Pharmacokinetics and Pharmacodynamics Applications in Pharmacotherapy

Dalia A. Hamdy
BPSc, MSc, PhD, RP(ACP), MRSC
4th March 2016
dr.daliahamdy@gmail.com
Pharmacokinetics and
Pharmacodynamics Applications in
Pharmacotherapy
Part I

Learning Objectives
1. Identify and provide examples using basic
pharmacokinetic concepts commonly used in clinical
practice, including
 elimination rate constant,
 volume of distribution,
 clearance,
 bioavailability.
Dr. Dalia A. Hamdy (FS15AY)2

Learning Objectives
2. Describe specific pharmacokinetic characteristics of
a. commonly used therapeutic agents:
 aminoglycosides
 vancomycin
 phenytoin
 digoxin
b. pharmacokinetic alterations in patients with renal and
hepatic disease.
3. Define important issues as they pertain to drug concentration
sampling and interpretation.

Session Outline (Part I)
 Introduction to Clinical Pharmacokinetics and
individualization of therapy
 Basic PK refresher
 Introduction to Transporters and metabolic enzymes
 Drug Interactions involving transporters/enzymes
 Pharmacogenetics and personalized medicine

References
 Smith CL. Updates in Therapeutics®: The Pharmacotherapy
Preparatory Review and Recertification Course. 2015 Edition. The
American College of Clinical Pharmacy.
Pharmacokinetics/Pharmacodynamics Chapter.
 Shargel L, Wu-Pong S, Andrew B.C.U. Applied Biopharmaceutics
and Pharmacokinetics. 5 th Edition. McGraw-Hil ; 2005
 Gibson G and Skett P. Introduction to Drug Metabolism. 3rd Edition.
Nelson Thrones ; 2001.
 Russel F.G.M. Transporters: Importance in Drug Absorption,
Distribution, and Removal. Enzyme- and Transporter-Based Drug-
Drug Interactions. Elservier; 2010.

References
 Mccarthy, J and Nussbaum, RL. Genomic and Precision Medicine
online course. University of California San Fransisco. Through
Coursera online courses.
 Shahin, MHA et al. Pharmacogenet Genomics. 2011 March ; 21(3):
130–135.
 Ekladious, SM et al. Mol Diagn Ther. 2013 Dec;17(6):381-90.

Pharmacokinetics & Pharmacodynamics

Revision
8 Dr. Dalia A. Hamdy (FS15AY)
I. Basic PK refresher

Revision
One compartment PK model:
-Denoted by a closed box
-Assumes the body is
composed of a single
homogenous compartment
-The drugs distributes equally
and uniformly to all the body

Revision
Two compartment PK model:
-Denoted by two closed boxes
-Assumes the body is
composed of a two
compartments
-Central ( highly perfused)
-Peripheral (poorly
perfused)
-The drug is usually eliminated
from the central compartment

Revision
Dose
Route of
administration
Elimination
rate
constant
Cp Zero order
Amount of drug
eliminated per unit
time is constant
First order
Amount of drug
eliminated per unit time
is proportional to the
drug remaining

Revision
Dose
Route of
administration
Elimination
rate
constant
Cp
The rate of change of
Cp at any time is
calculated by
Input-output

Revision
Dose
Route of
administration
Elimination
rate
constant
Cp
Routes of administration
1. IV Bolus
The entire dose enters
the body immediately
and 100% bioavailable
F=1
2. Continuous IV infusion
The dose is infused
slowly with constant
rate and 100%
bioavailable
F=1
3. Oral absorption
The dose is
administered orally in
form of granules,
tablets, liquids or
capsules, F is usually
less than 1

Revision
Dose
Route of
administration
Elimination
rate
constant
Cp
1. IV Bolus
y = 4.6449e-0.047x
R² = 0.9935
0.1
1
10
0 10 20 30 40 50
C0 = highest
concentration

Revision
Dose
Route of
administration
Elimination
rate
constant
Cp
C0 = 0
1
10
100
Cp(mg/L)
Time (h)
Css
Rate of drug input= Rate of drug output
(infusion rate) (elimination rate)

Revision
Dose
Route of
administration
Elimination
rate
constant
Cp
C0 = 0
1
10
100
Cp(mg/L)
Time (h)

Revision
Dose
Route of
administration
Elimination
rate
constant
Cp
3. Oral absorption
Cmax is when
Ka=K
C0 = 0
Concentration
Time
Cmax
tmax

IV Bolus IV infusion Oral absorption
Cp= C0X e-kt
Revision

Cp= C0X e-kt X (1- e-kt)
Revision
Ko
Vd·K
Ka·F ·Dose
Vd (Ka-K)
Χ (e-Kt -e-Kat)

K -slope (method
of residuals)
-slope (method of
residuals)
-slope post
infusion cessation
-slope (method of
residuals)
Revision
Ko
Vd·K
Ka·F ·Dose
Vd (Ka-K)
Χ (e-Kt -e-Kat)

K -slope (method
of residuals)
-slope (method of
residuals)
-slope post
infusion cessation
-slope (method of
residuals)
BE Ware of Flip-
Flop phenomenon
CL
=(Dose.F)/AUC
F=1 F=1 F≤1 (oral
clearance)
Revision
Ko
Vd·K
Ka·F ·Dose
Vd (Ka-K)
Χ (e-Kt -e-Kat)

K -slope (method
of residuals)
-slope (method of
residuals)
-slope post
infusion cessation
-slope (method of
residuals)
BE Ware of Flip-
Flop phenomenon
CL
=(Dose.F)/AUC
F=1 F=1 F≤1 (oral
clearance)
Vd= CL/K Note
Vc= Dose/C0
-If calculated from
oral data then it is
oral Vd
Revision
Ko
Vd·K
Ka·F ·Dose
Vd (Ka-K)
Χ (e-Kt -e-Kat)

Bioavailability
The rate and extent to which the active ingredients is
absorbed and available at systemic circulation
F = AUC test X Dose reference
AUC reference
Dose test
If test=IV Absolute Bioavailability
If test=other route Relative Bioavailability
Concentration
Time

Revision
AUC (Trapezoidal Rule)
What is the Difference Between IV Bolus and Oral?

Revision
Css Time to reach Css
What is the importance of a loading dose ?
LD = Css desired Χ Vd =
Css =
Ko
K
Ko
Cl

Revision
 What are the differences between one and two
compartments in infusion??

Hepatic Metabolism
Hepatic Clearance
CLT= CLr + CL nr
=CLr + CLH + CL other
Dr. Dalia A. Hamdy (FS15AY) 29
First Pass Metabolism
Hepatic clearance
First Pass
Portal vein
Hepatic Clearance
Hepatic artery
Relation between first pass,
extraction ratio and
bioavailability?!

First Pass Effect
1. Blood that perfuses through GI tissues passes
through the liver by means of the hepatic portal vein.
a. 50% rectal blood supply bypasses the liver
(middle and inferior hemorrhoidal veins).
b. Drugs absorbed in the buccal cavity bypass the
liver.
What about other routes of administration?
Intraperitoneal, nasal, iv, …etc?

First Pass Effect
2. Examples of drugs with significant first-pass effect

Enterohepatic Recirculation
-Drugs have biliary (hepatic) elimination and good oral
absorption
excreted through the bile into the duodenum,
metabolized by the normal flora in the GI tract,
reabsorbed into the portal circulation.
-Drug is concentrated in the gallbladder and expelled
on sight, smell, or ingestion of food. (lifecycle of bile)

Enterohepatic Recirculation

Practices

II. Introduction to
Transporters and metabolic
enzymes

Drug transporters
- Drugs enter to cells through diffusion and active transport.
- Active transport is through transporters (Membrane
transport proteins)
- Active transport can be divided into
- Primary: does not require ATP
- Secondary: uses energy

Drug transporters
- Play a critical role in absorption, distribution, and excretion of
drugs.
- There are two main classes of transporters
- Solute carriers (SLC)
- ATP binding cassette (ABC)

Drug transporters
Solute Carriers (SLC) Transporters:
Can be further divided into:
-- Organic anion transporting peptide (OATp)
- SLCO family of genes
- Organic anion transporter (OAT)
- acidic drug transport
- Part of SLC22A family of genes
- Organic cation transporter (OCT)
- Basic drug transport
- Part of SLC22A family of genes

Drug transporters
ATP binding cassette (ABC):
The subfamilies mostly involved in drug transport are ABCB, ABCC, ABCG
examples:
ABCB1 : P-glycoproteins (P-gp)/ Multidrug resistance protein (MDR)
ABCC2: Multidrug resistance associated protein (MRP2)
ABCG2: Breast cancer resistance protein (BCRP)

Drug transporters
- Mechanistically they are divided into
- Influx/Uptake transport proteins
Import drugs into the cells and do not usually require energy
- Efflux transporters
Export drug out of the cell. Usually against concentration gradient therefore
they need energy

Role of transporters in Absorption
 Enterocytes
PEPT1: peptide transporter
SLC15A family of genes
-Role of P-gp in oral
absorption?
- Digoxin
- Tacrolimus
Role of PEPT1:
acyclovir oral bioavailability
was enhanced by a factor of
2–3 via its valine ester
(valacyclovir), which is a
PEPT1 substrate

Role of transporters in Distribution and
elimination
 Hepatocyte
Role of BCRP in bile
excretion?
- topotecan
Role of bile salt export
pump, BSEP/ABCB11?
- Mostly removal of bile
acid to bile
- Vinblastine, taxol,
pravastatin

Role of transporters in Distribution and
elimination
 Human renal
proximal tubular cell
-Methotrexate and
NSAID interaction!

P-Glycoprotein
 functions as an efflux pump
 Results in opioids tolerance :
chronic use of opioids induces P-glycoprotein
decrease the opioid effect
 P-glycoprotein is also found in tumor cells, resulting
in the efflux of chemotherapeutic agents from the cell
and, ultimately, multidrug resistance.

Where is P-Gp Located?

 Xenobiotics undergo biotransformation before
being eliminated from our body.
 Drug Metabolism, mainly in liver, is usually
divided into 2 Phases:
 Phase 1: Functionalization reactions
(introduction of a functional group)
 Phase 2: Conjugative reactions
(Conjugation with endogenous compounds)
Metabolism

Phase 1 metabolism
By introducing or unmasking more polar
a functional gp
more readily
excretable
Metabolism
Chemical reactions
Oxidation
Reduction
Hydrolysis
Hydration
Isomerization
Dethioacetylation

Phase 1 metabolism
Drug Metabolism
Chemical
reactions
Enzymes involved Location
Oxidation Cytochrome P450, Flavin
monooxygenase,
Alcohol/aldehyde dehydrogenase,
Monoamine oxidase
Smooth
Endoplasmic
reticulum
Reduction Cytochrome P450, NADPH-
cytochrome P450 reductase,
carbonyl reductase
Smooth
Endoplasmic
reticulum
Hydrolysis Epoxide hydrolase, Amidases Cytosol

Phase 2 metabolism
By conjugation with an more polar
endogenous substance and water
soluble
more readily
excretable in
urine or bile
Metabolism
Chemical reactions
Glucuronidation/glycosidation
Sulfation
Methylation
Acetylation
Amino acid conjugation
Fatty acid conjugation

Phase 2 metabolism
- Conjugation reactions are mostly located in the
cytosol except for glucuronidation which occurs in
endoplasmic reticulum
1. UDP-Glucuronosyl transferase
2. Glutathione S-transferase
3. Sulfotransferase
4. Amino acid transferase
5. N-acetyl transferase
6. N-, O-, S- methyl transferase
Drug Metabolism

Cytochrome P450-Dependant Mixed Function
Oxidation Reactions:
Mixed function oxidases are membrane proteins
compose of
- CYP P450
- NADPH dependent CYP P450
- Phospholipids
Drug Metabolism

Drug Metabolism

Cytochrome P450-Dependant Mixed
Function Oxidation Reactions:
CYP P450:
- Terminal oxidase component of an electron
transfer system present in ER
RH ROH
- It is a haem-containing enzyme
(haemoprotein called protoporphyrin IX)
Drug Metabolism

CYP P450:
- Nomenclature is derived from the fact that the
cytochrome exhibits a spectral absorbance maximum
at 450 nm when reduced Fe(II) heme binds to CO.
- Is a family of enzymes rather than a single enzyme
Drug Metabolism

CYP P450 Nomenclature :
- Family: CYP + Arabic numerical (share > 40%
homology of amino acid sequence ex: CYP1 , CYP2,
CYP3..etc)
- Subfamily: Additional letter (share > 55% homology of
amino acid sequence ex: CYP1A , CYP2D,
CYP3A..etc)
- Isoenzyme : Additional Arabic number ex: CYP3A4
Drug Metabolism

CYP P450
 Inhibition is substrate-independent.
 Some substrates are metabolized by more than one CYP
(e.g., tricyclic antidepressants [TCAs], selective serotonin
reuptake inhibitors [SSRIs]).
 Enantiomers may be metabolized by a different CYP
(e.g., R- vs. S-warfarin).
 Differences in inhibition may exist within the same class
of agents (e.g., fluoroquinolones, azole antifungals,
macrolides, calcium channel blockers, histamine-2
blockers).

CYP P450
 Substrates can also be inhibitors (e.g., erythromycin,
verapamil, diltiazem)
 Most inducers and some inhibitors can affect more than
one isozyme (e.g., cimetidine, ritonavir, fluoxetine,
erythromycin).
 Inhibitors may affect different isozymes at different
doses
 fluconazole inhibits CYP2C9 at doses of 100 mg/day
or greater
 inhibits CYP3A4 at doses of 400 mg/day or greater

CYP P450 Nomenclature :
- Italics indicates genes (CYP3A4)
- Regular fonts indicate enzymes (CYP3A4)
- Small letters indicate mouse enzymes (cyp1a1)
http://study.hiberniacollege.net/novartis/2014/novartis_cl
pap/session3/task0/novartis_clpap_s3_t0_s3/presentati
on.html
Drug Metabolism

III. Drug Interactions
involving
transporters/enzymes

CYP3A4 and P-glycoprotein
Most CYP3A4 substrates are also P-glycoprotein
substrates
Many CYP3A4 inhibitors/inducers also inhibit/induce P-
glycoprotein, affecting bioavailability.
Examples of P-glycoprotein absorption drug interactions
a. Dabigatran is affected by rifampin, St. John’s wort,
quinidine, ketoconazole, verapamil, amiodarone,
and dronedarone.
b. Digoxin is affected by St. John’s wort, quinidine,
verapamil, amiodarone, and dronedarone or dabigatran.

CYP3A4 and P-glycoprotein
c. Human immunodeficiency virus protease inhibitors
are affected by rifampin and St. John’s wort.
Examples of P-Gp drug interactions at elimination
level: quinidine/digoxin, cyclosporine/digoxin, and
propafenone/digoxin

IV. Pharmacogenetics and
personalized medicine

Pharmacogenetics
The study of how genes affect a person’s response to
drugs
Pharmacology
(Science of Drugs)
Genomics
(Study of genes and
their functions)
Pharmacogenomics

What is a Gene?
DNA (deoxyribonucleic acid),
 the cell’s hereditary material.
 DNA is a polymer of nucleotides
(sugar, phosphate and one of four
nitrogenous bases (A,T,G,C)
DNA Sequence

What is a Gene?
 Human genome consists of
about 3.2 billion base pair (bp)
 Every person has two copies of
each gene, one inherited from
each parent (6.4 billion bp)
 DNA molecule is packaged into
thread-like structures called
chromosomes.
 23 pairs of Chromosomes
 Sex chromosome XX or XY
 22 pairs autosomes

What is a Gene?
 The exact function of most of the DNA in the
human genome is unknown
 Protein-coding genes ≈ 2%
 Blueprint for the production of proteins (enzymes,
structural elements, signaling molecules)

What is a Gene?
 The exact function of most of the DNA
in the human genome is unknown
 Protein-coding genes ≈ 2%

SNV and SNP
 Gene mutations
 Inherited from a parent
 Acquired during a person’s lifetime
 Mutations range in size from
 single base-pair mutation that occurs at a
specific site in the DNA sequence (SNV)
 to a large segment of a chromosome (CNV)
SNP = SNV
which occur in
at least 1-2%
of the
population

 Population in general is divided into
poor, intermediate, extensive, and ultrarapid metabolizers;
Thus metabolism is considered polymorphic.

.
Why is Pharmacogenomics and
SNP Knowledge important?

Personalized Medicine
“is the tailoring of medical treatment to the
individual characteristics of each patient”
The Age of Personalized Medicine
“The science of individualized prevention and
therapy”
National Institute of Health

optimize drug therapy, with respect to the patients' genotype,
to ensure maximum efficacy with minimal adverse effects
One Size fits all medicine
Vs.
Personalized medicine

Alleles and Egyptian Population
 Warfarin a good candidate for personalized medicine?
-Anticoagulant with narrow therapeutic window.
- Widely prescribed
-High interpatient variability individual in the required dose
due to different alleles of the following genes or enzymes
CYP2C9
VKORC1
CYP4F2
APOE
CALU

 Warfarin Dosing

 VKORC1 (1173C>T) contributes to the 20.5% of
warfarin dose variability.
 the warfarin algorithm developed by Egyptian
researchers were comparable with those of the
IWPC and Gage algorithms with the advantage of
using one SNP (VKORC1 1173C>T) only. (for
doses>35 mg/week)

FDA
 120 FDA approved drugs with Pharmacogenomic
Biomarkers in Drug Labeling
 includes specific actions to be taken based on the
biomarker information
 http://www.fda.gov/drugs/scienceresearch/researcha
reas/pharmacogenetics/ucm083378.htm

Drug
Therapeutic
Area
HUGO
Symbol
Referenced
Subgroup
Labeling
Sections
Warfarin
Cardiology or
Hematology
VKORC1
VKORC1
rs9923231 A
allele carriers
Dosage and
Administration
, Clinical
Pharmacology
Warfarin Cardiology or
Hematology
CYP2C9
CYP2C9
intermediate
or poor
metabolizers
Dosage and
Administration
, Drug
Interactions,
Clinical
Pharmacology

End of Part I

Dalia A. Hamdy
BPSc, MSc, PhD, RP(ACP), MRSC
11th March 2016
dr.daliahamdy@gmail.com
Pharmacokinetics and
Pharmacodynamics Applications in
Pharmacotherapy
Part II

Session Outline (Part II)
 Pharmacogenetics and personalized medicine
 Non Linear PK
 Data Collection and analysis
 PK in renally impaired patients
 PK in hepatic impaired patients
 Pharmacodynamics

References
 Smith CL. Updates in Therapeutics®: The Pharmacotherapy
Preparatory Review and Recertification Course. 2015 Edition. The
American College of Clinical Pharmacy.
Pharmacokinetics/Pharmacodynamics Chapter.
 Shargel L, Wu-Pong S, Andrew B.C.U. Applied Biopharmaceutics
and Pharmacokinetics. 5 th Edition. McGraw-Hil ; 2005
 Gibson G and Skett P. Introduction to Drug Metabolism. 3rd Edition.
Nelson Thrones ; 2001.
 Russel F.G.M. Transporters: Importance in Drug Absorption,
Distribution, and Removal. Enzyme- and Transporter-Based Drug-
Drug Interactions. Elservier; 2010.

References
 Mccarthy, J and Nussbaum, RL. Genomic and Precision Medicine
online course. University of California San Fransisco. Through
Coursera online courses.
 Shahin, MHA et al. Pharmacogenet Genomics. 2011 March ; 21(3):
130–135.
 Ekladious, SM et al. Mol Diagn Ther. 2013 Dec;17(6):381-90.

V. Non Linear PK

In Linear PK
 PK parameters will not change between single
and multiple doses
Non Linear Pk ( dose-dependant PK)
 Increased doses or chronic medication cause PK
deviation from those after single low dose
Nonlinear PK

Reasons:
 Saturable absorption
 Saturable protein binding
 Saturable metabolism (capacity limited metabolism)
 Saturable renal elimination
 Saturable biliary excretion
Nonlinear PK

Saturable Metabolism
Process that requires energy and has a
maximal rate
Described by
Michaelis-Menten kinetics
:
104
SteadystateconcentrationorAUC
Dose (mg)
Linear
Michaelis-Menten
Protein binding or
autoinduction
Dr. Dalia A. Hamdy (FS15AY)

Css (mg/L)
Rateofeliminationmg/L/day Vmax
maximum
rate of
metabolism
Km
Dr. Dalia A. Hamdy (FS15AY)
Michaelis-Menten Kinetics
Michaelis
constant
(affinity)
105

Rate of metabolism= Cp . Vmax
Cp + Km
At steady state:
Rate of drug input= Rate of drug output
Similar to
the PD Hill
equation

Dosing rate = Cp . Vmax
Cp + Km
Dosing rate = mg/day
Cp= mg/L
Vmax= mg/L/day
Km= mg/L

-dCp/dt = Cp . Vmax
Cp + Km
If Cp >>Km
Zero order kinetics
= Vmax

-dCp/dt = Cp . Vmax
Cp + Km
If Km>>Cp
First order kinetics
Units Vmax, K, Km
= Cp. Vmax
Km
K

Increase 100% of dose = increase 80% of Css
Increase 17% of dose=
Increase 81% of Css
Nonlinear Pk
0
5
10
15
20
25
30
0 1 2 3 4 5 6 7 8
Steadystateconcentration
Dose (mg)

VI. Data collection and
analysis

Timing of Collection
1. Ensure completion of absorption and distribution
phases
(especially digoxin [8–12 hours] and vancomycin [30–
60 minutes after 60-minute infusion]).
2. Ensure completion of redistribution after dialysis
(especially aminoglycosides [3–4 hours after
hemodialysis]).

Specimen Requirements
1. Whole blood: Use anticoagulated tube. Examples:
cyclosporine, amiodarone
2. Plasma: Use anticoagulated tube and centrifuge;
clotting proteins and some blood cells are maintained.
3. Serum: Use red top tube, allow to clot, and
centrifuge. Examples: most analyzed drugs including
aminoglycosides, vancomycin, phenytoin, and digoxin

Assay Terminology
1. Precision (reproducibility): Closeness of agreement
among the results of repeated analyses performed
on the same sample
a. Standard deviation (SD): Average difference of the
individual values from the mean
b. Coefficient of variation (CV): SD as a percentage
of the mean (relative rather than absolute variation)

4. Sensitivity: Ability of an assay to quantitate low drug
concentrations accurately; usually the lowest
concentration an assay can differentiate from zero.
5. Specificity (cross-reactivity): Ability of an assay to
differentiate the drug in question from like substances

Assay Methodology
1. Immunoassays
a. Radioimmunoassay
i. Advantages:
Extremely sensitive (picogram range)
ii. Disadvantages:
-limited shelf life kits due to short half-life of labels,
radioactive waste
-cross-reactivity.
• Used for digoxin and cyclosporine assay

Assay Methodology
b. Enzyme immunoassay;
e.g., enzyme multiplied immunoassay technique
(EMIT)
i. Advantages: Simple, automated, highly sensitive,
inexpensive and stable reagents, widely available
equipment, no radiation hazards
ii. Disadvantages:
- enzyme activity may be affected by plasma
constituents,
- less sensitive than radioimmunoassays

Assay Methodology
c. Fluorescence immunoassay:
TDx (e.g., fluorescence polarization immunoassay
(FPIA)): Most common therapeutic drug monitoring
assay
i. Advantages:
Simple, automated, highly sensitive, inexpensive and
stable reagents, inexpensive and widely available
equipment, no radiation hazards
ii. Disadvantages:
Background interference attributable to endogenous
serum fluorescence

Assay Methodology
2. High-pressure liquid chromatography
3. Gas chromatography–mass spectrometry and
liquid chromatography–mass spectrometry
4. Flame photometry
5. Bioassay

Population Pharmacokinetics in TDM
1. Population pharmacokinetics useful when:
a. Drug concentrations are obtained during
complicated dosing regimens
b. Drug concentrations are obtained before steady
state.
c. Only a few drug concentrations are feasibly
obtained (limited sampling strategy).
What is
population
PK?

Population Pharmacokinetics in TDM
2. Bayesian pharmacokinetics
a. Prior population information is combined with
patient-specific data to predict the most probable
individual parameters.
b. When patient-specific data are limited, there is
greater influence from population parameters; when
patient-specific data are extensive, there is less
influence.
c. With a small amount of individual data, Bayesian
forecasting generally yields more precise results.

Popular TDM Drugs

Popular TDM Drugs
Cyclosporine and
erythrocytes binding!

VI. PK in renally impaired
patients

PK in renal disease: considerations
Kidney:
The processes by which drug is excreted:
1. Glomerular Filtration
2. Active Secretion
3. Tubular reabsorption

1. Filtration
 GFR is used to describe kidney function.
The National Kidney Foundation defines normal kidney
function as
140 ± 30 mL/minute/1.73m2 for young healthy men
126 ± 22 mL/minute/1.73m2 for young healthy women

1. Filtration
CL due to glomerular filtration CLgf
CLgf= fu X GFR
fu= unbound fraction

Estimation of Kidney Function Through Glomerular
Filtration Rate (GFR)/Creatinine Clearance
1. Creatinine production and elimination
a. Creatine is produced in the liver.
b. Creatinine is the product of creatine metabolism
in skeletal muscle; formed at a constant rate for any
one person
c. Creatinine is filtered at the glomerulus, where it
undergoes limited secretion.

Estimation of Kidney Function Through Glomerular
Filtration Rate (GFR)/Creatinine Clearance
1. Creatinine production and elimination
.
d. CrCl is useful in approximating GFR because:
i. At normal concentrations of creatinine, secretion
is low.
ii. The creatinine assay picks up a noncreatinine
chromogen in the blood but not in the urine.

2. CrCl calculation to estimate GFR
• CrCl is calculated from a 24-hour urine collection
and the following equation:

3. CrCl estimation to estimate GFR
a. Factors affecting SCr concentrations
i. Sex
ii. Age
iii. Weight/muscle mass
iv. Renal function. Caveats: CrCl estimations worsen
as renal function worsens (usually an overestimation).

b. Jellife

 Factors Affecting CrCl estimates
1. Patient characteristics
2. Disease state and clinical conditions
3. Diet
4. Drugs and endogenous compounds

 Drug Dosing in renal diseases
1. Loading dose
a. In general, no alteration is necessary, but it should
be given to hasten the achievement of therapeutic
drug concentrations.
b. Alterations in loading dose must occur if the Vd is
altered secondary to renal dysfunction. Example:
digoxin

2. Maintenance dose:
Alterations should be made in either the dose or the dosing
interval.
a. Changing the dosing interval
i. Use when the goal is to achieve similar steady-state concentrations.
ii. Less costly
iii. Ideal for limited-dosage forms (i.e., oral medications)
b. Changing the dose
i. Use when the goal is to maintain a steady therapeutic concentration.
ii. More costly
Imp!

2. Maintenance dose:
Alterations should be made in either the dose or the
dosing interval.
a. Changing the dose and the dosing interval
i. Often necessary for substantial dosage adjustment with limited-
dosage forms
ii. Often necessary for narrow therapeutic index drugs with target
concentrations
(a) If a drug is given more than once daily, then adjust the interval.
(b) If a drug is given once daily or less often, then adjust the dose.
Imp!

VI. PK in hepatically impaired
patients

Revision
 ClH= Q.E
E=Extraction ratio range from 0-1
If E>0.7 High extraction ratio ClH is affected by Q
If E<0.3 Low extraction ratio ClH is affected by Clint
Clint = fu. Clint’
i.e. unbound fraction of the drug
Enzyme numbers and affinity
P.S. Intermediate E (0.3-0.7) is affected by both (Q & Clint)
Imp!

High Extraction Ratio Drugs
Discuss

Low Extraction Ratio Drugs
Discuss

PK in hepatic disease: considerations
A. Dosage Adjustment in Hepatic Disease
1. Clinical response is the most important factor in
adjusting doses in hepatic disease.
2. Low hepatic extraction ratio drugs (E<0.3)
a. Adjustment of maintenance dose is necessary only
when hepatic disease alters the intrinsic clearance
(Clint)
b. Alterations in protein binding alone do not require
alteration of maintenance dose, even though
total drug concentrations decline.
c. Loading doses may require reduction.

3. High hepatic extraction ratio drugs (E > 0.7)
a. Intravenous administration
i. Usually necessary to decrease maintenance dose
rate as hepatic blood flow changes
ii. Consider effect of hepatic disease on protein binding
as it alters free concentrations.
b. Oral administration: Similar to low hepatic
extraction ratio drugs; necessary to decrease
maintenance dose rate when hepatic disease alters
Clint

B. Rules for Dosing in Hepatic Disease
1. Hepatic elimination of high extraction ratio drugs is
more consistently affected by liver disease than
hepatic elimination of low extraction ratio drugs.
2. The clearance of drugs that are exclusively
conjugated is not substantially altered in liver disease.
(Phase II metabolism)

VI. Pharmacodynamics

Sigmoid Emax model
Emax: maximal effect
EC50: plasma conc needed
to get 50% Emax
Emax Model
concentration
Effect

Sigmoid Emax model
(Hill equation)
Effect = Emax. Cn
n= shape factor
Emax Model
concentration
EffectEC50 + Cn

Sigmoid Emax model
(Hill equation)
Effect = Emax. Cn
n= 1 simple Emax model
Emax Model
concentration
EffectEC50 + Cn

Observations regarding Emax model
1. Rate of decline in plasma concentrations is >>
That of effect
Emax Model
Why?
Exponential
linear

2. It is possible to see effect with no detectable
concentrations in plasma ? When?
Emax Model

3. In multicompartment drugs, where there is a long
distribution phase and effect receptors are located
in the peripheral compartment
……..in the effect
Emax Model

4. Concentrations should be measured
postdistributive to be indicative of that at site of
action (Css)
Emax Model

5. For some drugs there is no relation between
concentration and effect . This may indicate that
mechanism of the drug is really complicated.
Emax Model

6. Similar situation would be noticed when the entity
responsible for action is the metabolite. There
would be a lag and the response would differ
according to route of administration e.x. oral or iv
Emax Model

7. Chirality : chiral drugs administered as racemates
(equal proportions of two enantiomers) if there is a
difference in activity then total concentration would
not be indicative of the effect.
Emax Model

8. Single dose: it is hard to find relationship between
concentration and effect as in aspirin, beta
agonists.
Emax Model

It is time related discordance between effect and
plasma concentration
A. Clockwise:
-inhibitory metabolite
-depletion of substrate required for positive
response
-non stereospecific assays
Hysteresis

It is time related discordance between effect and
plasma concentration
B. Anticlockwise:
-Lag time for distribution
-Active metabolite
Hysteresis

End of Part II

Pharmacokinetics and Pharmacodynamics Applications in Pharmacotherapy

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