Basics of PK principles &

Drug Administration
MED5129 Drug Disposition

Dr Rafael Venson
School of Medicine, Dentistry and Nursing
[email protected]
 Aim of session:

To introduce the Drug Disposition course and discuss routes of drug administration and basic pharmacokinetic
parameters.

Intended Learning Outcomes (ILOs);

By the end of this session, students should:

• Describe some basic mathematic principles used when calculating pharmacokinetic parameters

• Describe different routes by which drugs can enter the body

• Describe the parameters that affect the pharmacokinetics of drug absorption into the systemic circulation following
administration
 Principles of PK calculations

• Drug elimination usually occurs by a First – order elimination process,

• Rate of change of drug Concentration (C) vs Time (t)

• e.g. Assume a single intravenous (IV) bolus dose (A) of a drug is administered and instantaneously distributes
to the tissues.
 Principles of PK calculations

First order elimination:

• Linear elimination kinetics

• A constant proportion of drug is eliminated per unit time

• Rate of change of drug amount (A) in systemic circulation, over time can be described by;

-kA, k = Rate of change of drug elimination

ka = Rate of change of drug absorption

This expression is difficult to work with and is more commonly used in its integrated form.
i.e. A = A0 e-kt
However, in practice drug concentrations are measured, rather than drug amounts.

Therefore, A = A0 e-kt becomes: Ct = C0 e-kΔt

where,
Ct = Concentration of drug at time (t) after the dose is administrated into volume

C0 = Concentration of drug immediately after bolus is administered.

k = the rate of change

e = the exponential function

Δt = change in time

So, for example, the drug concentration 6 hours after the IV bolus dose was administered:
C6h = C0 e-k6 ….. we will revisit this later.
Exponential growth or decay is found in many biological systems.

C6h = C0 e-k6

The shape of the growth/decay depends on the irrational number e (equal to 2.7183….) for the base.

e.g. e1 = 2.7183…

The inverse of exponential function is the logarithmic function.

The natural logarithm (ln or loge), will return the original exponent,
e.g. Ln (e1) = ln (2.7183…) = 1

If C = ex, then x is the logarithm of C to the base e; i.e. x = LnC = LogeC

Log10

If C = 10x, then x is the logarithm of C to the base 10

(e.g. 1000 is 103, so log10 of 1000 = 3)

LnC = log10C x Ln10 = log10C x 2.303

as 2.303 is a conversion factor from natural log to log10

We ALWAYS use natural logs (ln) for pharmacokinetics – as it is much easier and you do not need
to remember where to put the “2.303”….
 Drug Disposition

Laws of Logarithmics
ln (C1.C2) = ln C1 + ln C2

ln (C1/C2) = ln C1 – ln C2

Ln (Cn) = n ln C

Log10 10 = 1 Loge e (ln e) = 1

Log10 1 = 0 Loge 1 (ln 1) = 0

Log 0 = infinity (∞) Log 0 (ln 0) = infinity (∞)

 Calculation
Hierarchy

Pharmacokinetic calculations often include a variety of algebraic expressions

An order of operations should be adhered to;

1. Determine inner calculations first, i.e. those within brackets (parentheses).

2. Calculate exponentials outside brackets

3. Next multiplications / divisions

4. Add / subtract remaining terms

 Drug Disposition
Calculation Hierarchy
Pharmacokinetic calculations often include a variety of algebraic expressions

Concentration = (e-0.083x1 – e-0.22x1) mg/L

1. 1. 2.

= (0.118) = x 0.118 mgL-1

3. 3.

= 2.87 mgL-1
 Units

• Pharmacokinetic calculations must always include appropriate units for all parameters.

• Unit of time = usually in hours (h)

• Volume = Litres (L)

• Mass = grams (g), milligrams (mg), micrograms (µg)

• Concentration = mg/L, µg/L

• During assessment (coursework / examinations) marks will be deducted from student work that lacks appropriate
units.

• Common issue observed by markers during exams.

 Drug Disposition
Administration
Main routes of drug administration
 Drug Administration
https://www.boehringer-ingelheim.co.uk/

IV administered dose

e.g. oral
 IV Drug Administration.

Fastest route for administering a drug directly into the systemic circulation

• Drugs are aqueous solutions

• Suitable for drugs destroyed by chemical reaction (e.g. in stomach)
• Drugs with large molecular weight (e.g. heparin)
• Unconscious patients/fast administration required

Bolus dose = delivery of an amount of drug (mass, e.g. g/mg) within a specific short time, generally within minutes.

Following a single IV bolus dose administration;

• A very high peak concentration can be achieved as the drug is administered directly into the vasculature.
• The onset of action is immediate
• The entire administered dose (amount of drug) is available to produce the pharmacological effects
• Adverse reactions are difficult to reverse or control; accurate dose calculations are critical
Oral Drug Administration.

Small Intestine
• Higher pH to stomach (better for basic drugs)
• Greater surface area (mucosa)
• Passive diffusion
(rate determined by lipid solubility of drug)
 Drug absorption.
Absorption of drugs into the systemic circulation, requires diffusion of drug molecules across cell membranes that
form the barriers between compartments.

Cell membranes;
Small molecules pass through cell membranes by;
• Diffusion through lipids (non polar molecules)
• Diffusion through an aqueous channel
• Membrane transporters
– carry molecule across cell membrane
– e.g. levodopa, iron, calcium
• Pinocytosis
• Trapping within a small vesicle

• The mechanism of drug absorption is dependent on the lipid solubility & pH / pKa of the drug.
 pH and Ionisation.
Many drugs exist as weak acids or weak bases and therefore in both unionised and ionised forms; the ratio of which
varies with pH.
Weak Bases Ka
BH+ B + H+

Weak Acids Ka
AH A - + H+
The dissociation constant (pKa)
• pH when exactly half of the acid has dissociated
• Weak bases & weak acids only partially dissociate (depending on their functional groups)
• Concentrations of A- and AH are equal (50% dissociation)
• Determined by the Henderson – Hasselbalch equation:
• pKa = pH + log10

• pKa = pH + log10
 pH and Ionisation.
BH+ and A- are charged (ionised)
• Have very low lipid solubility
• virtually unable to permeate cell membranes unless a specific transport mechanism exists.

AH and B are neutral (“unionised/uncharged”)

• Has higher lipid solubility
• Not guaranteed to cross the membrane, other factors
• Lipid solubility of the uncharged species, B or AH will depend on the physiochemical structure of the drug.
 Drug distribution.

Once a drug enters the systemic circulation, it can distribute within the body
(extent of distribution is dependent on its physicochemical properties)
 Drug Disposition:
Fate of drug once enters the body
1. Characterisation of drug disposition is important for the determination and modification of dosing regimens for
individual and groups of patients.
• Dose Response

Dose = standardised quantity (amount) of drug administered

= expressed as mass i.e. µg, mg, g.
Response = biochemical/physiological effect produced when drug interacts with it’s receptor

However, we must consider Pharmacokinetic and Pharmacodynamic patient variability

e.g. A drug dose may be sub therapeutic for some patients or some patients may respond to treatment at
lower drug doses
Therefore, drug concentrations, not amount, are usually measured in plasma or serum (more often than blood).
• Dose Concentration Response
Concentration = amount of drug in a volume (systemic circulation; plasma concentration)
= expressed as mass (amount) per unit volume; µg/ml, mg/L
 Drug Disposition
• Pharmacokinetic and Pharmacodynamic patient – patient variability to consider
• Wide inter – patient variability leads to differences in response at similar drug
concentrations.

[Figure: Clinical Pharmacology & Therapeutics,

McKay, Reid & Walters, 8th Ed]
 Optimising drug treatment
based on circulating drug levels
MEC = Minimum Effective Concentration

= concentration required to produce the

required response

= below MEC drug is ineffective

- sub therapeutic range

MTC = Minimum Toxic Concentration

= concentration required to
just barely produce toxicity

= minimum concentration required

to produce a toxic effect
 Optimising drug treatment
based on circulating drug levels

Therapeutically effective area = Therapeutic window

Drugs with a wide therapeutic window are generally considered to be safer than those with a narrow therapeutic
window.
 Therapeutic Window

Drugs with wide therapeutic window:

• Usually do not require Therapeutic Drug Monitoring (TDM) e.g.
• Nonsteroidal anti – inflammatory drugs (NSAIDs); ibuprofen
• Calcium channel – blocking agents; nifedipine

Narrow therapeutic window drugs:

• Critical – dose drugs
• Small differences in the dose or concentration lead to serious therapeutic failures or serious adverse reactions that
require significant medical intervention
• Aim is to maintain a flat profile within a defined range, or achieve high peak C but low trough C
 Therapeutic Window

Therapeutic Drug Monitoring (TDM):

• Aims to produce a safe plasma drug concentration that does not exceed the minimum toxic concentration or fall
below the minimum effective concentration.

Pharmacokinetic population estimates:

• used for critical – dose drugs,
• are an approximation of the average plasma concentrations that are safe and effective in most patients.
 Pharmacokinetics
A.D.M.E.
Absorption

Distribution
Volume of distribution

Metabolism
Important interpatient variability in drug response

Excretion
Clearance (CL)
Elimination rate constant (k)
Elimination half life of drug (t1/2)

Knowledge of a drug’s disposition and the population PK estimate for that drug, allows the Clinical Pharmacologist
to determine an appropriate Therapeutic Drug Monitoring (TDM) regimen.
 Thank you.

Dr Rafael Venson
[email protected]