Clinical Pharmacy 1

Clinical Pharmacokinetics

An Thanh Pham, MSc.

Ho Chi Minh City, September, 2023 1

 Understand The concept and clinical significance of Clinical Pharmacokinetics

Learning Understand Internal processes, including absorption, distribution, metabolism,

and excretion

Objectives
Calculating parameters regarding absorption, distribution,
Apply metabolism, and excretion

Dose adjustment in patients with kidney disease and

Analyze patients with liver disease
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 Content
1. Definition and clinical significance

2. Internal processes

3. Clinical application

4. Dosage adjustment

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 1. Definition and clinical significance

1.1. Definition
Pharmacokinetics
• How the body interacts with drugs for the entire
duration of exposure
• The four main processes: absorption, distribution,
metabolism, and excretion (ADME)
Pharmacodynamics
• The effect of drugs on the body

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 1. Definition and clinical significance

1.2. Clinical significance

ü The flexibility to prescribe and administer medications
→ Provide the greatest benefit at the lowest risk
ü Make proper adjustments for each individual
ü Better estimate the locations and concentrations of a drug in different areas of
the body
ü Easily estimate safe medication dosing over a period of time

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 2. Internal processes

Absorption Distribution Metabolism Excretion

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 2. Internal processes
2.1. Absorption

The process that brings a drug from the administration into

the systemic circulation

Affects the speed and concentration at which a drug

may arrive at its desired location of effect

Includes liberation - the process by which the drug is

released from its pharmaceutical dosage form
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 2. Internal processes
2.1. Absorption

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Nunes, D.,et al(2022). Polymeric Nanoparticles-Loaded Hydrogels for Biomedical Applications: A Systematic Review on In Vivo Findings. Polymers, 14(5), 1010.
 2. Internal processes
2.1. Absorption

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Ramadon, D., et al (2022). Enhancement strategies for transdermal drug delivery systems: current trends and applications. Drug delivery and translational research, 12(4), 758–791.
 2. Internal processes
2.1. Absorption

Drug-specific factors

Factors that can affect

drug absorption

Patient-specific factors

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 2. Internal processes
2.1. Absorption

Drug-specific
factors

Physicochemical Pharmaceutical
aspects aspects

Inactive
Drug solubility pH and pKa Dosage form
ingredients
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 2. Internal processes
2.1. Absorption
Age

Gastric
GI content emptying
time

Patient
Pre- specific
systemic factors Intestinal
metabolis transit time
m

Disease
Blood flow
status
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 2. Internal processes

2.1. Absorption

Mechanisms of drug absorption

• Passive diffusion
• Carrier-mediated membrane transport:
o Active diffusion
o Facilitated diffusion

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 2. Internal processes
2.1. Absorption
Passive diffusion

Di L, Kerns EH. Chapter 9 - Transporters. In: Di L, Kerns EH, editors. Drug-Like Properties (Second Edition). Boston: Academic Press; 2016. p. 113-40.
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 2. Internal processes
2.1. Absorption
Carrier-mediated membrane transporters

Cole AS, Eastoe JE. Chapter 15 - Cellular organization. In: Cole AS, Eastoe JE, editors. Biochemistry and Oral Biology (Second Edition): Butterworth-Heinemann; 1988. p. 191-207.

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 2. Internal processes
2.1. Absorption
Diffusion and facilitated diffusion

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https://www.futurelearn.com/info/courses/introduction-to-human-cells-the-basis-of-life/0/steps/330525
 2. Internal processes
2.1. Absorption
Bioavailability (F)
• The fraction of the originally administered drug
that arrives in the systemic circulation
• Depends on the properties of the drug
and the mode of administration

mass of the drug delivered to the plasma

• F=
total mass of the drug administered

https://www.pharmaguideline.com/2021/07/bioavailability-of-drugs.html

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 2. Internal processes

2.1. Absorption
The area under curve (AUC)
• Calculate the bioavailability of drugs not delivered
intravenously:

AUC for X route of administration

F=
AUC for IV administration
• For a given dose, the AUC is proportional to the
decrease in clearance:

Dose
AUC =
Clearance https://clinicalinfo.hiv.gov/en/glossary/area-under-curve-auc

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 2. Internal processes
2.2. Distribution
• How a substance is spread throughout the body
• Be influenced by two main factors: diffusion and convection
• Associated factors:
oThe polarity, size, or binding abilities of the drug
oThe fluid status of the patient (hydration and protein
concentrations)
oThe body habitus of the individual

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 2. Internal processes
2.2. Distribution
The effective drug concentration
• The concentration of the drug at its designed receptor site
• A drug must reach its designated compartmental destination:
o Described by the volume of distribution (Vd)
o Not be protein-bound to be active

Jacques, E.R.; Alexandridis, P. Tablet Scoring: Current Practice, Fundamentals, and Knowledge Gaps. Appl. Sci. 2019, 9, 3066
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 2. Internal processes
2.2. Distribution
Volume of Distribution (Vd)
• Relating the total amount of drug in the body to the plasma drug concentration at a given time
" ($%) *
V! (L) = ' ($%/)) =Dx'

• Determined by the distribution and binding of the drug to extravascular tissues compared with plasma proteins
o High Vd More distribution to other tissue
o Low Vd Less distribution to other tissue
• Associated factors:
o Body mass
o Body composition
o Body water
o Adipose tissue
https://revisedental.com/lesson/pharmacokinetics/ 21
 2. Internal processes
2.2. Distribution

Volume of Distribution (Vd)

• When the drug is distributed throughout the body in the same concentration
as in the plasma:
!"#$%&' $"()
C=
*+

• After a rapid bolus dose, the Cmax is predicted:

+"(),-
Cmax =
*+

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 2. Internal processes
2.2. Distribution

Free Protein bound

• Act at its pharmacologically active • The principal proteins for binding
sites (receptors), cross into other drugs are albumin and alpha-acid
fluid compartments or be eliminated glycoprotein

• The free concentration at receptor • Any reduction in plasma protein

sites in plasma is more closely binding increases the amount of
effective than the total concentration drug available to act on receptors
in plasma → an increased toxicity

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 2. Internal processes
2.2. Distribution
Protein Binding
Age

Liver or
kidney
disease

Nutrition
status

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 2. Internal processes
2.3. Metabolism
• The processing of the drug by the body into subsequent
compounds
• Convert the drug into more water-soluble substances
Renal clearance
• Prodrug administration: metabolism may be required to
convert the drug into active metabolites

Wilkinson, Grant R. "Drug metabolism and variability among patients in drug

response." New England Journal of Medicine 352.21 (2005): 2211-2221.

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 2. Internal processes
2.3. Metabolism
Liver

Gastrointestinal tract

Skin

Plasma

Kidney

Lung

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 2. Internal processes
2.3. Metabolism
Phase I metabolism (modification) Phase II metabolism (conjugation)

Polar groups (charged to permit electrostatic

Forms readily excretable, nontoxic substances
interactions) → Lipophilic molecules

Involves the metabolite with glucuronic acid,

Through oxidation, reduction, or hydrolysis →
acetyl groups, sulfates, amino acids, or
Facilitate water-solubility
glutathione

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 2. Internal processes
2.4. Excretion

https://www.pharmacologyeducation.org/clinical-pharmacology/clinical-pharmacokinetics 28
 2. Internal processes
2.4. Excretion
Clearance
• The volume of blood cleared of a drug in a period of time
→ Maintain the dose rate of a drug required to achieve a target plasma concentration at a steady state
• The total or systemic CL as follows:
CL = CL$ + CL% + CL&'%()
• Associated factors:
o Drug characteristics
o Blood flow
o Organ status (usually kidneys)

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 2. Internal processes
2.4. Excretion
Renal clearance
Measure the rate of excretion of the drug in urine and changes in the drug plasma concentration
at the same time:
CL$ = (F* xGFR) +CL+(,)('-&. +CL)(/0+&)1'-&.
• F* : the fraction of the total drug concentration that is unbound to plasma proteins
• GFR: Glomerular filtration rate
• CL+(,)('-&. : due to active secretion in the kidney tubules
• CL)(/0+&)1'-&.: reabsorption from the glomerular filtrate back to the circulation

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 2. Internal processes
2.4. Excretion
vA constant rate of metabolism and/or elimination independent of
Zero-order the concentration of a drug
kinetics vAlcohol and phenytoin elimination

First-order vThe proportion of the plasma concentration of a drug

kinetics vA constant 't' with decreasing plasma clearance over time

vWhen the administration of a drug and the clearance are balanced

Steady-state vAltered by changes in dosing interval, total dose, or the clearance
of a drug
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 2. Internal processes
2.4. Excretion
Half-life
• The amount of time for serum drug concentrations to decrease by 50%
5.789 5.789:;! >.<!?>.<" <=
t2/4 = = → k= =
$ <= '!?'" ;#

• Major determinant of the duration of action after a single dose

• Becomes altered due to changes in the clearance parameters that come with disease or age
• The time required to reach steady-state plasma concentrations: approximately 4–5*t1/2 after
drug initiation

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 2. Internal processes
2.4. Excretion
Half-life curve

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Hallare J, Gerriets V. Half Life. [Updated 2023 Jun 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan.
 3. Clinical application
3.1. Relation between Dosing Regimen and Drug Effect

Lea-Henry TN, et al. Clinical Pharmacokinetics in Kidney Disease: Fundamental Principles. Clin J Am Soc Nephrol. 2018 Jul 6;13(7):1085-1095. 34
 3. Clinical application
3.2. Dosing regiment

()*)+,-.
• The change in plasma concentration: ΔC = /!

Δ0) /!
• Loading dose: C= ()*

()*)1,-.
• Rate in: 2
=CLx average C ss

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 3. Clinical application

3.3. Capacity limited clearance

• A drug is eliminated by the liver: the metabolic pathway to become saturated
Saturated

First-order Zero-order

• For the majority of drugs eliminated by the liver:

o The effect is not seen at normal therapeutic doses
o Only occurs at very high supratherapeutic levels

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 3. Clinical application

3.4. Increasing clearance

The drug concentration increases

The plasma protein binding sites become saturated

The ratio of unbound drug to bound drug increases

The elimination of these drugs increases

disproportionate to the total concentration
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 3. Clinical application
3.5. Estimation of creatinine clearance
• Undertake a 24-hour urine collection coupled with a plasma creatinine measurement
34,567 ,8 9:.;7<6<6
• Rate of excretion (mg/h)= =>

• At steady state: rate in = rate out

• Rate of administration = rate of elimination = CL × Css
?;7. ,8 @:,1597<,6
• Creatinine clearance = 0""

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 3. Clinical application
3.6. Estimation of kidney function

http://www.nephjc.com/news/new-gfr-equations 39
 4. Dosage adjustment

4.1. Dose adjustment in patients with kidney disease

How does kidney disease affect the drug kinetics?
• Patient susceptibility: patients with renal failure may be more
vulnerable to a certain drug effect
• Pharmacodynamic change: a drug effect may be increased
or decreased
• Pharmacokinetic change: higher steady-state concentrations

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 4. Dosage adjustment
4.1. Dose adjustment in patients with kidney disease
Dose The severity of kidney disease
adjustment The proportion of the drug eliminated by the kidney
depends on:
The risk of adverse effects from the drug
The duration of treatment

59 ≥ GFR ≥ 45

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https://www.hse.ie/eng/services/list/2/gp/antibiotic-prescribing/drug-interactions/renal-impairment-summarynew.html
 4. Dosage adjustment
4.1. Dose adjustment in patients with kidney disease
Formulae used in estimating glomerular filtration rates

Stefani M, Singer RF, Roberts DM. How to adjust drug doses in chronic kidney disease. Aust Prescr. 2019 Oct;42(5):163-167. 42
 4. Dosage adjustment
4.1. Dose adjustment in patients with kidney disease
Drug classes requiring dose adjustment in chronic kidney disease

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https://www.rxfiles.ca/rxfiles/uploads/documents/ltc/HCPs/CKD/SDIS.Renal_newsletter.pdf
 4. Dosage adjustment
4.2. Dose adjustment in patients with liver disease
How does liver disease affect the drug kinetics?
• Reduced portal blood flow → the pre-systemic elimination of high-extraction drugs
• Decreased synthesis of transport proteins (albumin and alpha-glycoprotein)
→ the bioavailability of drugs highly bound to plasma proteins
• Reduced drug-metabolizing hepatic enzymes → the amount of plasma active metabolite
→ the effectiveness and the toxicity

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 4. Dosage adjustment
4.2. Dose adjustment in patients with liver disease
The Child-Pugh classification

https://digestivedashboard.nl/2020/06/06/child-pugh-score/ 45
 Exercise
Case study 1:
• Mr. A is a 70-year-old man (68 kg, 1.70 m ). He was prescribed Cefpodoxime 10 mg/kg once daily.
• Cefpodoxime levels were taken 1 hour and 9 hours after the first dose and reported as 21 mg/L and
13 mg/L, respectively.

Questions 2:
a. Calculate the patient's elimination constant k
b. Calculate the plasma concentration at Co immediately
c. Calculate the level that the patient can achieve immediately before his next dose (using the plasma
concentration at Co )
d. Calculate the dosage interval for C=1.5 mg/L
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 Exercise
Case study 2:
• Ms. B is a 35-year-old woman (53 kg, 1.60 m), who was given Omeprazole 40mg (IV), 12 hourly (6
a.m. and 6 p.m.).
• She responds well to this treatment; unfortunately, two doses are missed after two days of treatment
(the evening and the following morning doses).
• She was given a loading dose at 11 a.m. before restarting her maintenance therapy.

Questions:
a. Was Ms. B at a steady state before the medication was omitted?
(CL=mx0.04 L/h/kg, Vd =m×0.45L/kg)
b. Estimate Omeprazole concentration at 11 a.m.
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 Exercise
Case study 3:
• Mr. C, a 65-year-old man (70 kg, 1.75 m), was confused and agitated when wandering the street. He
was admitted to the hospital. He told the doctor that he was taking medicines for a mental disorder.
• Current laboratory results are:
o Lithium: 2.5 mmol/L (0.6–1 mmol/L)
o Creatinine: 175 μmol/L (65.4 to 119.3 μmol/L).

Questions:
a. Calculate the patient's pharmacokinetic parameters: creatinine clearance (CrCl), volume of
distribution (Vd), elimination constant (k) [CL(Li) = 0.25 × CrCL; Vd (Li)= 0.7 L/kg]
b. Estimate the time for C=1 mmol/L

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 References

1. Roger Walker, [2012], Clinical Pharmacy and Therapeutics, 5rd edition, Churchill Livingstone, England.
2. Alagga AA, Gupta V. Drug Absorption. [Updated 2023 Jun 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK557405/
3. Onetto AJ, Sharif S. Drug Distribution. [Updated 2023 Jun 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK567736/
4. Price G, Patel DA. Drug Bioavailability. [Updated 2023 Jul 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK557852/
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https://www.ncbi.nlm.nih.gov/books/NBK547662/
7. Miniaci A, Gupta V. Loading Dose. [Updated 2023 Jun 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK557418/
8. Kyriakopoulos C, Gupta V. Renal Failure Drug Dose Adjustments. [Updated 2023 Aug 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023
Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560512/
9. Verbeeck R. K. (2008). Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. European journal of clinical pharmacology, 64(12), 1147–1161.

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