! assessed in the early stages of drug development to identify potential dosing
ranges or physiological safety issues

As can be seen from the discussion above, pharmacokinetics and

pharmacodynamics can be seen as two sides of the same coin. PK and PD have a
definite relationship, assessing how much drug gets to the site of action and then
what that action is. Both activities are essential in the complete investigation of the
interaction between the drug and body, and play significant roles in both drug
development and their continual use in the clinical setting.