Pharmacokinetics 4

Quantitative pharmacokinetics

A/Professor Ken Rodgers

School of Life Sciences

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 Learning objectives
u Explain how drug clearance (CL) determines steady-state
plasma concentration
u Calculate the half-life, volume of distribution, clearance and
loading doses of drugs
u Explain how the timecourse of drug clearance can be
described using one or two compartment kinetic models
u Understand differences between first-order and zero-order
(saturation) kinetics
u Explain the pharmacokinetics of alcohol, including why alcohol
has a constant rate of metabolism per hour

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 Reference

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 Definitions

uPharmacokinetics = Time course of drug

concentrations attained in different
compartments of the body during or after
dosing

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 Time course of drug concentration in plasma or blood

Absorption,
distribution and
metabolism all
start here!

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 Time course of drug concentration

Cma
x

tmax

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 Drug elimination
uIrreversible loss of drug from the
body

uMetabolism CH3 H

aspirin salicylic acid

uExcretion

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 Drug clearance 1
u Clearance (CL) is the volume of plasma cleared
of drug per unit time (L/hr)

u Relatesrate of drug elimination to its plasma

conc (Cp) (mg/L)

u Rate of drug elimination = Cp x CL (mg/hr)

u Formost individuals at therapeutic concs CL is

the same at different drug doses (Q) (NB: not in
overdose)
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 Drug clearance
u http://sepia.unil.ch/pharmacology/index.php?id=62

Clearance (CL) is the volume of plasma cleared of

drug per unit time (L/hr)

At steady state CL = infusion rate / Css = L/h

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 Drug clearance 2
Clearance
❚ describes the efficiency of elimination
❚ is additive
CLtotal = CLrenal + CLnon-renal
CLtotal = CLrenal+ CLmetab + CLbile + CLlung +….

Renal Clearance
CLrenal = CLfiltration + CLsecretion - CLreabsorption

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 Drug excretion 1
Drugs filtered into Active secretion
urine here of drugs here

CLrenal = CLfiltration + CLsecretion - CLreabsorption

Passive reabsorption
of drugs here

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 Single compartment model

Initial conc.
= C0

Elimination = +
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 Drug clearance 2
C0

u For most drugs, elimination

follows an exponential time
course with a constant half-
life (t1/2) independent of Cp
u Known as first-order kinetics
u t1/2 is directly proportional to
Vd and inversely
proportional to CL
u The initial plasma
concentration (C0) = Q/Vd C0 = 1000 µg/ml
1 half-life = 500 ug/ml
u Rate of decay described by:
2 = 250
−CL 3 = 125
()
C t = Co exp
Vd
t 4 = 62.5
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 Half-life visualisation
u https://sepia2.unil.ch/pharmacology/wp-content/uploads/2019/0

After 4-5 half-lives there is not

enough drug left to have an
effect

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 Drug clearance 3
u Effects of changes in dose and elimination rate
u Drugs a and b differ only in their elimination t1/2.
u Curve b’ shows the plasma conc time course for a smaller dose of b.
u The t1/2 does NOT depend on the dose (= 0.693/Kel or Kel = 1/slope)

Half-life (t1/2) = 0.693/0.05

= 13.9 h
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 Drug clearance 4
t1/2 = 0.693/Kel
so Kel = 0.693/t1/2
CL = Vd x Kel
Clearance is
defined as the
volume of plasma
that is cleared of
drug per unit time

u CL = Vd x 0.693/t1/2

u t1/2 = 0.693 x Vd = mL = min

CL mL/min

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 Half-life and Vd

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 Clearance and half-life

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 Drug clearance 5
u Takes approximately 4-5 Infusion rate = Css x CL

t1/2 for Cp to reach the

steady state: X = Q/T
Q = dose
u ~5% of Css after infusion is T = dosing interval
stopped (effectively eliminated)
u ~95% of Css after infusion is
started
Multiples % of Css after % of Css after
of half-life infusion stopped infusion started
1 50 50
2 25 75
3 12.5 87.5
4 6.25 93.75
5 3.125 96.875
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 Steady-State
• attained after ~4-5
half-lives
• time to steady-state
independent of dosage

Fluctuations
• proportional to dosage
interval half-life

Sa
me
do
se
Multiples of half-lives
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 Repeated dosing
uDrugs normally given repeatedly (p.o.) rather than single
injection or constant IV
uWhat is appropriate dose that must be given repeatedly?
uHow often must drug be given to:
u maintain therapeutic levels?
u avoid toxic concentrations?

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 Concept of therapeutic range

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 Repeated dosing – plasma
concentrations

MSC

MSC = Maximum safe concentration

MEC = Minimum effective
concentration

Between these two values =

Therapeutic window

MEC

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 Repeated doses

u Ifdosing interval < 4.5 x t1/2, drug will

accumulate

u With repeated fixed dosing (or IV infusion) it

takes 4.5 x t1/2 of a drug to reach max.
absorption

u Therefore, after 4.5 x t1/2, rate of drug elimination

= rate of drug absorption/supply = maximal
accumulation = steady state (Css)
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 Dosing interval 1

u There are two opposing forces at work

u Patient compliance
u Less often a drug can be given, better will be
patient compliance

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 Dosing interval 2
u Fluctuations in plasma concentration
u Fluctuations will oscillate with a range of Q/Vd
u Less often a drug is given, greater will be fluctuations in Cp
u Cp falls below therapeutic levels
u toxic Cp may also be reached

Toxic

Therapeutic

Sub-
Therapeutic

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 Variations in absorption
u Slowerabsorption decreases peak Cp and
prolongs duration

t1/2

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 Single compartment model

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 Two compartment models
u Very often, however, a fast- and slow- phase of loss of drug from
plasma is noted

u The fast phase is characterised as distribution from plasma to

the tissues

u The slow phase equates to elimination from the plasma

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 Two compartment models
u Most drugs are described by a two compartment model

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 Two compartment models
u Most drugs are described by a two compartment model

t1/2

Plasma Tissues
t1/2

Kinetics of diazepam elimination in humans following a single dose. The experimental data (black
circles): After a fast phase (~8 hours) the curve becomes linear (slow phase). Plotting the deviation of the
early points (pink shaded area) from this line on the same coordinates (red symbols) reveals the fast phase.)
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 Loading doses
u Sometimes not practical to wait 4-5 t1/2 to attain Css
u Eg. digoxin (t1/2 ≈ 36 hrs), severe CHF needs immediate Rx
u Would take >6 days to achieve Css (less to reach MEC)
u Avoid problem using loading dose (QL) = Vd x target Cp

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 Dosage adjustment for impaired elimination 1

uDuration of action and potency of most

drugs is dependent on metabolism
(hepatic) and/or excretion (renal)

uCa. 20% of drugs are cleared unchanged

through kidneys (eg gentamicin,
cisplatin)

uThus must alter dose of drug given to

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patients with these dysfunctions Slide 33 of 45
 Dosage adjustment for impaired elimination 2

u Dosing in renal impairment

Drug clearance (CL) ∝ creatinine clearance (CrCL)
u Elderly patients (declines 1%/yr from 30 y.o.), or patients
with renal failure, using drugs with low therapeutic index
€ u Cockroft & Gault equation used to adjust drug doses
(140 − age) × weight(kg) ×F
CrCL(ml/ min) =
800 × [Cr ](mmol/l)
u Where F = 1 for males, 0.85 for females
u Check fraction excreted unchanged (fu) (see next slide)
€ DR patient # calculated CrCL &
= (1− fu) + fu% (
DR normal $ 100 (ml/min) '

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 Dosage adjustment for impaired elimination 3

u Dose adjustment required for renal

impairment
u ‘fu’ = fraction excreted unchanged

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 Dosage adjustment for impaired elimination 4

u Dosing in liver disease

u There is no simple measure for hepatic impairment
u Albumin conc and prothrombin index indicate ability to synthesise proteins
and thus liver enzymes but only indicate severe, chronic dysfunction
u For albumin <30 g/L (normal 36-55 g/L) and/or raised INR indicate severe
liver dysfunction
u High hepatic CL drugs – decrease dose by 50% (see next slide)
u Low hepatic CL drugs – decrease dose by 35%
u ‘Start low, go slow’

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 Dosage adjustment for impaired elimination 5

u Fraction of drug removed from blood in one

passage through liver is the extraction ratio (ER)

[drug]in − [drug]out
Extraction ratio (ER) =
[drug]in

Hepatic CL = Hepatic blood flow ×ER

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 Dosage adjustment for impaired elimination 5

u These drugs are subject to first-pass metabolism and altered

blood flow (eg in CHF)

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 Zero-order elimination 1
u Theoretically all drugs could saturate their metabolising pathways (eg. enzymes or pumps)
u For most drugs this occurs above therapeutic concs (eg only with overdose)
u For a few drugs this occurs at therapeutic concs

u This is known as zero-order elimination (saturable kinetics)

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 Zero-order elimination 2
u Below Km, rate of elimination is proportional to Cp
u Above Km, rate of elimination becomes independent of Cp

Vmax = maximum rate of

reaction

Km (Michaelis constant) =
dCp Vmax ×Cp
= concentration at half
dt Km + Cp
maximal rate of reaction

u Most drugs have therapeutic concs well below Km, therefore

first-order
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 Zero-order elimination 3
u Examples of drugs undergoing zero-order elimination
include:
u Aspirin (saturates with one to two 300 mg tablets)
u Coumarins
u Ethanol (Km = 0.01%, legal limit for driving = 0.05%)
u Quinidine (narrow therapeutic index)
u Heparin
u Tetracycline
u Amylobarbitone
u Phenytoin (narrow therapeutic index, Km 7 mg/l, therapeutic
range 10-20 mg/l)
u Can also occur in overdose situations, with high Cp

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 Zero-order elimination 4

u Rate of eliminated is
independent of drug starting
concentration
u t1/2 is dependent on drug
starting concentration
u Eg. Ethanol = 4 mmol/hr
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 Zero-order elimination 5

u Once the Cp producing the maximal rate of

metabolism is exceeded, the Cp will, in
principle, increase indefinitely and a steady
state Cp will not be reached

u Therefore, Cp should be regularly measured

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Comparison of non-saturating and saturating kinetics for drugs given orally every 12 hours. The
curves show an imaginary drug, similar to the antiepileptic drug phenytoin at the lowest dose, but with linear
kinetics. The curves for saturating kinetics are calculated from the known pharmacokinetic parameters of
phenytoin. Note that no steady state is reached with higher doses of phenytoin, and that a small increment in
dose results after a time in a disproportionately large effect on plasma concentration. With linear kinetics, the
steady-state plasma concentration is directly proportional to dose.
 Question

Drug Y has a steady-state plasma concentration of 1000

mg/L, a half-life (t1/2) of 1 hour and undergoes first-order
elimination. What will be the approximate plasma
concentration (Cp) 4 hours after I.V. infusion is
discontinued?
(A) 10 mg/L
(B) 250 mg/L
(C) 40 mg/L
(D) 62.5 mg/L
(E) cannot be answered without knowledge of the
dose given

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